Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 34 Primary Antibody Deficiencies 481


concentrations to IgA deficiency to IgA deficiency with IgG
subclass deficits to frank CVID have been documented in both
sporadic and familial cases. 2
CVID is a diagnostic category of primary immunodeficiencies
that includes a number of immune disorders. Most patients of
Northern European descent with CVID exhibit a distinctive
phenotype characterized by a broad deficiency of Ig isotypes in
spite of the presence of normal numbers of surface Ig bearing
B-cell precursors in peripheral blood. Almost all of these patients
are IgA deficient and, by definition, demonstrate total serum
IgG levels of <500 mg/dL. Some IgG subclasses are more affected
than others, with the sequential order of involvement being IgG4
> IgG2 > IgG1 > IgG3. Most patients are also deficient in IgM
and IgE.
Patients with uncomplicated conditions demonstrate normal
cell-mediated immunity, although a minority of patients may fIG 34.4 Hypogammaglobulinemic Sprue in a 41-Year-Old
have evidence of T-cell dysfunction as well as other hematopoietic White Male With Common Variable Immune Deficiency (CVID)
cell types. In some cases, B-cell numbers are reduced, although and Insulin-Dependent Diabetes Mellitus. The patient suffered
not to the extent exhibited by disorders of pre-BCR formation from intractable diarrhea. Shown is a hematoxylin and eosin
or BTK signaling. (H&E) stain of a duodenal biopsy obtained by endoscopy. The
IgAD and CVID have been associated with congenital infection villi are blunted, and there is a marked increase in intraepithelial
with rubella virus, CMV, and T. gondii. The administration of lymphocytes. However, unlike typical celiac disease, the villi are
certain drugs has also been linked to a depression in serum Ig not completely blunted, and few plasma cells are seen. The
levels (see Table 34.1). Several medications used to treat epilepsy patient is homozygous for the HLA-DQ2, -DR17(3), -B8 haplotype.
have been associated with the development of antibody deficien- Although the patient failed to respond to a gluten-free diet, the
cies. For example, up to 20% of patients treated with phenytoin diarrhea resolved with corticosteroid therapy.
develop a mild decrease in serum IgA levels, and a minority may
progress to a CVID-like phenotype. Medications used for the
treatment of rheumatoid arthritis, inflammatory bowel disease,
and chronic myelogenous leukemia can also decrease production species and thus require antibiotic therapy. Paradoxically, antigen-
of antibody. Persistence of antibody deficiency usually requires specific IgE can be produced in sufficient quantities to enable
choosing between discontinuation of the drug and persisting anaphylactic reactions.
infection with the virus or parasite. Recovery of Ig production Patients with CVID are often anergic, but only a minority
may take months to years. suffers infections characteristic of cell-mediated immune dysfunc-
tion, including mycobacteria, P. jiroveci, and fungi. CD8 T-cell
Clinical Manifestations numbers may be depressed in such patients. Most viral infections
Although some patients with CVID have reduced numbers of are cleared normally. Exceptions include enteroviral infections,
circulating B cells, the majority has normal quantities of IgA, including meningoencephalitis, as well as hepatitis B and C,
IgG, and IgM-bearing B-cell precursors in the blood. Defects in which can progress to chronic active hepatitis. Lack of humoral
+
B-cell survival, number of circulating CD27 memory B cells immunity enhances susceptibility to viral reactivation. Untreated
+
+
(including IgM CD27 B cells), B-cell activation after antigen patients often complain of recurrent herpes zoster (shingles).
receptor cross-linking, T-cell signaling, and cytokine expression Autoimmune diseases are common in CVID. Coombs-positive
have been observed. Both increases and decreases in the relative hemolytic anemia with idiopathic thrombocytopenic purpura,
numbers of CD4 to CD8 T cells are common, and cutaneous a combination known as Evans syndrome, may predate the
anergy is a frequent finding. diagnosis of CVID.
The clinical manifestations of CVID are similar but more Noncaseating granulomas in the lungs, lymph nodes, skin,
severe than the ones seen in IgAD. Respiratory symptoms often bone marrow, and liver reminiscent of or indistinguishable from
begin with recurrent sinusitis, otitis media, and mild bronchitis. sarcoid-like syndrome is more common in African Americans
The frequency and severity of the upper respiratory infections but can be seen in up to one-fifth of all patients. Occasionally
worsen in the young adult, and lower respiratory infections, the granulomas result from mycobacterial and fungal infections.
such as pneumonia, become common. Apparently asymptomatic, In the majority of cases, the cause remains unclear, and the
untreated patients may suffer recurrent subclinical pulmonary granulomas resolve spontaneously.
infections that can lead to irreversible chronic lung damage with There is an increased risk for the development of GI and
bronchiectasis, unilateral hyperlucent lung, emphysema, and cor lymphoid malignancies, especially non-Hodgkin lymphomas.
pulmonale. Recurrent cellulitis, boils, folliculitis, impetigo, or Confounding the diagnosis of malignancy is the patients’
erythroderma can be presenting complaints. propensity to develop benign lymphoproliferative disorders.
Intermittent or chronic diarrhea due to G. lamblia is a common Lymphadenopathy, splenomegaly, or a combination of both is
complaint. Patients can develop a malabsorption syndrome that common in untreated patients.
resembles celiac sprue but is unresponsive to gluten avoidance
(Fig. 34.4). Untreated patients often complain of asymmetrical, Origin and Pathogenesis
oligoarticular arthralgias or frank arthritis, which in some cases The typical presenting manifestation of CVID is hypogamma-
reflect infections with encapsulated organisms or with Mycoplasma globulinemia, not agammaglobulinemia, suggesting a partial or

482 PARt fouR Immunological Deficiencies


varying block in B-cell maturation. Careful analysis of B cells which is unique for BAFF, is expressed on B cells and on resting
in patients has also revealed a spectrum of immune deficiency T cells. The BAFF/APRIL system plays a key role in mature
ranging from the nearly complete absence of memory B cells to B-cell homeostasis and development. BAFF and APRIL can also
a less severe disorder. All of these findings serve to underline induce class switching in naïve human B cells. Loss-of-function
the complex etiology for the disorder, and many details remain (autosomal recessive) or altered-function (autosomal dominant)
to be elucidated. The MHC represents the most common genetic TACI alleles have been found in approximately 10% of patients
22
31
susceptibility locus for CVID. Because of linkage disequilibrium, with CVID in many series. Two polymorphic alleles, A181E
the gene, or genes, within this locus that create susceptibility and C104R, are prominent in patients with CVID who have
have yet to be identified with certainty. Non–MHC-associated TACI alterations. These alleles are also present in approximately
single-gene defects have been identified, although they represent 2% of the normal population, suggesting that the presence of
only a minority of patients with CVID. These include function-loss these altered alleles functions as a susceptibility factor for the
mutations in genes involved in late-stage B cell–T cell communica- development of the disease. Family members may have IgA
tion, late-stage B-cell growth factors, and B-cell and T-cell signal- deficiency or may have no evidence of immune dysfunction.
ing and activation pathways (see Table 34.1). These include the However, patients with CVID who have these altered alleles have
genes for ICOS (CVID1), an immune costimulator molecule a higher prevalence of complications from CVID, including lym-
32
used by T cells to activate B cells in germinal centers; BAFFR phoproliferation, splenomegaly, and autoimmune phenomena.
(CVID4) and TACI (CVID2), the receptors for BAFF, CD19 BAFF-R deficiency has been reported in four patients with CVID
(CVID3), CD21 (CVID7), and CD81 (CVID6), components of to date. 30
the B-cell costimulatory receptor; CD20 (CVID5), an important
marker of B-cell differentiation; and LRBA, Cytotoxic T lym- CD20 (CVID5)
phocyte antigen-4 (CTLA-4), PKCδ, Tweak, PIK3CD, PIK3R1, CD20 encodes a B-cell membrane–spanning molecule important
NF-κB2, and KMT2D, which are involved in B-cell and T-cell in B-cell proliferation and differentiation. It is expressed from
signaling pathways. TLR7 and TLR9 activation can be deficient early pre-B until mature B-cell stage but is lost on differentiation
in these patients, although the genes are intact. 27 to plasma cell. One case of a female consanguineous patient
with CD20 deficiency with low IgG and normal IgA and IgM
The Major Histocompatibility Complex levels and impaired antibody responses to pneumococcal polysac-
A large array of genes that play important roles in the control of charides, has been reported. 30,33
the immune response are located in the MHC on chromosome 6
(Chapter 5). Studies at the University of Alabama at Birmingham ICOS (CVID1)
have shown that in the Southeastern United States the majority ICOS is a T-cell surface receptor that is important for germinal
of patients with IgAD and CVID share parts or all of one of center formation, terminal B-cell differentiation, effector T-cell
three extended MHC haplotypes marked by either HLA-DQ2, responses, and immune tolerance. Patients with ICOS deficiency
-DR17(3), and -B8 or HLA-DQ2, -DR7, and -B44. The combined have low to absent B cells, and some have varying degrees of
results of three studies of patients from Alabama, New England, defective T-cell signaling. They present with recurrent respiratory
and Australia indicated a 13% prevalence of immunodeficiency in tract infections and autoimmune complications. 30,33
individuals homozygous for HLA-DQ2, -DR17(3), and -B8. These
MHC alleles are also more common in patients who suffer from The LRBA (Cvid8)–CTLA-4 Axis
diabetes mellitus, pernicious anemia, celiac disease, autoimmune Lipopolysaccharide-responsive beige-like anchor protein (LRBA)
thyroid disease, and myasthenia gravis. Some individuals with is a cytosolic protein that functions in vesicle trafficking,
TACI mutations inherited MHC haplotypes associated with autophagy, and cell survival. It is expressed by almost all cell
28
the disease, and the combination of specific MHC and KIR types with higher expression in immune effector cells. CTLA-4
29
alleles also increases susceptibility. This suggests that epistatic is an inhibitory T-cell receptor (TCR) that competes with the
interactions between different susceptibility alleles may influence costimulatory protein CD28 for binding CD80/86, thereby
the penetrance of the disorder. preventing excessive T-cell activation and maintaining immune
tolerance. LRBA plays a role in CTLA-4 surface expression.
The CD19 (CVID3), CD81 (CVID6), CD21 (CVID7) B-Cell Patients with LRBA deficiency display early-onset hypogam-
Coreceptor Complex maglobulinemia with autoimmunity and inflammatory bowel
CD21 (complement component C3d/Epstein-Barr virus receptor disease. They show reduced levels of at least two Ig isotypes
2) binds to membrane- IgM-bound antigen when complement (IgM, IgG, or IgA) and suffer from recurrent infections, autoim-
C3d is also attached to that antigen (Chapter 21). In association munity, and chronic pulmonary and GI disorders.
with CD81 and CD19, this coreceptor complex enhances the Patients with haploinsufficiency of CTLA-4 presented with
antigen-binding signal, promoting B-cell activation. Patients with autoimmunity, recurrent infections, benign lymphoproliferation,
mutations in CD19, CD21, and CD81 have been reported. 30 and varying levels of Igs and B-cells, and T-cell defects. 30,33
The BAFF–BAFFR (CVID4)–TACI (CVID2) Axis PKCδ Deficiency
The TNF family members B-cell activating factor of the TNF PKCδ plays a key role in BCR-mediated signaling downstream
family (BAFF) and a proliferation-inducing ligand (APRIL) of BTK and is important in B-cell proliferation, apoptosis, and
bind to two receptors, B-cell maturation antigen (BCMA) and tolerance. PKCδ deficiency presents with a variable phenotype,
transmembrane activator and calcium-modulator and cyclophilin with one affected patient having a CVID-like characteristics
ligand interactor (TACI), both members of the TNF-R family. (hypogammaglobulinemia and severe infections) and others
BCMA is expressed exclusively on B cells, whereas TACI is having lupus or autoimmune lymphoproliferative syndrome
expressed on activated T cells as well. A third receptor, BAFF-R, (ALPS)–like disease. 30

CHAPtER 34 Primary Antibody Deficiencies 483


as the main cause for KS. Similar to CVID, patients with KS
TWEAK Deficiency have recurrent infections, reduced Ig levels, and autoimmunity. 34
A patient with TNF-like weak inducer of apoptosis (TWEAK)
deficiency displayed low to normal IgG, low IgM, and low IgA Treatment and Prognosis
and had a history of pneumococcal meningitis, osteomyelitis, Therapy in CVID begins with the aggressive treatment of ongoing
thrombocytopenia, and neutropenia. The patient had an auto- infections and the institution of prophylactic measures to prevent
somal dominant mutation in TNF superfamily member 12 or ameliorate future infections. Patients suffering from moderate
(TNFSF12), which encodes TWEAK. 30 upper respiratory tract infections and bronchitis will likely benefit
from empiric therapy with agents effective against encapsulated
NF-κB1 (CVID12) and NF-κB2 (CVID10) Deficiency organisms. The concomitant inheritance of MBL protein defi-
The NF-κB1 and NF-κB2 (noncanonical) pathways are important ciency appears to further predispose to the development of
in B cell signaling, with NF-κB2 having a more limited set of bronchopulmonary complications, such as bronchiectasis, lung
3
involved receptors, such as ICOS, TACI, BAFR-R, and BCMA, fibrosis, and respiratory insufficiency. The course of treatment
whereas NF-κB1 affects T-cell and TLR signaling as well. for patients with immunodeficiency is often prolonged, and
Heterozygous mutations in NF-κB2 were identified in at intravenous administration of antibiotics may be required.
least 10 patients who presented with early-onset CVID with The most effective therapy for hypogammaglobulinemia is Ig
autoimmunity and recurrent sinopulmonary infections. Patients replacement. A number of studies have demonstrated a steadily
with NF-κB2-deficiency display panhypogammaglobulinemia, decreasing incidence of infection with increasing frequency of Ig
aberrant B-cell subsets, and some degree of T-cell and NK-cell administration. At higher doses, even patients with bronchiectasis
dysfunction. Half of these also suffer from pituitary hormone may experience improvement in pulmonary function. Each patient
deficiencies. may demonstrate his or her own individual response to therapy,
Patients with NK-KB1 autosomal dominant mutations that exhibiting dramatic differences in the frequency and severity
create an unstable and rapidly degrading protein have recurrent of infections, with moderate changes in the replacement dose.
infections, autoimmunity, benign lymphoproliferative disease, Patients suffering from a serious acute infection often benefit
and lymphoma. 30 from one-time booster doses of Ig. Ultimately, replacement
dosage must be individualized based on the response of the
PI3K Mutations patient. Adverse reactions occur most frequently at the time
Heterozygous mutations in P1K3CD, which encodes the P13K of the first administration of Ig, likely because of concurrent
catalytic subunit p110δ, have been reported in over 50 patients infection increasing the potential for generation of immune
with CVID-like disease. The mutation leads to P13K signaling complexes.
pathway overactivity. Such patients suffer from respiratory tract Some patients with CVID can sustain severe anaphylaxis when
infections, skin infections, autoimmunity, and lymphoma. The given IVIG or other blood products that contain serum or plasma.
phenotype associated with dominant gain of function P1K3CD These patients may possess anti-IgA antibodies, including IgE
7
mutations is currently referred to as activated phosphatidylinositol anti-A antibodies. For patients with a history of severe adverse
3-kinase δ syndrome (APDS). reactions, it is advisable to try batches of IVIG with the lowest
PIK3R1 encodes the P13K regulatory subunit p85α. Splice-site IgA possible and to test the patient with the different batches in
mutation of p85α results in a loss of an exon of p85α, which is an intensive care unit. Once the clinician has identified a batch
important in inhibiting the catalytic activity of p110d. This also that can be tolerated, the patient may receive therapy under
results in autosomal dominant overactive P13K signaling. A single more relaxed conditions.
patient with a homozygous P1K3R1 mutation causing complete Serum Ig concentrations in patients with CVID may change
2
loss of p85α expression has been found with agammaglobulinemia over time, with rare patients regaining normal serum IgG levels
and absence of B cells, suggesting complete absence of p85α and no longer requiring Ig therapy. Careful review of the clinical
reduces inhibiting P13K signaling. 30 history of these patients may reveal evidence of exposure to
pharmacological agents associated with the development of
Other Genes: BLK, IRF2BP2, IKAROS hypogammaglobulinemia (e.g., phenytoin). However, the over-
A heterozygous loss of function mutation in BLK has been whelming majority of patients require replacement therapy
noted in related patients with CVID. These patients have for life.
respiratory tract infections and bacterial skin infection with Although IgG can be replaced, at present IgM and IgA cannot
panhypogammaglobulinemia. be provided to patients. The absence of these multimeric proteins
A gain of function mutation in IRF2BP2 has been found in may help explain why even patients on high-dose replacement
members of a family with CVID. These patients have autoimmune therapy may continue to suffer from recurrent sinusitis or GI
35
disease and respiratory tract infections. discomfort. Recurrent sinusitis can be ameliorated with con-
Heterozygous mutation in the gene IKZF1, encoding the tinued prophylactic therapy with antibiotics. Patients with CVID
transcription factor IKAROS, was recently found in patients with also are at risk of infection by G. lamblia as well as other enteric
CVID and low B-cell numbers. These patients have progressive pathogens. Some patients develop lactose intolerance or gluten-
loss of B cells and serum Igs. 30 sensitive enteropathy. Gluten avoidance ameliorates symptoms
in only a minority of cases. A majority responds to corticosteroids
Kabuki Syndrome or anti-TNF agents. The use of these agents can be a double-edged
Kabuki syndrome (KS) is a rare but recognizable condition that sword, however, since resistance to infection will decrease in a
consists of a characteristic face, short stature, cardiac anomalies, patient who already has immune deficiency. Other patients develop
a variable degree of intellectual disability, and immunological a malabsorption syndrome that can lead to hypoalbuminemia
defects. Mutations in KMT2D and KDM6A have been identified and hypocalcemia (as a result of malabsorption of vitamin D),

484 PARt fouR Immunological Deficiencies


36
and decreased levels of vitamin A and carotene. The cause of SELECTIVE IGG SUBCLASS DEFICIENCIES
diarrhea and malabsorption in this latter patient subset remains
unclear, and treatment is limited to supportive measures, with Diagnosis
vitamin and mineral replacement as indicated. A diagnosis of clinical immunodeficiency should be supported
Patients with bronchiectasis should be treated aggressively by clear evidence of functional impairment. Most individuals
with replacement therapy. In severe cases, aggressive pulmonary with modest reductions in serum IgG subclass levels are function-
toilet will benefit the patient, including bronchodilator therapy, ally normal. Indeed, individuals with deletions of the heavy chain
position and postural drainage, or other physical therapies. The Ig gene locus, some of whom completely lack IgG1, IgG2, IgG4,
38
use of corticosteroids should be avoided. and IgA have been reported to be asymptomatic.
Mothers with IgA deficiency may fail to secrete IgA in their The diagnosis of a functional IgG subclass deficiency can
colostrum. Although colostral IgM levels may be elevated in an thus be made with confidence only when there is both a significant
attempt to compensate for the lack of maternal IgA, the newborn decrease in the serum concentration of a specific isotype and
remains relatively unprotected against intestinal pathogens. Of there is clear evidence of abnormal specific antibody production.
greater concern is the fact that the babies of mothers with Up to 10% of normal males and 1% of normal females have
untreated CVID are born in a state of humoral immunodeficiency IgG4 deficiency, which makes a diagnosis of immunodeficiency
and thus are at risk for life-threatening sinopulmonary infection. as a result of an isolated IgG4 subclass deficiency problematic.
To compensate for the loss of IgG across the placenta and to Among patients with a deficiency of IgG1 or IgG3, documentation
provide the infant with the passive immunity that will be required, of the ability to produce protective titers of antitetanus toxin
the dose of replacement gammaglobulin therapy should be and antidiphtheria toxin antibodies following standard tetanus
increased by 50% during the third trimester of pregnancy. toxoid and diphtheria immunizations is a strong indication that
Splenomegaly is common in untreated patients. Hypersplenism replacement gammaglobulin therapy is likely unwarranted.
in most patients responds to aggressive therapy with antibiotics Similarly, documentation of a strong antipneumococcal polysac-
and IVIG. The presumption is that the hypersplenism is secondary charide response in patients with an apparent IgG2 deficiency
to reactive hyperplasia of lymphoid follicles within the spleen would suggest gammaglobulin replacement is likely not required.
attempting to respond to infection. Development of esophageal IgG2 levels normally begin to rise in childhood later than other
varices or other hematological manifestations of hypersplenism subclasses. Conversely, the lack of a response to vaccination calls
(refractory thrombocytopenia, anemia, neutropenia, and lym- for appropriate prophylactic antibiotic therapy before a trial of
phopenia) may require splenectomy as the therapy of last resort. IVIG is attempted.
The outcome for most such patients has been good, with resolu-
tion of symptoms, although patients with altered TACI alleles Clinical Manifestations
tend to do less well. The clinical spectrum of isolated IgG subclass deficiency is quite
The development of a constellation of pulmonary abnormali- variable, and deficiencies of each of the four IgG subclasses have
ties that include granulomatous and lymphoproliferative histo- been described. Some individuals are referred to the clinical
pathologic patterns (lymphocytic interstitial pneumonia [LIP], immunologist with only a mild reduction of total IgG, but most
follicular bronchiolitis, and lymphoid hyperplasia), termed symptomatic patients have marked deficiencies of one or more
granulomatous–lymphocytic interstitial lung disease (GLILD), IgG subclass despite normal total IgG concentrations. Since
can be an ominous sign. These patients appear more likely to IgG1 makes up the majority of serum IgG in most patients,
develop granulomatous liver disease, autoimmune hemolytic a deficiency of IgG1 tends to correlate with depressed serum
anemia, lymphoproliferative disease, and progressive pulmonary levels of total IgG.
disease. 37 Determination of IgG subclasses is rarely performed on
asymptomatic individuals; thus most patients with an isolated
IgG2 deficiency come to medical attention as a result of recurrent
sinusitis, otitis media, or pulmonary infections. Individuals may
have few residual symptoms between infections, but some have
tHERAPEutIC PRINCIPLES severe chronic inflammation with refractory sinusitis, pulmonary
fibrosis, or bronchiectasis. Because protective antibodies directed
• The primary goal of treatment is to keep the patient infection free. against carbohydrate antigens are usually of the IgG2 subclass,
• In patients whose respiratory mucosa is intact, intravenous or subcutane- many affected patients exhibit an impairment of their ability to
ous replacement immunoglobulin G (IgG) therapy is generally effective
in protecting the patient from pulmonary infections. mount specific protective responses to encapsulated pathogens.
39
• For those patients who have developed bronchiectasis or who continue However, normal responses have also been described. Many
to subject themselves to environmental toxins (e.g., smoking), replace- clinicians would agree, however, that patients with IgG2 deficiency,
ment IgG will ameliorate but may not prevent all such infections. who suffer from recurrent sinopulmonary infections and who
• Because mucosal Ig cannot be replaced, even patients on adequate respond to less than half of the polysaccharide antigens with
IgG replacement therapy remain at risk for sinus or gastrointestinal which they have been challenged, meet the standard for functional
infections.
• Prophylactic antibiotics that are effective against encapsulated organisms immune deficiency and thus warrant aggressive prophylactic
can significantly reduce the frequency of upper respiratory tract therapy up to and including Ig replacement should the infections
infections in patients who continue to suffer in spite of replacement be severe.
therapy with intravenous immunoglobulin (IVIG). IgG3 deficiency can occur alone or in association with IgG1
• Prolonged diarrhea in patients with hypogammaglobulinemia is often deficiency. Recurrent infection of the respiratory tract with
caused by Giardia lamblia and responds well to metronidazole therapy. chronic lung disease has been reported. With a serum half-life
• Patients with primary antibody deficiencies should not receive live
vaccines. only 2 weeks, IgG3 levels may be consumed rapidly during the
40
course of an active infection in an otherwise normal individual.

CHAPtER 34 Primary Antibody Deficiencies 485


Before making the diagnosis of IgG3 deficiency, serum levels of Analysis of a group of well-characterized patients, mostly
IgG3 should be rechecked when the individual is asymptomatic. female, with a history of RESPIs and normal serum Ig levels
Compared with the serum, IgG4 is overrepresented in secre- revealed a high prevalence of the same MHC haplotypes observed
23
tions, and IgG4-committed B cells are present at mucosal sites, in IgAD, selective IgG subclass deficits, and CVID. These patients
suggesting a role in mucosal immunity. Since IgG4 is normally tend to respond to aggressive antibiotic therapy, including
present in the serum in very low concentrations, the significance prophylaxis.
of a low serum level in a patient with recurrent infection remains
unclear. SELECTIVE LIGHT-CHAIN DEFICIENCY
Origin and Pathogenesis Selective deficiencies of either κ or λ light chains have been
The origin of IgG subclass deficiency is unknown. Homozygous reported. 44-46 In one such case, the patient was the offspring of
deletions of portions of the Ig heavy chain constant locus associ- a consanguineous (uncle–niece) union; and in the second, a
ated with total absence of IgG2, IgG3, and IgG4 or combinations molecular analysis demonstrated different loss of function
of these isotypes have been described in healthy individuals. mutations in the patient’s Cκ alleles. The parents of these children
IgG2 deficiency is often found in association with selective had no health difficulties, but each of the patients required medical
IgA deficiency with or without IgG4 deficiency, and patients attention for recurrent sinopulmonary infections and diarrhea.
with selective IgG subclass deficiencies have been shown to have Two of the patients with κ deficiency exhibited IgA deficiency,
inherited the same MHC haplotypes as those who suffer from and the remaining patients with κκ deficiency and λ deficiency
IgAD and CVID. These observations suggest that patients with had panhypogammaglobulinemia.
recurrent infections have a more complex defect than the mere
elimination of one or more IgG isotype. In some instances, TRANSIENT HYPOGAMMAGLOBULINEMIA
subclass deficiency is associated with a T-cell defect, as in OF INFANCY
chronic mucocutaneous candidiasis and ataxia–telangiectasia.
IgG subclass deficiency can be acquired. Acute infections, Diagnosis
medications, chemotherapy, irradiation, surgery, and human As infants make the transition from dependence on maternal
immunodeficiency virus (HIV) infection have all been temporally Ig to reliance on endogenously produced antibodies, they suffer
linked to the development of a deficiency in one or more IgG a physiological nadir of serum Ig at 4–6 months of age, a period
subclass. 41 associated with susceptibility to mild upper respiratory infections
and otitis media (see Fig. 34.2). Children who (i) exhibit serum
Treatment and Prognosis concentrations of one or more of the three major Ig classes that
The natural history of IgG subclass deficiency plus or minus fall below the 95% confidence interval (CI) for age on ≥2 occasions
42
IgA deficiency, especially in children, is not constant. Associated during infancy, (ii) demonstrate a rise in these values to or toward
allergic rhinosinusitis and asthma must be aggressively treated normal over time, and (iii) lack features consistent with other
with conventional therapy for these disorders, as these conditions forms of primary immunodeficiency fall within the catch-all
increase the risk of purulent sinusitis and pneumonia. Causes diagnosis of transient hypogammaglobulinemia of infancy
of anatomical obstruction should be sought when persistent (THI). 47,48 By definition, the diagnosis of THI can be made with
infection of a sinus or pulmonary segment is the presenting certainty only in retrospect.
complaint; the role of surgical therapy for anatomical obstruction
should not be overlooked. Clinical Manifestations
Many patients with IgG subclass deficiency do well on pro- Ig concentrations are rarely measured in infants unless there
phylactic antibiotics and will never need Ig supplementation. is some reason to suspect an immunodeficiency. Most patients
However, Ig replacement therapy can be beneficial in patients with this diagnosis come to medical attention because of either
with severe, recurrent infections. Patients who begin therapy recurrent infections or as a result of routine screening studies of
should improve within the first 2 months, but to avoid the placebo relatives of other patients with immunodeficiency. Yet bearing
effect, a full 6-month trial is recommended. in mind that 2.5% of normal infants will fall below the 95% CI
range at any one time, the diagnosis of THI is remarkably rare.
ANTIBODY DEFICIENCY WITH NORMAL SERUM Among two major centers, one in the United States and one in
IMMUNOGLOBULIN LEVELS Germany, the diagnosis was given to only 16 of 18 000 children
in whom the index of suspicion warranted Ig determinations. 49,50
Occasional patients may present with normal serum Ig concentra- Patients with THI typically are able to synthesize specific
tions and a selective inability to respond to infections with antibodies in response to immunization with T-dependent
51
pyogenic organisms. Diagnosis requires documentation of an antigens (e.g., tetanus and diphtheria toxoids). They may have
inability to respond to antigenic challenge. These patients may difficulty, however, responding to polysaccharide antigens (e.g.,
respond to replacement Ig therapy. The antibody response to isohemagglutinins and vaccination with Pneumovax23). Some
specific polysaccharide antigens can be very selective. In human, will fail to sustain protective antibody responses to antigens.
most protective anti-H. influenzae type b (anti-Hib) antibodies Most patients with THI, especially those ascertained as a result
utilize the rare VκA2 gene. The Navajo population in the of family studies or mild upper respiratory infections alone,
Southwestern United States suffers a 5- to 10-fold increased exhibit fewer infections over time. The great majority of infants
incidence of Hib disease. This population also exhibits a high with THI will normalize their serum Ig levels within 24 months
prevalence of an A2 allele with a defective recombination signal of age. However, a minority fails to normalize IgG, continues to
sequence, preventing use of germline-encoded antibodies that suffer with recurrent infections, and may develop evidence of
can generate protective antigen-binding sites. 43 autoimmune disease. These patients often become part of the

486 PARt fouR Immunological Deficiencies


hypogammaglobulinemia syndrome complex that includes CVID 4. De Greef GE, van Tol MJ, Van Den Berg JW, et al. Serum
and may ultimately require long-term therapy with gamma- immunoglobulin class and IgG subclass levels and the occurrence of
globulin, prophylactic antibiotics, or both. homogeneous immunoglobulins during the course of ageing in humans.
Mech Ageing Dev 1992;66:29–44.
Treatment and Prognosis 5. Stiehm ER, Fudenberg HH. Serum levels of immune globulins in health
and disease: a survey. Pediatrics 1966;37:715–27.
Children with suspected THI should be monitored with serial 6. Soothill JF, Hayward AR, Wood CB. Pediatric immunology. Oxford, UK:
determination of serum Igs and isohemagglutinin titers to confirm Blackwell Scientific Publications; 1983:463–4.
acquisition of normal immune function. Some children will not 7. Gharib A, Caperton C, Gupta S. Anaphylaxis to IGIV in
achieve normal levels of IgG for several years, and some will immunoglobulin-naive common variable immunodeficiency patient in
remain IgG subclass or IgA deficient. Treatment of THI with the absence of IgG anti-IgA antibodies: successful administration of low
IVIG is generally not warranted unless the child suffers from IgA-containing immunoglobulin. Allergy Asthma Clin Immunol
persistent, recurrent, invasive infections, including pneumonia. 2016;12:23.
8. Carr TF, Koterba AP, Chandra R, et al. Characterization of specific
antibody deficiency in adults with medically refractory chronic
oN tHE HoRIZoN rhinosinusitis. Am J Rhinol Allergy 2011;25:241–4.
9. Lopez-Herrera G, Vargas-Hernandez A, Gonzalez-Serrano ME, et al.
• Elucidation of the molecular basis of selective defects in humoral Bruton’s tyrosine kinase—an integral protein of B cell development that
responses to pathogens, in part through the use of high-throughput also has an essential role in the innate immune system. J Leukoc Biol
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• Further elucidation of the molecular basis of common variable immune immunodeficiencies: genes can throw slow curves. Curr Opin Infect Dis
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11. Sigmon JR, Kasasbeh E, Krishnaswamy G. X-linked agammaglobulinemia
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FRONTIERS IN RESEARCH 12. Stewart DM, Tian L, Notarangelo LD, et al. X-linked
hypogammaglobulinemia and isolated growth hormone deficiency: an
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antibody deficiency. There has been remarkable progress in the agammaglobulinemia: impact of disease on daily lives, quality of life,
identification of single-gene disorders since that time. However, educational and socioeconomic status, knowledge of inheritance, and
for the majority of patients the underlying pathogenesis of the reproductive attitudes. Medicine (Baltimore) 2008;87:253–8.
most common manifestation of primary antibody deficiency in 14. Conley ME, Dobbs AK, Farmer DM, et al. Primary B cell
our population, that is, hypogammaglobulinemia in the adult, immunodeficiencies: comparisons and contrasts. Annu Rev Immunol
still remains unclear. It seems increasingly likely that this disorder 2009;27:199–227.
is multifactorial in nature, dependent on the inheritance of one 15. Boisson B, Wang YD, Bosompem A, et al. A recurrent dominant negative
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normal serum Ig levels also remains unclear. The availability of J Exp Med 2012;209:463–70.
whole exome sequencing and whole-genome sequencing has 18. Durandy A, Kracker S. Immunoglobulin class-switch recombination
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alleles will be found in the next decade. type IV phenotype who recovered spontaneously during late childhood
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20. Kawai T, Nishikomori R, Heike T. Diagnosis and treatment in anhidrotic
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for self-assessment questions. See inside cover for registration 21. Hennig C, Baumann U, Ilginus C, et al. Successful treatment of
details. autoimmune and lymphoproliferative complications of patients with
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28. Salzer U, Chapel HM, Webster ADB, et al. Mutations in TNFRSF13B 1990;116:529–38.
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36. Sneller MC, Strober W, Eisenstein E, et al. NIH conference. New cases, and long-term follow-up. J Pediatr 1978;92:347–53.
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1993;118:720–30. of infancy: five new cases, review of the literature and redefinition. Acta
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chemotherapy for treatment of granulomatous and lymphocytic 51. Tiller TL Jr, Buckley RH. Transient hypogammaglobulinemia of infancy:
interstitial lung disease (GLILD) in patients with common variable review of the literature, clinical and immunologic features of 11 new
immunodeficiency (CVID). J Clin Immunol 2013;33:30–9. cases, and long-term follow-up. J Pediatr 1978;92:347–53.

CHAPtER 34 Primary Antibody Deficiencies 487.e1


M u L t IPLE-CH o ICE Q u ES t I o NS

1. A 50-year-old man presents with a history of two pneumonias smoked, and testing for cystic fibrosis is negative. She com-
in the last 2 years. He has suffered occasionally with sinusitis plains of dyspnea on climbing more than one flight of stairs
and bronchitis since childhood, but these infections have and suffers with fatigue. She suffered pneumonia once as a
readily responded to antibiotic therapy, and he denies dyspnea child. What would be the best approach?
on exertion. A grandson is receiving therapy for an unknown A. The patient has selective IgA deficiency. She should be
immune deficiency. Serum immunoglobulin (Ig) levels are treated with antibiotics, as needed, for infections.
drawn. IgM is <20 g/dL. IgG is 100 mg/dL. IgA is <7 mg/dL. B. The patient may have an IgG subclass deficiency in addition
Flow cytometry reveals rare B cells. He has no response to to IgA deficiency. She should be treated with prophylactic
pneumococcal polysaccharide vaccination. What is the most antibiotics, since gammaglobulin replacement is contra-
likely diagnosis? indicated for patients with IgA deficiency.
A. Hyper-IgM syndrome C. The patient may have an IgG subclass deficiency in addition
B. Common variable immune deficiency to IgA deficiency. She should be treated with gammaglobulin
C. X-linked agammaglobulinemia replacement therapy.
D. Autosomal agammaglobulinemia
3. A 2-month-old baby girl presents with her second episode
2. A 35-year-old woman presents with a 10-year history of of bacterial pneumonia. Serum immunoglobulin (Ig) levels
recurrent sinopulmonary infections. She has suffered with are drawn. IgM is 100 g/dL. IgG is 100 mg/dL. IgA is <7 mg/
allergic rhinitis since childhood and was diagnosed with celiac dL. Flow cytometry reveals normal B-cell numbers. What is
disease at age 15 years. Serum immunoglobulin (Ig) levels the most likely diagnosis?
are drawn. IgM is 100 g/dL. IgG is 650 mg/dL. IgA is <7 mg/ A. Selective IgA deficiency
dL. Flow cytometry reveals normal B-cell numbers. After B. Transient hypogammaglobulinemia of infancy
vaccination with Pneumovax23, she responds to only five of C. Common variable immune deficiency
23 pneumococcal polysaccharide antigens. She has never D. Maternal common variable immune deficiency

35









Primary T-Cell Immunodeficiencies



Chaim M. Roifman







This chapter is dedicated to the diagnosis and management of The most clinically severe and studied group of patients are
inherited immune defects associated predominantly with T-cell those traditionally designated as having severe combined immu-
dysfunction. One of the central roles of T cells is the coordination nodeficiency (SCID). The clinical hallmarks of SCID include
of both the humoral and cell-mediated arms of the immune consistent clinical presentation in the first year of life, with
system; therefore T-cell deficiencies are often accompanied by repeated life-threatening bacterial, viral, or fungal infections,
1
dysfunction of other cell types, such as B and natural killer (NK) chronic diarrhea, and failure to thrive. Evaluation of the immune
cells. The focus of this chapter is on primary immunodeficiencies system typically reveals profound T-cell lymphopenia of <500
2,3
that are profound enough to require hematopoietic stem cell CD3 cells, or according to more stringent definitions, <300 T
transplantation (HSCT) or other modalities of management and cells. Invariably, in vitro responses to mitogens are severely
treatment directed at T-cell absence or dysfunction. depressed and T-cell receptor excision circle (TREC) numbers
4
are markedly reduced or below detection. The identification of
T-CELL IMMUNODEFICIENCIES these cases by TREC-based newborn screening (NBS) is the
earliest alert of T-cell deficiency. 5
KEY CONCEPTS
T-Cell Immunodeficiency COMBINED IMMUNODEFICIENCY
• A group of disorders are caused by defects in genes critical to the The second large group of disorders with significant T-cell
growth, maturation, and survival of T lymphocytes. deficiency is loosely designated as combined immunodeficiency,
• Some defects may also affect other arms of the immune system, which is arbitrarily defined by the presence of >300–500 autolo-
such as B cells, natural killer (NK) cells, or components of innate gous CD3 cells/µL in the circulation. The omission of “severe”
3,4
immunity. from this category of patients might be misleading, as many of
• The immune defects may be one feature of a multisystem these patients present with signs and symptoms indistinguish-
syndrome.
• The age of presentation and diagnosis varies widely from early infancy able from SCID. This category of heterogeneous deficiencies
(or at birth when detected through newborn screening) to adulthood. can be further subdivided into subgroups that are discussed
• The spectrum of clinical manifestations is wide and encompasses in detail in this chapter. They include T-cell deficiencies that
presentation at early infancy with extreme susceptibility to opportunistic invariably or frequently present with normal or close to normal
infections (severe combined immunodeficiency [SCID]) or disorders numbers of circulating lymphocytes, such as zeta-associated
featuring predominately autoimmunity or predisposition to cancer protein-70 (ZAP-70) deficiency. Other disorders are caused by
(combined immunodeficiency [CID]). 3
hypomorphic mutations in genes associated with SCID and
are therefore frequently referred to as “leaky SCIDs.” A third
subgroup encompasses patients with multisystem syndromes
SEVERE COMBINED IMMUNODEFICIENCY that include variable degrees of T-cell deficiency, such as cartilage
hair hypoplasia and DiGeorge syndrome. Finally, a fourth group
KEY CONCEPTS involves more selective T-cell defects, such as FOXP3 deficiency,
Severe Combined Immunodeficiency which predispose patients to a limited array of infections or are
associated with autoimmunity or lymphoid malignancies. There
• Infants present typically at 4–6 months of age with severe persistent may be a wide range of clinical manifestations, from typical
infections, oral thrush, chronic diarrhea, and failure to thrive. Siblings SCID presentation to mild or delayed presentation. Laboratory
of affected patients and cases detected through newborn screening features are also extremely variable but universally reflect T-cell
are diagnosed before symptoms occur. 6,7
• By definition, affected infants have a permanent profound T-cell dysfunction.
lymphopenia of <300–500 CD3 cells/µL, with or without reduced
numbers of circulating B cells and natural killer (NK) cells. OMENN SYNDROME
• Invariably, in vitro responses to T-cell mitogens are depressed and
+ +
T-cell receptor excision circle (TREC) levels are low or undetectable. Omenn syndrome (T B SCID; OMIM #603554) is an aberrant
• Ideally, patients with severe combined immunodeficiency (SCID) should inflammatory process associated with “leaky SCID” phenotypes,
be placed in protective isolation and offered hematopoietic stem cell
transplantation (HSCT) (or, in some cases, gene therapy). which characteristically allow for thymic escape and propagation
8
of poorly controlled T-cell clones. T-cell development is severely
489

490 ParT fOur Immunological Deficiencies



KEY CONCEPTS Regardless of the molecular cause, treatment with corticoster-
Combined Immunodeficiency oids and cyclosporine are effective in controlling inflammation,
improving skin lesions, and reducing lymphadenopathy and
• Arbitrarily defined as a T-cell deficiency with >300–500 autologous hepatosplenomegaly. Ultimately, a cure can be achieved only
CD3 circulating cells/µL, which may be reduced or dysfunctional. with HSCT. 11
• Circulating autologous T cells may be the typical feature of the defect
or may be caused by genetic variants leading to an incomplete defect SEVERE COMBINED IMMUNE DEFICIENCY
(leaky severe combined immunodeficiency [SCID]).
• Clinical manifestations may be indistinguishable from SCID. SCID is characterized by near complete absence of circulating
• Others may present with SCID and aberrant inflammatory syndrome
(Omenn syndrome) consisting of erythroderma, lymphadenopathy, autologous T cells and impaired B-cell function. Defects in the
and eosinophilia. differentiation and maturation of T-lineage cells in the thymus
• Frequently, the predominant presenting manifestation can be autoim- are a primary cause of T-cell deficiency (Fig. 35.1). In particular,
munity or lymphoid malignancy. mutations affecting T-cell activation or downstream signaling
• In vitro responses to mitogens and T-cell receptor excision circle molecules can result in SCID or CID (Fig. 35.2).
(TREC) levels may be depressed or normal. The T-cell repertoire is
often abnormal, as are T-cell subpopulations (regulatory T cells [Tregs] SCID With T-Cell Lymphopenia (T B )
−
+
and memory cells). Immunoglobulins and specific antibodies are − +
variable. This T B group of patients (Table 35.2) is the most frequently
identified phenotype of SCID (28 to 50% of all cases) and is
believed to occur at a frequency of 1:50,000 live births. 1
restricted because of inefficient deletion and suppression of
self-reactive T cells and dysregulated lymphostromal cross-talk γc (IL-2Rγ) Deficiency
in the thymus. The condition is associated with hypomorphic Common gamma chain (γc) or interleukin-2 receptor gamma
mutations of various SCID-causing genes, including RAG1/2, (IL-2Rγ) deficiency (OMIM #300400) is transmitted in an
Artemis, DNA ligase IV, RMRP, ZAP-70, IL2RG, IL7Rα, CD3δ, X-linked manner. Affected males have mutations in the IL-2Rγ
and ADA (Table 35.1). In addition to typical SCID manifestations, chain, also known as the common gamma chain because of its
patients present with features including generalized erythroderma, critical role as a coreceptor in IL-4, IL-7, IL-9, IL-15, and IL-21
which may be accompanied by alopecia, loss of eyebrows and receptors. Multiple pathways downstream of these receptors are
eyelashes. Marked enlargement of lymph nodes, liver, and spleen essential for differentiation and growth of T cells and NK cells,
are frequently present. hence the abnormal immune profile and profound defect in
The hallmarks of laboratory findings are elevated serum T-cell and NK-cell maturation. Affected males typically present
immunoglobulin E (IgE) levels and increased eosinophil counts. at 3–6 months of age, with failure to thrive and repeated microbial
T-cell number may be normal or even elevated, but the T-cell and fungal infections. Infections are fatal unless HSCT is
repertoire is skewed with overrepresentation of a few T-cell clones administered.
9
and underexpression or absence of most other Vβ families Evaluation of the immune system typically reveals extremely
−
− +
(Chapter 8). Skin biopsy reveals acanthosis and parakeratosis. low to absent T and NK cells, while sparing B cells (T B NK ).
Dyskeratosis and spongiosis are seen in the Malpighian layer, In vitro responses to mitogens are profoundly depressed, TRECs
and vacuolization is often observed in the basal layer. The thymus are undetectable, and the thymus appears dysplastic with absence
is dysplastic, and expression of the transcription factor auto- of Hassall corpuscles and disrupted architecture.
immune regulator (AIRE) in medullary thymic epithelial cells γc deficiency may have an atypical presentation because of
is reduced. 10 hypomorphic mutations. Various degrees of autologous T-cell
or NK-cell levels have been reported. Importantly, patients with
the R222C mutation can present with SCID-like symptoms but
TABLE 35.1 T-Cell Immunodeficiency have normal numbers of T cells and NK cells, near normal
With autologous T Cells associated With responses to mitogens, normal TREC levels, and structurally
12
Omenn Syndrome normal thymus gland. Cure can be achieved by providing HSCT.
Gene therapy has recently been attempted but remains an
Immune experimental procedure.
Gene Defect Phenotype additional features
−
+
RAG1 T B NK + None JAK3 Deficiency
RAG2 T B NK + None Janus kinase-3 (JAK3) deficiency (OMIM #600802) is an inherited
−
+
−
+
Artemis T B NK + Irradiation sensitivity autosomal recessive mutation mimicking the presentation of γc
DNA ligase IV T B NK + Irradiation sensitivity, deficiency. This is expected, as JAK3, a lymphoid specific tyrosine
−
+
microcephaly kinase, is a signaling molecule downstream of the γc receptor.
−/+
+
Adenosine deaminase T B NK −/+ Multisystem Upon IL-2 binding, JAK3 phosphorylates signal transducer and
involvement
ZAP-70 T B NK + None activator of transcription (STAT) factors, which dimerize and
+
+
+
+
RMRP T B NK − Short stature, translocate to the nucleus, where they bind regulatory elements,
metaphyseal dysplasia thus inducing target genes.
+
+
γc (IL-2Rγ) T B NK − None Patients typically present with SCID features, but similar to γc,
IL-7Rα T B NK + None patients with JAK3 deficiency may also present with combined
+
+
+
+
22q11.2 microdeletion T B NK + DiGeorge syndrome immunodeficiencies and autologous T cells. Milder phenotypes of
+
+
CD3δ T B NK + None
T-cell deficiency caused by hypomorphic mutations in JAK3 have
+
T = >500 CD3 cells/µL also been described. Some patients have been diagnosed during

CHaPTEr 35 Primary T-Cell Immunodeficiencies 491


ADA, γc, JAK3
deficiency

NK cell






DN γδ T cell
Pro/Pre-T
Thymus CD3δ, CD3ε
RAG, Artemis
deficiencies
pTα b α β ZAP 70 αβ T cell
+
deficiency CD8
DP
Stem Lymphoid DN DN CD4+
cell progenitor Pro/Pre-T Pre-T
CD8+
ADA, γc, CD45, PNP IL2Rα, CD3γ
JAK3. IL-7Rα deficiency deficiency αβ T cell
deficiencies CD4 +
HLA
Class II deficiency




B cell

ADA, RAG, Artemis
deficiency
fIG 35.1 Impaired Maturation of T-Lineage Cells in the Thymus Can Lead to Profound T-Cell
Deficiency. Lymphoid progenitor cells originating from bone marrow reach the thymus and
mature into functional T cells. During differentiation, naïve thymocytes (DN, double-negative cells)
undergo β chain rearrangement and pairing of the β chain with the pre-Tα chain, giving rise to
cells expressing both CD4 and CD8 (DP, double-positive cells). After positive and negative selection,
thymocytes downregulate the expression of either CD4 or CD8, resulting in single-positive cells.
These cells emigrate from the thymus to blood and secondary lymphatic organs, where they
encounter antigens and exert their biological functions. Various defects in this process can cause
profound T-cell deficiencies. Blocked lines indicate specific stages impaired by known genetic
abnormalities. Some defects may also interfere with maturation of B and natural killer (NK) cells.
ADA, adenosine deaminase deficiency; γc- gamma common chain of the interleukin (IL)-2 receptor;
JAK3, Janus activated kinase 3; IL7Rα, alpha chain of the IL7 receptor; DN, double-negative;
RAG, recombination activating genes; PNP, purine nucleoside phosphorylase; ZAP-70, Zeta chain
associated protein kinase 70; IL2Rα, alpha chain of the IL2 receptor.


late childhood (age 6 years), with some remaining asymptomatic. evaluation reveals the absence of circulating T cells but preserved
+
− +
Additionally, patients may present with lymphoproliferative B and NK cells (T B NK ). Cure can be attained with HSCT.
disorder, whereas others remain asymptomatic, despite carrying
the same mutation. CD45 Deficiency
CD45 deficiency(OMIM*151460) is an extremely rare autosomal
IL-7Rα Deficiency recessive form of SCID. CD45 is a receptor tyrosine phosphatase
IL-7 receptor α (IL-7Rα) deficiency is transmitted in an autosomal that regulates Src tyrosine kinases involved in T-cell receptor
recessive manner and is caused by mutations in the IL-7Rα chain. (TCR) and B-cell receptor (BCR) signaling. In the absence of
Together, IL-7Rα chain and γc forms the IL-7R (OMIM*146661), functional CD45, thymocytes are prevented from transitioning
+
+
+
which is essential for the normal development of T cells. This from CD4 CD8 double-positive cells to single-positive CD4 or
+
receptor mediates survival and proliferative signals to thymocytes CD8 expressing mature T cells. Patients present with a SCID
during the early stages of cell maturation. Patients carrying such phenotype and assessment of immunity shows low to absent
− +
+
mutations present in early infancy with typical features of SCID. T cells but normal numbers of B and NK cells (T B NK ).
+
+
Even mutations that preserve the production and expression of Interestingly, while TCRαβ T cells are absent, TCRγδ cells are
the faulty IL-7Rα chain result in a SCID phenotype. Immune preserved.

492 ParT fOur Immunological Deficiencies



Nucleus

FOXN1 CIITA RFX5
RFXAP
RFXANK
Cytoplasm



TAP TAPBP MHC





Antigen-presenting cell
Peptide
CD40
IL2 CD40L CD4
IL7 CD8
IL2Rβ
IL2Rα γc ξξ δεγ T cell
IL7Rα γc ORAI1


Ick LAT PLC1 PIP 2
JAK1 JAK3 JAK1 JAK3 CD45 ZAP-70 IP 3 Ca 2+
VAV SLP76 GRB2
CBL SOS Ca 2+
WASP
STAT DaG Calcineurin
P P
STAT Cytoskeleton Ras PKCθ
rearrangement
MAPK NF-κB NFAT
Cytoplasm

RAG1 ATM DCLREIC
RAG2 Nibrin MREIIA
LIG4 Cernunnos
Nucleus
fIG 35.2 T-Cell Signaling Cascade. Activation of T cells, such as following engagement of
peptide-major histocompatibility complex (MHC) with the T-cell receptor (TCR), involves signaling
through interleukin (IL) receptors, coreceptors, and calcium channels. Recruitment of additional
intracellular molecules trigger changes in gene expression, cytokine secretion, and receptor
expression. TAP, transporter associated with antigen presentation; TAPBP, TAP binding protein;
MHC, major histocompatibility complex; CIITA, class II MHC transactivator; IL7, interleukin (IL)-7;
IL7Rα, alpha chain of the IL7 receptor; CD40L, CD40 ligand; ZAP70, zeta chain–associated protein
kinase 70; JAK, Janus activated kinase; γc- gamma common chain of the IL-2 receptor; LCK,
lymphocyte-specific protein tyrosine kinase; STAT, signal transducer and activator of transcription;
CBL, Casitas B-lineage lymphoma; WASP, Wiskott-Aldrich syndrome protein; SLP76, SH2 domain
containing leukocyte protein of 76 kDa; LAT, linker for activation of T cells; PLC1, Phospholipase
C 1; GRB2, growth factor receptor–bound protein 2; DAG, diacylglycerol; RAS, Rat sarcoma;
MAPK, mitogen-activated protein kinase; PKC, protein kinase C; NF-κB, nuclear factor kappa-
light-chain-enhancer of activated B cells; NFAT, nuclear factor of activated T-cells; RAG, recombination
activating genes; LIG4, DNA ligase 4; ATM, ataxia telangiectasia mutated; DCLRE1C, DNA cross-link
repair 1C; MRE11A, MRE11 meiotic recombination 11 homologue A; RMRP, RNA component
of mitochondrial RNA-processing endoribonuclease.

CHaPTEr 35 Primary T-Cell Immunodeficiencies 493


−
+
TABLE 35.2 Severe Combined Immunodeficiency (SCID) With T-Cell Lymphopenia (T B )
Disease (Immune Molecular Defect/Presumed
Phenotype) Inheritance Pathogenesis additional features Treatment
−
+
γc deficiency (T B NK ) − X-linked Abnormal signaling through None Hematopoietic stem cell
interleukin (IL)-2R and other transplantation (HSCT)
receptors containing γC (IL-4, IL-7,
IL-9, IL-15, IL-21)
+
−
−
JAK3 deficiency (T B NK ) AR Abnormal signaling downstream of None HSCT
γc
+
−
+
IL-7Rα deficiency (T B NK ) AR Abnormal IL7R signaling None HSCT
CD45 deficiency (T B NK ) + AR Impaired TCR and BCR signaling None HSCT
−
+
+
+
−
CD3δ deficiency (T B NK ) AR Arrest of thymocytes differentiation Thymus size may be normal HSCT
at the CD4 CD8 stage
−
−
+
−
CD3ε deficiency (T B NK ) + AR Arrest of thymocytes differentiation None HSCT
−
−
at the CD4 CD8 stage; absent γ/δ
T cells
+
−
CD3ζ deficiency (T B NK ) AR Abnormal signaling None HSCT
+
Coronin-1A deficiency AR Abnormal T-cell egress from thymus Normal thymus size; attention HSCT
−
+
(T B NK ) and lymph nodes; defect in actin deficit disorder; growth
+
assembly retardation
+
−
+
FOXN1 deficiency (T B NK ) AR Impaired maturation of thymus and Alopecia; nail dystrophy HSCT, thymus transplantation
epithelial cells
production of specific antibodies in response to vaccination is
CD3–TCR Complex Defects impaired. Imaging can detect a thymus shadow. The associated
Biallelic mutations in the CD3δ (OMIM *186790), ε (OMIM syndromic features consist of developmental delay, growth
*186830), and ζ (OMIM *186780) coreceptor chains can result retardation, low cognitive functions, and attention deficit disorder.
+
− +
in a typical SCID phenotype (T B NK ). Together with CD3γ Immune function can be restored with HSCT.
(OMIM *186740), these transmembrane proteins function as
signaling molecules for the antigen recognizing TCR heterodimer, FOXN1 Deficiency (Combined Immunodeficiency With
which is composed of either the αβ or γδ chains. CD3δ deficiency Alopecia Totalis)
leads to a complete absence of both the αβ and γδ TCR on Forkhead box protein N1 (FOXN1) deficiency (OMIM #601705)
circulating CD3 cells because of blockade in thymocyte develop- is an autosomal recessive syndrome encompassing alopecia, which
ment at the CD4, CD8 double-negative to double-positive stage. affects the scalp, eyebrows, and eyelashes; nail dystrophy, which
The thymus appears normal in size but lacks Hassall corpuscles. is noted at birth; and profound cellular immunodeficiency. The
Complete deficiencies (null mutations) in CD3ε and CD3ζ also syndrome is caused by mutations in the FOXN1 gene, a member
result in a lack of circulating T cells. Atypical presentations are of the forkhead/winged helix transcription factor family, which
associated with leaky defects of CD3ε or CD3δ. Although clinical is mainly expressed in the thymus epithelium and in skin. FOXN1
presentation could be indistinguishable from typical SCID, these plays a critical role in the maturation of the thymus and skin
patients may have a sizeable amount of autologous T cells epithelial cells. A deleterious mutation in this gene was identified
+ +
+
(T B NK ). Cure of CD3 deficiencies can be achieved with HSCT. 13 in nude athymic mice. Patients can present at 2–4 months with
Omenn syndrome, recurrent infections, and failure to thrive.
SCID With T-Cell Lymphopenia and Syndromic Features Circulating lymphocytes may be low or normal with CD4
Coronin-1A Deficiency lymphopenia, and yet the TCR repertoire is restricted. Circulating
−
−
Coronin-1A (OMIM *605000) is a leukocyte-specific signaling T cells are phenotypically immature and double CD4 CD8 .
molecule, which is essential for TCR ligation–dependent genera- While TRECs are low, in vitro responses to mitogens are variable.
2+
tion of inositol-1,4,5-triphosphate (IP3). IP3 mediates Ca release Both HSCT and thymus transplantation have been tried in these
from intracellular stores and is critical for the proper function patients. HSCT led to full engraftment and infection-free clinical
of downstream signaling enzymes, culminating in T-cell activation recovery. However, immune reconstitution and maturation of
and survival. In addition, coronin-1A is essential for lymphocyte donor stem cells are still in question. Thymus transplantation
migration and lymphocyte homeostasis. appears successful, with recovery to lymphocyte repertoire and
Patients with coronin-1A deficiency (OMIM #615401), an function.
autosomal recessive condition, can present during infancy with − −
− +
+
a SCID phenotype (T B NK ), including oral thrush, recurrent SCID With T-Cell and B-Cell Lymphopenia (T B )
respiratory infections, BCG lymphadenitis, or Epstein-Barr virus Up to 30% of all SCID cases appear to lack both circulating T
(EBV)–associated lymphoproliferation. Others may present at cells as well as B cells (Table 35.3).
a much older age (11 years) with EBV-associated lymphoprolifera-
+
+ +
tion and a T B NK CID presentation. Evaluation of the immune RAG1/2 Deficiency
system reveals a very low number of circulating T cells, absent This type of SCID (OMIM #601457) has an autosomal recessive
naïve T cells, abnormal T cell repertoire and markedly reduced pattern of inheritance and is caused by mutations in the recom-
TREC levels. In-vitro responses to mitogens are variably reduced. bination activating genes RAG1 (OMIM *179615) and RAG2
Serum immunoglobulin levels are within normal range but (OMIM *179616). Recognition of different antigens is mediated

494 ParT fOur Immunological Deficiencies



TABLE 35.3 Severe Combined Immunodeficiency (SCID) With T- and B-Cell
−
−
Lymphopenia (T B )
Disease (Immune Molecular Defect/Presumed
Phenotype) Inheritance Pathogenesis additional features Treatment
−
−
RAG1/2 deficiency (T B NK ) + AR Defective V(D)J recombination None Hematopoietic stem cell
transplantation (HSCT)
Artemis deficiency (T B NK ) AR Defective V(D)J recombination, None HSCT
+
−
−
radiation sensitivity; DCLRE1C
gene defects
+
−
DNA-PK deficiency (T B NK ) AR Defective V(D)J recombination None HSCT
−
DNA Ligase IV deficiency AR Defective V(D)J recombination, Growth delay; microcephaly; HSCT
(T B NK ) radiation sensitivity bone marrow abnormalities;
−
+
−
lymphoid malignancies
Cernunnos deficiency AR Defective V(D)J recombination, Growth delay; microcephaly; HSCT
−
+
−
(T B NK ) radiation sensitivity bird-like facies; bone defects
AK2 deficiency/reticular AR Impaired mitochondrial energy Deafness gCSG
−
−
−
dysgenesis (T B NK ) metabolism and leukocyte HSCT
differentiation
Adenosine deaminase AR Accumulation of toxic purine Neurological, hepatic, renal, lung, HSCT, PEG-ADA, gene
deficiency (T B NK ) nucleosides skeletal and bone marrow therapy
−
−
−
abnormalities
by antigen-specific TCR or BCR. This requires the production KEY CONCEPTS
of variable regions of the antigen receptors, a process known as
V(D)J recombination (Chapter 4). Proper recognition of BCR Diagnosis of T-Cell Immunodeficiencies
and TCR are important for maturation of these lineages as well • T-cell receptor excision circle (TREC)–based newborn screening detects
as clonal expansion. RAG1 and RAG2 are the chief enzymes all types of profoundly lymphopenic T-cell severe combined immuno-
responsible for recombination of the antigen receptors. Patients deficiency (SCID) and may detect some, but not all, cases of combined
who carry null mutations present with typical SCID features at immunodeficiency (CID).
infancy; however, hypomorphic mutations can be associated with • Immunophenotyping remains an indispensable tool in the diagnosis
Omenn syndrome. Other leaky phenotypes have been reported of all types of T-cell immunodeficiencies. When needed, expanding
with moderate lymphopenia and autoimmunity; EBV-associated the panel of markers to detect regulatory T cells (Tregs) as well as
naïve and memory T cells and B cells can be valuable.
lymphoproliferation or noninfectious granulomas of the skin, • Genetic analysis has become the gold standard for diagnosis of T-cell
bones, lymphoid tissues, and the respiratory system; and CD4 immunodeficiency. Modern next-generation sequencing allows for
lymphocytopenia. analysis of SCID or CID panels. Whole exome sequencing enables
Diagnosis is supported by flow cytometry showing marked identification of both known as well as novel defects in the immune
reduction in circulating T and B cells in null mutations or by system.
profoundly skewed T-cell repertoire in hypomorphic cases. • Basic functional assays, such as responses to mitogens, are still widely
used to aid in the diagnosis of SCID and CID. Analysis of cytokine
Autologous cells fail to respond to mitogens or antigens and secretion, cytokine autoantibodies, and detailed study of T-cell receptor
TREC levels are low. Immunoglobulins (Igs) and specific antibod- repertoire all contribute to better defining immunodeficiency. Novel
4
ies are lacking. Cure can be achieved by administering HSCT, mutations should be assessed by studying their impact on protein
11
even in cases of Omenn syndrome. Gene correction is currently translation and function.
being investigated as an alternative option to HSCT. 14 • Thymus biopsies can be helpful when considering high-risk procedures,
such as hematopoietic stem cell transplantation (HSCT). Although
Artemis Deficiency normal thymus morphology cannot exclude primary T-cell deficiency,
abnormal thymus architecture and abnormal Hassall corpuscles are
Artemis deficiency is an autosomal recessive disorder caused by specific and sensitive predictors of primary T-cell deficiency. This
mutations in the DNA cross-link repair 1C (DCLRE1C) gene invasive procedure should be restricted to cases where all other
(OMIM *605988), encoding the protein Artemis. Similar to diagnostic tools remain inconclusive, and a life-saving procedure is
RAG1/2, DCLRE1C is obligatory for DNA recombination of considered. It should only be performed in centers with abundant
antigen receptors, by opening RAG-generated coding hairpins experience with this procedure.
in a DNA protein kinase-dependent manner. Artemis is critical
for the repair of genomic lesions and is essential for genomic
stability. Clinically, patients may present with typical SCID
features. Hypomorphic mutations in the Artemis gene may present − −
with Omenn syndrome, and EBV-associated lymphoma has also SCID With T-Cell and B-Cell Lymphopenia (T B ) and
been reported. HSCT remains the sole modality for curing this Syndromic Features
condition. Because of the genomic instability caused by Artemis DNA-PKcs Deficiency
deficiency, these patients may be sensitive to ionizing radiation DNA-dependent protein kinase, catalytic subunit (DNA-PKcs)
and possibly chemotherapy, and therefore reduced intensity deficiency is caused by mutations in the PRKDC gene (OMIM
conditioning is advised. *600899) and is transmitted in an autosomal recessive manner.

CHaPTEr 35 Primary T-Cell Immunodeficiencies 495


The serine/threonine kinase recognizes open DNA ends and is
part of a complex involved in the nonhomologous end joining Adenosine Deaminase Deficiency
(NHEJ) pathway essential for DNA recombination. Clinical Adenosine deaminase (ADA) deficiency (OMIM #102700) is an
presentation is indistinguishable from SCID, with virtually absent autosomal metabolic disorder caused by deleterious mutations
T cells and B cells but normal NK cells. These patients may in the ADA gene (OMIM*608958). This is a critical enzyme that
15
present with severe neurological abnormalities. HSCT may be aids in the degradation and salvage of purine pathway metabolites
a curative option, although caution must be exercised during the and is essential for multiple processes, such as energy transfer
conditioning regimen because of the underlying defect in DNA and DNA metabolism. Damage to various tissues and lesions in
repair. the immune system are caused by toxic accumulation of unde-
graded metabolites, such as deoxyadenosine. Thymocytes are
DNA Ligase IV Deficiency particularly sensitive, but B cells and NK cells are also frequently
DNA ligase IV deficiency (OMIM #606593) is clinically pleo- affected. Because toxicity to lymphocytes is lineage specific and
− +
− −
morphic with presentations ranging from intact immunity to a time dependent, patients may present with T B or T B phe-
SCID phenotype. Other features include facial dysmorphia, notype. Some may have Omenn syndrome and present with
+ −
+ + 19
various degrees of developmental delay, and microcephaly. These T B or T B . Mutations that spare some ADA activity may
20
features are consistent with DNA ligase IV knock-out mice, which result in a delayed presentation. Patients with ADA deficiency
are characterized by defective lymphogenesis and neurogenesis. mostly present with typical SCID features or Omenn syndrome,
DNA ligase IV is a component of the NHEJ complex and par- while patients with “partial deficiencies” can present with CID,
21
ticipates in the repair of DNA double-strand breaks that arise autoimmunity, and susceptibility to malignancy. Other associated
during DNA damage, such as from ionizing radiation, or the features include brain anomalies resulting in various levels of
endogenous recombination process. Hypomorphic mutations developmental delay and bone, liver, lung, and kidney anomalies.
in DNA ligase IV can be associated with increased sensitivity to Standard diagnostic tools for this disorder demonstrate barely
16
radiotherapy, EBV-associated lymphoproliferation and T-cell detectable ADA enzyme activity and increased accumulation of
leukemia. Diagnosis may be challenging, with immune evaluation purine metabolites in blood or urine. The diagnosis can be
revealing low to absent T cells and B cells during infancy in confirmed by genetic analysis. Polyethylene glycol-conjugated
some patients, whereas in others diagnosis may be delayed to ADA (PEG-ADA) can be used for “detoxification”; however,
the second decade of life in individuals with various degrees of salvage of complete or even partial immunity may not be achieved,
22
lymphopenia and hypogammaglobulinemia. Microcephaly and and efficacy may be short lived. HSCT remains the treatment
developmental delay can help in the diagnosis if present. HSCT of choice if a full human leukocyte antigen (HLA)–matched
was attempted in patients with DNA ligase IV deficiency with related donor is available. For other patients, gene therapy is
limited success because of increased toxicity of conditioning gradually becoming standard of care. 23
regimens as well as graft-versus-host disease (GvHD).
Cernunnos Deficiency COMBINED IMMUNODEFICIENCY
Patients with Cernunnos deficiency (OMIM #611291) present (SCID PHENOTYPE)
early in life with profound T-cell lymphopenia, progressive
− −
decrease in B cells (T B SCID), and microcephaly. The syndrome Combined immunodeficiencies presenting with features typical
has an autosomal recessive pattern of inheritance. Cernunnos of SCID are summarized in Table 35.4.
(OMIM *611290) forms a complex with DNA ligase II and XRCC4
and likely plays an important role in the NHEJ pathway. Disrup- ZAP-70 Deficiency
tion of Cernunnos, like other members of this pathway, is ZAP-70 deficiency (OMIM #269840) is a rare CID with an
associated with radiosensitivity. Clinical presentation consists autosomal recessive pattern of inheritance. The disease was first
of recurrent infections, as in typical SCID, as well as developmental described as a novel immunodeficiency with normal numbers
delay, microcephaly, urogenital and bone malformations, and of circulating CD4 cells but CD8 lymphopenia. ZAP-70 is a
facial dysmorphic features. protein tyrosine kinase critical in mediating T-cell receptor
signaling. Upon phosphorylation and activation, ZAP-70 phos-
AK2 Deficiency (Reticular Dysgenesis) phorylates a host of downstream molecules culminating in T-cell
24
Adenylate kinase-2 (AK2) deficiency, also known as reticular proliferation and maturation. Patients typically present within
dysgenesis (OMIM #267500), is a profound inherited immune defi- the first 2 years of life with repeated severe microbial infections
ciency characterized by severe lymphopenia and marrow failure. indistinguishable from SCID. However, unlike typical SCID,
The disorder has an autosomal recessive pattern of inheritance patients with ZAP-70 deficiency also present with palpable lymph
and is caused by mutations in the AK2 gene. 17,18 Mitochondrial nodes, visible tonsils, and a normal thymus shadow on imaging.
AK2 catalyzes the reversible phosphorylation between nucleoside Rarely, patients present with autoimmune manifestations, Omenn
triphosphates and monophosphates. AK2 defects are associated syndrome, hemophagocytic lymphohistiocytosis (HLH), sub-
with impaired mitochondrial energy metabolism and leukocyte cutaneous nodules, or lymphoma. 25,26
differentiation. Patients suffer repeated bacterial, viral, and fungal Immune evaluation reveals normal numbers of circulating
17
4,7
infections and have bilateral sensorineural deafness. Patients lymphocytes but marked reduction in CD8 cells. Responses
present in infancy with profound neutropenia and lymphopenia, to mitogens are depressed; however, the T-cell repertoire of CD4
the thymus is dystrophic, and TRECs are undetectable. Diagnosis cells appears normal. The thymus gland is fully developed with
is confirmed by genetic analysis. Bone marrow reconstitution can normal architecture and normal corticomedullary distinction,
be achieved with HSCT and remains the most effective modality including the presence of Hassall corpuscles. However, the
of treatment. corticomedullary ratio appears increased. B-cell number and Ig

496 ParT fOur Immunological Deficiencies



TABLE 35.4 Combined Immunodeficiency (Severe Combined Immunodeficiency
[SCID] Phenotype)
Molecular Defect/Presumed
Disease Inheritance Pathogenesis features Treatment
ZAP-70 deficiency AR Abnormal T-cell receptor signaling Normal thymus size; increased Hematopoietic stem cell
corticomedullary ratio transplantation (HSCT)
Major histocompatibility AR Absence of human leukocyte Recurrent infections; gastrointestinal Supportive
complex (MHC) class II antigen (HLA) class II molecules manifestations; hepatic abnormalities
deficiency
MHC class I deficiency AR Impaired expression of HLA class Respiratory infections; skin Supportive
I molecules granulomatous lesions
DOCK2 deficiency AR Impaired T-cell homing Viral and bacterial infections HSCT
CD3γ deficiency AR Arrest of thymocyte differentiation Thymus size may be normal HSCT
at the CD4 CD8 stage
−
−
CARD 11 / BCL10 / MALT1 AR Abnormal signaling upstream of Opportunistic infections HSCT
NF-κB pathway
TTC7A deficiency AR TTC7A gene defects; impaired Intestinal atresia HSCT
regulation of transcription, cell
cycle, protein degradation and
trafficking
2+
ORAI-1, STIM-1 Impaired Ca fluxes Autoimmunity; ectodermal dysplasia HSCT


levels are normal. NK cells may be reduced in some patients
(personal communication). Allogeneic HSCT can completely MHC Class I Deficiency
correct the immunodeficiency. This is a rare autosomal recessive immune deficiency characterized
by partial expression of HLA class I molecules (OMIM #604571).
MHC Class II Deficiency (Bare Lymphocyte Syndrome) The decrease in HLA class I expression is caused by mutations
MHC class II deficiency is a rare immunodeficiency characterized in TAP1 (OMIM *170260) or TAP2 (OMIM *170261). These
by the lack of expression of HLA class II molecules (OMIM endoplasmic adenosine triphosphate (ATP)–binding transporters
#209920). The deficiency is caused by mutations in genes encoding are essential for processing the association of endogenous peptides
transactivating elements critical for regulating HLA class II with MHC class I molecules. MHC class I molecules that do not
expression. Such deleterious disease causing mutations have been bind high affinity peptides do not cross the Golgi apparatus.
identified in the class II transactivator (CTIIA), the regulatory Recently mutations in the genes encoding tapasin and β 2 micro-
factor–associated protein (RFXANK or RFX-B), the fifth member globulin, involved in antigen and HLA class I molecule processing,
of the regulatory factor X family (RFX5) and the regulatory have been shown to result in a similar deficiency. Patients present
factor–associated protein (RFXAP). during childhood or later in life with lung infections and/or skin
HLA class II is expressed on thymic epithelial cells, antigen- granulomatous lesions. The diagnosis is suspected when HLA
presenting cells (APCs), and activated lymphocytes. The structure class I expression is decreased upon immunophenotyping.
and function of these molecules, which are required for T-cell Confirmation of the diagnosis is obtained by genetic analysis.
maturation and antigen presentation, are discussed in detail in Treatment remains supportive in nature.
Chapters 5 and 6.
Clinical manifestations are highly variable with some patients DOCK2 Deficiency
presenting with features of typical SCID, including oral thrush, Dedicator of cytokinesis 2 (DOCK2) deficiency (OMIM #616433)
Pneumocystis jiroveci pneumonia, and failure to thrive. Others is an autosomal recessive combined immunodeficiency. DOCK2
may have a milder course. Chronic enterocolitis and sclerosing (OMIM *603122) mediates cytoskeletal reorganization through
cholangitis are common and are caused by infections. Menin- Rac activation and is required for lymphocyte homing to lymphoid
goencephalitis caused by enteroviruses, herpes simplex, or adeno- tissues. Indeed, DOCK2-deficient mice exhibit lymphocyte
viruses has also been reported. Autoimmune cytopenias are migration defects.
common. Patients with DOCK2 deficiency experience severe invasive
Historically, the diagnosis relied on demonstrating the lack bacterial and viral infections at early childhood. Patients may
of MHC class II expression on APCs by flow cytometry. Lym- have T-cell lymphopenia and reduced in vitro T-cell proliferation,
phocyte counts are usually normal, but CD4 lymphocytopenia reduced circulating B cells, defective NK-cell activity, and antibody
27
is frequently observed. In vitro responses to mitogens may be deficiency. Although experience is very limited, HSCT may
normal or depressed, but TREC levels are within normal limits. cure this condition.
The definitive diagnosis is made by mutational analysis. Overall,
the prognosis for patients with this condition is poor. Patients CD3γ Deficiency
usually die within the first or second decade of life, as a result CD3γ deficiency (OMIM #615607) is caused by mutations in
of infections or infection-related organ damage. HSCT is offered, the CD3γ chain and is transmitted in an autosomal recessive
but outcomes are usually poor, with a high rate of engraftment manner. Patients can present with a SCID phenotype or with
failures, severe GvHD, and poor immune reconstitution. Sup- delayed atypical features, consisting of infections or autoimmunity.
portive treatment consists of antibiotics and Ig replacement. This unusual heterogeneous clinical pattern has been observed

CHaPTEr 35 Primary T-Cell Immunodeficiencies 497


in patients of Turkish or Spanish descent. Autologous T cells of this condition is poor. Although HSCT can replenish the
30
have partial TCR/CD3 expression with only mild lymphocytopenia hematopoietic system, this does not solve the complex and
+ +
+
(T B NK ). In vitro responses of mitogens are depressed, and fatal gastrointestinal (GI) manifestations. Combined gut and
TRECs can be reduced. Although some of these patients present bone marrow transplantation could be attempted.
as typical SCIDs or with severe colitis, other family members
with an identical mutation appear well, even into adulthood. Calcium Channel Defects (ORAI-1, STIM-1 Deficiencies)
This is an autosomal recessive disorder caused by mutations
CARD11/BCL10/MALT1 (CBM) Complex Deficiencies in ORAI-1 (OMIM *610277) and STIM-1 (OMIM *605921).
33
CARD11/BCL10/MALT1 deficiencies are autosomal recessive ORAI-1 is a transmembrane protein, which at tetramer configura-
2+
immunodeficiencies caused by mutations in signaling molecules tion constitutes the pore-forming structure of a Ca channel.
upstream of the NF-κB pathway. Upon TCR or BCR stimulation, STIM-1 is a calcium sensor of the endoplasmic reticulum (ER)
2+
caspase recruitment domain family, member 11 (CARD11) is and controls calcium entry after ER store depletion. Both Ca
phosphorylated, enabling its association with BCL10–MALT1 influx into the cell as well as release from cytosolic stores are
complex, to form the CBM complex. The CBM complex allows mediated through the TCR and BCR, and are critical for down-
for activation of the NEMO–IκB kinase (IKK) complex, which stream signaling. Patients may present in infancy with recurrent
34
induces phosphorylation of IκB and causes its breakdown. As a severe infections indistinguishable from SCID. Patients with
consequence, NF-κB is released and translocates into the nucleus, STIM1 deficiency can also present with autoimmune features,
where it acts as a transcription factor, controlling multiple cellular such as arthritis and cytopenia, as well as lymphoproliferative
processes, such as cell proliferation, differentiation, and survival. manifestations. Both deficiencies may present with severe eczema
Patients with CARD11 deficiency (OMIM #615206) may and syndromic features, including nail dysplasia and anhydrosis,
28
present with a SCID phenotype. They also suffer gingivitis ectodermal dysplasia, and generalized myopathy. Immune evalu-
and aphthous ulcers. Patients with MALT1 deficiency (OMIM ation shows normal to elevated lymphocyte counts and TREC
#615468) present at a later age during childhood with severe levels, and responses to mitogens are depressed. Ig levels are
29
enterocolitis and recurrent lung infections. Evaluation of the normal, but specific antibodies are variable. TCR-mediated
2+
immune system in CARD11 deficiency shows normal number cytosolic rise in Ca is low. HSCT can be effective in reversing
of circulating T cells, B cells, and NK cells, but regulatory T cells the immunodeficiency, but not the syndromic features.
+ +
(Tregs) are absent (T B SCID). Responses to mitogens are reduced
but not absent, and TRECs and the TCR repertoire are normal.
B cells appear immature, which explains the panhypogamma- COMBINED IMMUNODEFICIENCIES WITH
globulinemia found in these patients. Patients with MALT1 VARIABLE SEVERITY (NON-SCID)
deficiency present similarly; however, although Ig levels are normal,
antibody production is faulty. Cure can be achieved with HSCT. Combined Immunodeficiency With
Autosomal dominant CARD11 deficiency is caused by a Immune Dysregulation
dominant negative monoallelic mutation and results in combined Combined immunodeficiencies characterized by autoimmune
immunodeficiency, severe atropy and autoimmunity. manifestations are summarized in Table 35.5.
COMBINED IMMUNODEFICIENCY (SCID IL-2Rα (CD25) Deficiency
PHENOTYPE) AND SYNDROMIC FEATURES IL-2 receptor α (IL-2Rα or CD25) deficiency is a complex immune
dysregulation disorder that has an autosomal recessive pattern
TTC7A Deficiency (MIA Syndrome) of inheritance (OMIM #606367). Biallelic mutations in the CD25
+ +
+
TTC7A deficiency is a rare autosomal recessive disorder in which gene result in combined immunodeficiency (T B NK ). The high
obstructions occur at various levels of the gut, hence the designa- affinity IL-2 receptor must be composed of all three components,
tion multiple intestinal atresia (MIA) syndrome (OMIM the γ chain (γc), β chain (CD122), and α chain (CD25), to be
30
#243150). Patients may also have severe lung disease and functional. Although the β and γ chains are constitutively
pulmonary calcifications. Immune deficiency is commonly expressed on T cells, expression of the α chain is limited to early
associated with this syndrome and is frequently severe. Patients thymocytes, Tregs and activated T cells. The inability to form
31
may present with typical SCID features, albeit with various the high affinity receptor results in faulty T-cell differentiation,
levels of autologous T cells. The disease is caused by mutations loss of central and peripheral tolerance, and failure to respond
in the TTC7A gene (OMIM *609332), which encodes a protein appropriately to infections. Affected infants present with recurrent
containing nine tetratricopeptide repeat (TPR) domains. These infections, lymphadenopathy and hepatosplenomegaly, a variety
domains are degenerate 34-amino acid repeat motifs and appear of autoimmune features, and eczematous skin lesions. Patients
to play a role in multiple cellular processes, such as transcription, may present immediately after birth with diabetes mellitus and
cell cycle, protein degradation, and trafficking. may suffer severe chronic lung disease or pulmonary bleeding.
Evaluation of the immune system in TTC7A deficiency Autoimmune lymphocytic infiltrates can be identified in multiple
reveals T-cell lymphopenia and markedly depressed responses tissues, including lung, liver, gut, and bone. Autoimmune disorders
to mitogens. The TCR repertoire is restricted, and TRECs are include primary cirrhosis, colitis, thyroiditis, or insulin-dependent
low. The thymus appears dysplastic with poor corticomedullary diabetes mellitus.
demarcation, as well as poorly developed Hassall corpuscles. Evaluation of the immune system reveals reduced numbers of
Nonimmune manifestations are striking, with intraluminal circulating T cells, which are unable to respond to mitogens or
calcifications. In some patients, atresias cannot be detected; rather, antigens, but normal B cells. The thymus appears dysplastic with
severe colitis with characteristic features of mucosal atrophy absent Hassall corpuscles and loss of corticomedullary demarca-
32
and massive enterocyte apoptosis is present. The prognosis tions. Thymocytes do not express CD1 and fail to downregulate

498 ParT fOur Immunological Deficiencies



TABLE 35.5 Combined Immunodeficiency With Immune Dysregulation
Molecular Defect/Presumed
Disease Inheritance Pathogenesis features Treatment
Interleukin (IL)-2Rα / AR Impaired T-cell differentiation Recurrent infections; Hematopoietic stem cell
CD25 deficiency autoimmunity transplantation (HSCT)
FOXP3 deficiency X-linked Impaired regulatory T cell (Treg) Autoimmunity; impaired barrier HSCT
development function in skin and gut;
enteropathy
IL-10, IL-10R deficiency AR Impaired antiinflammatory cytokine Early onset inflammatory bowel HSCT
production disease (IBD); autoimmunity
IKK2 deficiency AR Disruption of NF-κB pathway Recurrent fungal and viral HSCT
infections; failure to thrive
DOCK8 deficiency AR Disruption in cell adhesion and Recurrent infections; atopy; early HSCT
migration onset malignancy; autoimmunity
RHOH deficiency AR Defective Rho guanosine Human papilloma virus (HPV) HSCT
triphosphatase (GTPase) infections
expression resulting in impaired
T-cell receptor (TCR) signaling
MAGT1 / CTPS1 / SH2DIA X-linked, AR Variable depending on associated Epstein-Barr virus (EBV) HSCT
/ BIRC 4 defect lymphoproliferation
PNP deficiency AR Abnormal purine metabolism Recurrent infections; HSCT
autoimmunity, neurological
abnormalities
DiGeorge syndrome AD Deletion in chromosome 22q11.2 Omenn syndrome; Truncus Supportive
resulting in impaired TBX1 arteriosus; autoimmunity;
transcription factor, affecting cardiac defects; hypocalcemia;
developmental processes dysmorphism; cleft palate; short
stature; neuropsychiatric
problems
Wiskott-Aldrich syndrome X-linked recessive Impaired actin cytoskeleton Eczema; autoimmunity; HSCT
rearrangement and malignancy
immunological synapse
formation
Ataxia telangiectasia AR Impaired DNA repair and cell cycle Cerebellar ataxia; telangiectasias; Supportive
regulation predisposition to malignancy;
radiosensitivity
Nijmegen breakage AR Impaired DNA repair and cell cycle Microcephaly; growth retardation; Supportive
syndrome regulation predisposition to malignancy;
radiosensitivity



levels of the antiapoptotic protein Bcl-2. This results in marked offers the best option for cure, particularly if performed early
reduction of apoptosis and the expansion of autoreactive clones before irreversible organ damage occurs. 35
in multiple tissues. The markedly reduced Tregs in the absence
of CD25 explains the uncontrolled expansion of these clones, IL-10 and IL-10Rα and IL-10Rβ Deficiencies
resulting in autoimmunity. HSCT cures this disorder. IL-10, produced mainly by T cells and macrophages, is a key
antiinflammatory cytokine. Biallelic deleterious mutations in
FOXP3 Deficiency IL-10 (OMIM *124092) or its receptor IL-10R, composed of α
Mutations in the Forkhead box protein P3 (FOXP3) gene cause (OMIM *146933) and β (OMIM *123889) chains, causes early-
an X-linked recessive disorder, also known as IPEX (immune onset severe inflammatory bowel disease (OMIM #613148,
36
dysregulation/polyendocrinopathy/enteropathy/X-linked) syn- #612567). Patients suffer perianal abscesses and fistulas that
drome (OMIM #304790). The protein encoded by FOXP3, termed often require surgical intervention. Some patients with IL-10/
scurfin, is a transcription factor that plays a critical role in the IL-10R deficiency also develop other autoimmune manifestations,
+
+
development and function of CD4 CD25 Tregs (Chapter 18). such as rheumatoid arthritis. Treatment with immunosuppressive
Affected patients suffer from severe autoimmunity in infancy. agents may provide partial and temporary remission. Only HSCT
Severe enterocolitis is often the presenting feature. Insulin- proved effective in completely reversing colitis. However, other
dependent diabetes mellitus, hepatitis, autoimmune cytopenias, autoimmune features, such as arthritis, may persist.
and arthritis are frequent. Patients may also have increased
frequency of invasive bacterial infections. Circulating lymphocytes IKK2 Deficiency
are present in normal numbers, and they respond normally to IKK2 deficiency (OMIM #615592) is a combined immunode-
mitogen stimulation. TREC levels are also normal. However, the ficiency that is inherited in an autosomal recessive manner and
+
+
+
number and function of CD4 CD25 FOXP3 Tregs is reduced. is caused by biallelic mutations in the IKBKB gene (OMIM
Patients have normal Ig and antibody levels, as well as increased *603258), leading to disruption of the nuclear factor-κB (NF-κB)
autoantibodies against various tissues. Immunosuppressive drugs pathway. The NF-κB pathway regulates immune responses, cell
34
can transiently control the autoimmune phenomena, but HSCT activation and growth, as well as cell survival. The canonical

CHaPTEr 35 Primary T-Cell Immunodeficiencies 499


pathway encompasses the NF-κB essential modulator (IKKγ, or are normal, and responses to mitogens are normal in most
NEMO), IKK1 (IKKα), and IKK2 (IKKβ). Upon activation of patients. Some patients suffer bacterial infections as well as chronic
the complex, IKK2 phosphorylates inhibitors of NF-κB, which EBV viremia, and HSCT has been sometimes successful. 42
are degraded, therefore allowing nuclear translocation of NF-κB EBV-induced lymphoid proliferation and lymphoma (OMIM
and DNA binding. Patients present with oral thrush, pulmonary #613011) can also be caused by biallelic mutations in the IL-2
38
43
infections, and invasive bacterial infections. Evaluation of the inducible T-cell kinase (ITK) gene. X-linked lymphoproliferative
immune system reveals normal numbers of circulating T cells syndrome-1 (XLP, OMIM #308240) and -2 (XLP2, OMIM
but reduced NK cells. Responses to mitogens are variable, TREC #300635) are caused by hemizygous mutations in SH2DIA (XLP1)
44
levels are normal, and the TCR repertoire is intact. The B-cell and BIRC4 (XIAP), respectively. Patients can present with
−
+ +
38
compartment lacks memory B cells (T B NK ). HSCT is a overwhelming EBV infection causing liver necrosis and failure,
plausible choice for treatment; however, results so far are very aplastic anemia, or with chronic EBV infections culminating in
limited and variable. Like other NK-κB pathway disorders, malignant lymphoma. Some patients present with hypogam-
engraftment may be incomplete using current bone marrow maglobulinemia and antibody deficiency, and some others may
45
transplantation protocols. develop hemophagocytic lymphohistiocytosis. XLP2 is more
46
frequently associated with chronic colitis. Lymphocyte numbers
DOCK8 Deficiency and response to mitogens are typically normal, whereas NK-cell
Dedicator of cytokinesis 8 (DOCK8) deficiency (OMIM #243700) activity may be impaired. HSCT can reverse the susceptibility
is an autosomal recessive combined immunodeficiency combined to EBV. 45
39
with severe atopy. DOCK8 interacts with Rho guanosine tri-
phosphatases (GTPases) and is believed to be involved in COMBINED IMMUNODEFICIENCY WITH IMMUNE
cytoskeletal rearrangement, affecting cell adhesion and motility. DYSREGULATION AND SYNDROMIC FEATURES
Patients suffer recurrent respiratory infections and, less frequently,
invasive bacterial and fungal infections. In addition to severe PNP Deficiency
eczema, patients may have extensive warts and molluscum Purine nucleoside phosphorylase (PNP) deficiency (OMIM #
contagiosum. Food allergies, asthma, and anaphylaxis have also 613179) is an autosomal recessive multisystem syndrome caused
been documented. Immunological assessment shows great vari- by mutations in PNP, a key enzyme in the purine salvage pathway.
ability with variable number of T cells and B cells but increased PNP catalyzes the phosphorylation of guanosine, deoxyguanosine,
eosinophil counts. Responses to mitogens appear normal. IgG inosine, and deoxyinosine. This pathway is responsible for balanc-
is elevated, but other serum Ig levels and specific antibodies are ing the production of dephosphorylated purines and degradation
39
variable. Treatment is dictated by the various atopic and infec- to uric acid and salvage back to the nucleotide level. Lymphotoxic-
tious manifestations. ity is caused by accumulation of dGTP in mitochondria inducing
apoptosis, and T-cell toxicity may be related to the need for high
RHOH Deficiency deoxyguanosine phosphorylation activity in T cells. Indeed,
This is an autosomal recessive immunodeficiency caused by PNP-deficient mice created by gene targeting have no detected
mutations in the Ras homologue gene family member H gene PNP activity and demonstrate a sharp reduction in T-cell numbers
+
+
(RHOH; OMIM *602037), which is mostly expressed in the and function due to loss of double positive CD4 CD8 progenitors,
hematopoietic system. Upon ligation of TCR, RhoH undergoes as well as progressive loss of peripheral T cells.
phosphorylation on tyrosine residues and leads the recruitment Patients with PNP deficiency display similar abnormalities
4
of Zap-70 and Lck to downstream signaling pathways. Patients in T-cell maturation and function. The thymus appears partially
may present with persistent skin infections, granulomatous lung dysplastic. Circulating T-cell numbers are reduced, and T-cell
disease, and Burkitt lymphoma. Circulating lymphocytes, Igs, function is depressed. Igs and specific antibody levels may be
and antibody production are all normal, and in vitro responses variable. B- and NK-cell numbers are variable. Patients with
to mitogens are variable. 40 PNP deficiency typically present with a triad of features, including
recurrent infections, autoimmune manifestations, and various
COMBINED IMMUNODEFICIENCY WITH neurological abnormalities. Infections may be consistent with
EBV-INDUCED LYMPHOPROLIFERATION SCID, but severe bacterial infections have been mostly reported
in older patients with delayed presentation. Autoimmune features
EBV-induced chronic infection and lymphoproliferation is the include cytopenias, systemic lupus erythematosus (SLE), and
major clinical presentation of a growing number of newly arthritis, and neurological features consist of ataxia and various
described inherited immunodeficiencies. Inheritance can be degrees of behavioral and mental retardation. Diagnosis is
X-linked or autosomal recessive according to the gene affected. confirmed by demonstrating markedly reduced PNP enzyme
Hemizygous mutations in the magnesium transporter 1 (MAGT1) activity in red blood cells (RBCs) or T cells, reduced uric acid,
2+
gene (OMIM *300715) causes reduced TCR-mediated Mg as an increase of deoxyguanosine and other metabolites in blood
2+
well as Ca influx into T cells (OMIM #300853). This ultimately and urine, and by genetic analysis of the PNP gene. HSCT
results in abnormal downstream activity of transcription factors. may reverse the immunodeficiency, but not the neurological
Patient CD4 T cells are reduced, but the total numbers of CD3 manifestations.
cells, B cells, and NK-cells are normal. EBV related infections
41
or lymphoma may develop at any age. A similar clinical picture DiGeorge Syndrome
(OMIM #615897) is found in patients with biallelic CTP synthase DiGeorge syndrome (DGS; OMIM #188400) comprises thymic
42
1 (CTPS1; OMIM *123860) mutations. The nucleotide cytidine- hypoplasia, parathyroid hypoplasia, and outflow tract malforma-
5’-triphosphate (CTP) is needed for the metabolism of RNA tions of the heart. The syndrome is caused by a 1.8–3.0 Mb
and DNA. Circulating lymphocyte counts are variable, Ig levels hemizygous deletion in chromosome 22q11.2. Haploinsufficiency

500 ParT fOur Immunological Deficiencies


of the TBX1 gene (OMIM *602054), which is localized within involved in protecting DNA repair. ATM is a serine/threonine
the deleted region, can be solely responsible for this disorder. protein kinase that activates signaling pathways upon double-
Less frequently, DGS can be caused by defects in other chromo- strand breaks, which occur naturally during Ig and TCR rear-
somes, notably 10p13. DGS is one form of several phenotypically rangement or upon stress posed by ionizing radiation. It is also
overlapping disorders, including conotruncal anomaly and involved in cell cycle control and may act as a tumor suppressor
velocardiofacial syndrome. Clinically, patients may present with gene.
neonatal hypocalcemia and susceptibility to opportunistic infec- Affected individuals present in early childhood with progressive
tions. Cardiac malfunctions typically include tetralogy of Fallot, truncal ataxia, which is frequently misdiagnosed in infancy as
truncus arteriosus, and interrupted aortic arch. Facial signs consist cerebral palsy. Choreoathetosis and dystonia, ocular motor apraxia,
of retromicrognathia, small teeth, short filtrum, hypertelorism, and dysarthria are common. At 3–5 years of age telangiectasias
and low-set and malformed ears. Pulmonary, renal, skeletal, become increasingly prominent in the eyes and ear lobes. Typically,
ophthalmological, and GI defects can also occur. patients become wheelchair dependent during the second decade
Molecular diagnosis is made by using chromosomal microarray of life. Most patients die by the age of 30 years, with rare survivors
or array comparative genomic hybridization or by sequencing who live to the end of the fourth decade. Patients die of progressive
the TBX1 gene. Because of the poor development of the thymic restrictive lung disease, infections, or cancer. Lymphoma, leukemia,
gland, patients with DGS usually have T-cell lymphopenia, which and ovarian and stomach cancers are the most common malignan-
frequently improves with age but may never reach normal levels. cies associated with AT, and a high risk of developing breast
A small group of patients are born with little to no detectable cancer is a prominent feature of heterozygotes.
circulating T cells and are therefore designated as suffering from Diagnosis of this condition is supported by demonstrating
“complete DGS.” Management is dictated by the presenting increased frequency of chromosomal breakage and elevated levels
features of this heterogeneous syndrome. Calcium supplements of alpha-fetoprotein, which reflect the defect in DNA repair and
and 1,25-cholecalciferol may be needed to treat hypocalcemia. liver tissue immaturity, respectively. Immune investigations show
Blood products, if needed (normally during heart surgery), should decreased circulating T cells and abnormal in vitro response
be CMV-free and irradiated to eliminate allogeneic T-cell transfer to mitogens. The thymus is dysplastic, and TREC levels are
and to prevent GvHD. Thymic tissue transplantation has been markedly reduced. IgA is low in about 50% of patients, and
attempted in cases with complete DGS, although the effects are IgG levels vary from extremely low to normal levels. IgM may
difficult to evaluate, since children with DGS tend to improve be increased, a phenotype mimicking hyper-IgM syndrome
spontaneously with age. (HIGM). The diagnosis is confirmed by identifying mutations
in the ATM gene. Treatment is mostly supportive and limited
Wiskott-Aldrich Syndrome to intravenous immunoglobulin (IVIG) and antibiotics, when
Wiskott-Aldrich syndrome (WAS; OMIM #301000) is a rare indicated, as well as physiotherapy. Nijmegen breakage syndrome
X-linked recessive condition caused by mutations in the WAS (OMIM #251260), an AT-like syndrome, is caused by biallelic
gene. The WAS encoded protein is predominately expressed in hypomorphic mutations in MRE11, which encodes a protein
hematopoietic cells, and its main function is to activate actin involved in cell cycle control and double-strand DNA repair. In
assembly by binding to the Arp2/3 complex. The WAS protein addition to the typical AT feature, Nijmegen breakage syndrome
(WASP) is required for TCR-mediated formation of the immu- is characterized by microcephaly, bird-like facial features, and
nological synapse, which is a process dependent on actin rear- growth retardation.
rangement. Patients are typically diagnosed in infancy, and their
condition is characterized by thrombocytopenia, eczema, and COMBINED IMMUNODEFICIENCY WITH
47
recurrent infections. Platelet volume is reduced and appears IMMUNOOSSEOUS DYSPLASIA
to be rapidly cleared from the circulation. The abnormal coagula-
tion in these patients is associated with bloody stools and life- This group of combined immunodeficiencies characterized by
threatening intracranial bleeding. Patients with this syndrome walking and growth disturbances is summarized in Table 35.6.
occasionally have increased susceptibility to bacterial, viral, and
opportunistic organisms, including P. jiroveci pneumonia. Cartilage Hair Hypoplasia
Autoimmunity and malignancy, particularly lymphoma, have McKusick-type metaphyseal chondrodysplasia, also known as
been frequently reported in these patients. T-cell numbers tend cartilage hair hypoplasia (OMIM #250250), is an autosomal
to decrease over time, resulting in mild-to-moderate lymphopenia, recessive syndrome that was first recognized in the Amish and
and in vitro responses to mitogens are frequently normal. Typically, later in the Finnish population. The condition is characterized by
IgM is low, IgG is normal, whereas IgA and IgE are elevated. short-limb dwarfism, various degrees of T-cell immunodeficiency,
Splenectomy should be avoided. HSCT successfully cures these fine and sparse hair, Hirschsprung disease, and increased risk of
patients. Gene therapy for this condition is currently being malignancy. This syndrome is caused by mutations in the RNase
48
studied. Recently, a patient with a similar phenotype to WAS MRP (RMRP) gene (OMIM *157660), a ribonuclease that is
was shown to have a mutation in the WASP-interacting protein present in both the nucleus and mitochondria. Uniquely, this gene
(WIP). WIP stabilizes WASP, preventing its degradation. product does not undergo translation but functions as a protein in
the cleavage of RNA during mitochondrial DNA synthesis, as well
Ataxia Telangiectasia (Louis-Bar Syndrome) as clearing of nuclear pre-rRNA. Immune function is variable, and
Ataxia telangiectasia (AT; OMIM #208900) is an autosomal patients may present with profound T-cell lymphopenia, depressed
recessive multisystem disorder characterized by cerebellar ataxia, mitogenic responses, and a dysplastic thymus. Some cases present
+ +
telangiectasias, immunodeficiency, and highly increased predis- with Omenn syndrome (T B SCID). Other patients have various
position to malignancy. AT is a result of deleterious mutations degrees of T-cell lymphopenia. Nonimmune features consist of
in the ATM gene (OMIM *607585), which encodes a key protein spondylometaphyseal dysplasia, small caliber and hypoplastic hair

CHaPTEr 35 Primary T-Cell Immunodeficiencies 501



TABLE 35.6 Combined Immunodeficiency With Immunoosseous Dysplasia
Molecular Defect/Presumed
Disease Inheritance Pathogenesis features Treatment
Cartilage hair hypoplasia AR Defect in RMRP gene resulting in impaired Metaphyseal dysplasia; fine Hematopoietic stem cell
ribosomal assembly and cell cycle and sparse hair transplantation (HSCT)
regulation
Schimke immunoosseous AR Impaired DNA stress response enzyme Epiphyseal dysplasia; renal Supportive
dysplasia dysfunction; autoimmunity;
non-Hodgkin lymphoma
Roifman immunoskeletal AR Impaired tartrate-resistant phosphatase Spondyloenchondrodysplasia; Supportive
syndrome (SPENCD) (TRAP) enzyme function, accumulation of autoimmunity; neurological
phosphorylated osteopontin abnormalities






with lack of central pigment core, and skin hypopigmentation. Infections are controlled with immunoglobulin replacement
There is an increased risk of non-Hodgkin lymphoma and basal in these patients.
cell carcinoma with this syndrome. HSCT has proven curative
of the immune abnormalities in these patients. SPENCDI–Roifman Immunoskeletal Syndrome
This syndrome was first described in 2000 as a novel combina-
Schimke Immunoosseous Dysplasia tion of features encompassing combined immunodeficiency,
The major features of Schimke immunoosseous dysplasia autoimmunity, and spondylometaphyseal dysplasia (OMIM #
50
(SIOD; OMIM #242900), an autosomal recessive syndrome, 607944). One patient died of noninfectious encephalopathy,
are spondyloepiphyseal dysplasia, progressive renal failure, and and some others had arthritis, SLE, and thrombocytopenia, in
45
moderate cellular immunodeficiency. The disease is caused by addition to lung disease. Renella et al. highlighted the type of
mutations in the SWI/SNF matrix actin-dependent regulator of spondylometaphyseal dysplasia as spondyloenchondrodysplasia
chromatin subfamily A-like gene (SMARCAL1) encoding a DNA (SPENCD), confirming the initial observation of autoimmunity
stress response enzyme. Patients with SIOD present with growth in this syndrome. The spectrum of clinical features was further
retardation before and after birth. In addition to progressive renal expanded to include cerebral calcifications and other neurological
failure, patients may have cerebral vascular accidents, dental and abnormalities. SPENCD is a rare skeletal dysplasia characterized
skin abnormalities, and dysmorphic features. Immune function by metaphyseal and vertebral lesions consisting of chondroid
is variable, with mild to moderate lymphopenia and somewhat tissue. Over the years, evidence for both autosomal dominant and
reduced in vitro responses to mitogens. Consequently, they develop recessive inheritance was proposed. Mice lacking tartrate-resistant
recurrent viral and fungal infections. Treatment is supportive, phosphatase (TRAP) display skeletal abnormalities identical to
and some patients may benefit from renal transplantation. the patients. Consequently, sequencing of the ACP5 gene (OMIM
*171640), which encodes TRAP, identified deleterious biallelic
Roifman Syndrome mutations in humans. 52,53 Immune abnormalities include T-cell
Roifman Syndrome (OMIM #616651) was first described as lymphopenia with reduced responses to mitogens and antigens,
a novel association of immunodeficiency, spondyloepiphyseal and an inability to produce specific antibodies. Patients frequently
chondro-osseous dysplasia, retinal dystrophy, growth and have autoantibodies, such as antinuclear factor (ANF) and anti-
developmental delay, and distinctive facial dysmorphism. 49 DNA. Treatment so far has been limited to replacement of Igs,
This syndrome is caused by distinct mutations in the small antibiotics, and immunomodulation of the various immune
nuclear RNA (snRNA) gene RNU4ATAC (OMIM*601428), which manifestations.
is essential for minor intron splicing. About 800 genes have one
or more minor introns, and these are dependent on the minor COMBINED IMMUNODEFICIENCY WITH BONE
spliceosome for correct splicing. Since many of these genes are MARROW FAILURE
involved in basic cellular functions, such as DNA replication
and repair or RNA processing, incorrect splicing can alter cell Immune deficiencies associated with bone marrow failure are
function and survival. Mutations in the Stem II domain of the presented in Table 35.7.
gene appear obligatory for this syndrome. Patients with Roifman
Syndrome frequently suffer repeated microbial infections such IKAROS Deficiency
as otitis media, cellulitis and pneumonia as well as viral and IKAROS deficiency is extremely rare combined immunodeficiency
fungal infections (HSV, PJP). associated with bone marrow failure (OMIM #616873). IKAROS
Atopy and autoimmune manifestations are also common, is a hematopoietic-specific transcription factor (OMIM *603023)
including eczema, asthma, arthritis, hemolytic anemia, colitis, affecting pluripotent stem cells that control T-cell differentiation,
54
and autoimmune hepatitis. Antibody deficiency and hypogam- B-cell V(D)J recombination, and NK-cell development. Patients
maglobulinemia are present in all cases, and circulating B cells may present with recurrent pulmonary infections or disseminated
are usually reduced, especially memory B cells. T cell lymphopenia, viral infections in teenage years, or during infancy with bone
55
low CD8+ T cells, abnormal T cell repertoire, as well as low in marrow aplasia and near absent B and NK cells. T cells can be
vitro responses to antigens are also recorded. normal in number, but the response to mitogens is absent

502 ParT fOur Immunological Deficiencies



TABLE 35.7 Combined Immunodeficiency With Bone Marrow failure
Molecular Defect/Presumed
Disease Inheritance Pathogenesis features Treatment
Dyskeratosis congenita X-linked, AR, AD Defective telomere processing Nail and skin defects; noninfectious Hematopoietic stem cell
proteins, genomic instability enteropathy; developmental delay; transplantation (HSCT)
microcephaly; cerebellar hypoplasia
IKAROS deficiency AD Impaired lymphocyte development Recurrent infections; severe aplastic HSCT
and proliferation, V(D)J anemia
rearrangement
AK2 deficiency AD Impaired mitochondrial energy Severe marrow failure; bilateral HSCT
(reticular dysgenesis) metabolism, severe lymphopenia sensorineural deafness




TABLE 35.8 Progressive T-Cell Combined Immunodeficiency

Disease Inheritance Molecular Defect/Presumed Pathogenesis features Treatment
STAT1 dysfunction AR, AD Impaired cytokine signaling Autoimmunity Hematopoietic stem cell
transplantation (HSCT)
RelB deficiency AR Disruption of NF-κB noncanonical pathway Failure to thrive; autoimmunity HSCT
STK4 deficiency AR Abnormal apoptosis Epstein-Barr virus (EBV) HSCT
lymphoproliferation




−
+ −
(T B NK ), and Igs are low. The thymus appears large and upon TCR or BCR binding, suggesting that it plays a role in
hyperplastic. HSCT is the only effective treatment proposed. 55 TCR mediated cell polarization.
Immune evaluation in these patients revealed T cell lympho-
Dyskeratosis Congenita penia, hypogammaglobulinemia, antibody deficiency and
Dyskeratosis congenita (DKC; OMIM #305000) is a complex neutropenia.
and fatal disorder caused by mutations in genes that encode Patients are typically susceptible to severe varicella zoster virus
telomere processing proteins. Inheritance can be X-linked in the and recurrent molluscum contagiosum. Infections were well
case of mutations in dyskerin, the most common cause of DKC, controlled with replacement immunoglobulin therapy.
autosomal recessive when mutations in telomerase reverse
transcriptase (TERT), NOP10, NHP2, and C160ORF57 are found, PROGRESSIVE T-CELL OR COMBINED
or autosomal dominant in cases with mutations in telomerase IMMUNODEFICIENCY
RNA component (TERC), TERT, and TNF2. 56
Common hallmarks of this group of disorders are bone marrow Immune deficiencies characterized by a progressive decline in
failure, repeated infections, nail dystrophy, and leukoplakia. T- and/or NK-cell numbers and functions are summarized in
Pulmonary fibrosis and colitis are frequently observed. Some Table 35.8.
patients have additional syndromic features and present early
in life with significant intrauterine growth retardation, short STAT1 Dysfunction
stature, microcephaly, and cerebellar hypoplasia, a constellation Mutations in the gene for the DNA-binding transcription
57
of features also known as Hoyeraal-Hreidarsson syndrome. Other factor—STAT1 (OMIM *600555)—have been associated with
patients present in adolescence or later in life with progressive an array of different clinical phenotypes ranging from complete
bone marrow failure. Immune abnormalities are highly variable, deficiencies (autosomal recessive; OMIM #613796), which are fatal
with a wide range of presentations from extreme T-cell lympho- in early infancy, to chronic mucocutaneous candidiasis 58,59 or mild
− −
penia and occasional profound B-cell lymphopenia (T B SCID) persistent oral thrush (autosomal dominant; OMIM #614892).
to mild lymphopenia. Similarly, T-cell function, serum Ig levels, One subgroup of patients with monoallelic STAT1 mutations
and specific antibody formation are variable. Allogeneic HSCT appear to have a distinct course. They suffer from repeated and
has been attempted in patients with DKC, primarily for bone severe viral and fungal infections that are ultimately fatal, and most
marrow failure or malignancy, with disappointing results because of them die before the age of 20 years. Most have severe colitis as
of drug toxicity and frequent failure of engraftment. well as multiple autoimmune features. Evaluation of immunity
is normal in these patients, featuring a progressive decline and
Moesin Deficiency (MSN Deficiency) loss of T cells and NK cells, decreasing T-cell functions, and a
This is a newly described combined immunodeficiency which structurally abnormal thymus gland. Usually, by the end of the
is inherited in an X-linked manner and caused by mutations in first decade of life, these patients have all of the typical clinical
the cytoskeletal protein moesin (OMIM *309845). Moesin is a and immunological features of combined immunodeficiency.
member of the ezrin-radixin-moesin family of proteins that link In this chapter, we will only describe the phenotype of STAT1
the cortical actin filaments to the plasma membrane. The active dysfunction.
form of moesin is predominantly expressed in lymphocytes where The STAT1 gene encodes two isoforms, α and β. STAT1β acts
it is believed to sustain cell shape. Moesin is dephosphorylated as a dominant negative inhibitor, whereas STAT1α plays a critical

CHaPTEr 35 Primary T-Cell Immunodeficiencies 503


role in signaling responses to a variety of cytokines, such as system. Early diagnosis is critical to minimizing morbidity and
interferon-α (IFN-α), IFN-β, IFN; IL-2, -3, -6, -9, -10, -11, -12, improving quality of life, and with the increasing implementation
and -15; growth hormone fibroblast growth factor; epidermal of NBSs, patients now have a greater chance of being diagnosed
growth factor; and others. Cytoplasmic STAT1 is activated through shortly after birth. Importantly, measures that minimize exposure
tyrosine phosphorylation by members of the JAK kinase family, of patients to infections, including use of irradiated and filtered
which results in its translocation to the nucleus and subsequent blood products, avoidance of live vaccines, and nutritional
binding to target DNA segments. Typically, these patients harbor support, should also be considered as part of therapy.
de novo mutations in the DNA-binding domain of STAT1.
Although increased tyrosine phosphorylation of STAT1 or even THEraPEuTIC PrINCIPLES
enhanced DNA binding may be observed, STAT1 function is
altered and patients’ cells produce reduced amounts of IL–2, Management of Severe Combined
IFN-γ, and other cytokines, hence the designation of STAT1 Immunodeficiency
60
dysfunction. HSCT has been attempted with variable degrees • Patients should be kept in a protective isolation environment, receive
of success. 61,62 prophylactic antibiotics, immunoglobulin replacement, and enhanced
nutrition.
RelB Deficiency • Patients should only receive cytomegalovirus (CMV)–free, irradiated
+ +
+
This is a newly described CID (T B NK ) that is inherited in an blood products and irradiated breast milk. Breast feeding should be
63
autosomal recessive mode. The immunodeficiency is caused discontinued if the mother is CMV positive.
by mutations in RELB (OMIM *604758), a key component of • Live attenuated vaccines should be avoided.
• The immune defect in severe combined immunodeficiency (SCID),
the NF-κB pathway. Lymphocyte antigen receptors, multiple and in many cases of combined immunodeficiency (CID), can be
cytokines, and infective agents all use the NF-κB signaling corrected by administration of allogeneic hematopoietic stem cell
64
pathway. The pathway consists of five members, including RelA, transplantation (HSCT).
RelB, c-Rel, and the precursor proteins NF-κB1 (p105) and • Best results are achieved using an human leukocyte antigen (HLA)–
NF-κB2 (p100), which are processed to the active forms p50 identical family donor.
and p52, respectively. Two NF-κB pathways are recognized, the • Patients with autologous T cell should receive myeloablative conditioning
to improve engraftment and sustained long-term immune reconstitution.
classical pathway, mediated by RelA, and the alternative (non- • Gene therapy should be offered in selected types of SCID, such as
canonical) pathway, which uses RelB. Activation of RelB requires adenosine deaminase (ADA) deficiency, whereas this procedure remains
inducible processing of p100 and p52. Unlike the classical pathway, experimental in other conditions.
which is engaged by many receptors, the alternative pathway is
37
used by TNFRSF12A, LTβR, CD40, and BAFF-R. Patients with
RelB deficiency present in the first year of life with failure to Newborn Screening
thrive, recurrent infections, and autoimmune disorders. In vitro Patients with SCID usually die of overwhelming infections or
responses to mitogens are depressed, the TCR repertoire is suffer associated catastrophic complications once maternally
restricted, and TRECs are abnormal. Production of specific transferred antibodies have been metabolized, usually within
antibodies in response to vaccination is impaired. The thymus 3–6 months after birth. However, if diagnosed early and before
appears moderately dysplastic. Both memory T and B cells are the onset of complications, most of these patients can be treated
reduced or absent. 63,65,66 HSCT has been successful in two patients successfully with HSCT.
who received the procedure. TRECs, which are produced during programmed gene rear-
rangement of progenitor T cells in the thymus, were identified
STK4 (Mst1) Deficiency as a useful biomarker of both thymic function and the production
This is an autosomal recessive combined immunodeficiency of newly formed T cells. Since the thymus is invariably dysfunc-
characterized by a progressive loss of T cells and declining function tional in SCID, the use of TREC detection in blood from Guthrie
(OMIM #614868). The deficiency is caused by biallelic mutations spots serves as an ideal NBS tool. 67
in serine threonine kinase 4 (STK4). STK4 functions as a pro- NBS utilizing TRECs detects most cases of phenotypic SCID,
apoptotic factor by promoting Fas-mediated apoptosis. STK4-null especially those who have lymphocytopenia of less than 300–500
+
mice demonstrate increased apoptosis leading to T- and B-cell CD3 cells/µL. It may also detect other conditions where the
lymphopenia, as well as depletion of the thymus gland. Patients patient presents at birth with profound lymphopenia—such as
present with oral thrush and mucocutaneous candidiasis, recurrent ataxia telangiectasia, Nijmegen breakage syndrome, Di George
bacterial and viral lung infections, and EBV-induced B-cell syndrome, CHARGE, Rac2 and DOCK8 deficiencies, as well as
lymphoproliferation. Skin manifestations include disseminated trisomy. 21
warts and molluscum contagiosum. Evaluation of the immune However, cases that are phenotypically similar to SCID, such
system reveals progressive decrease in T and B cells and an altered as ZAP-70 deficiency or other CIDs with a severe phenotype
+
TCR Vβ repertoire. Serum Igs, including IgE, are elevated, and (CD3 >300–500 cells/µL) may be missed. This highlights the
autoantibodies have been observed. Autoimmune cytopenias need consider other methodologies, such as next generation
have also been reported. HSCT is the treatment of choice. sequencing, which have the capacity to detect these cases at birth.
DIAGNOSIS, MANAGEMENT, AND TREATMENT OF Isolation
T-CELL AND COMBINED IMMUNODEFICIENCY Patients with primary immunodeficiency are susceptible to
recurrent and opportunistic infections, posing an immediate
The current approach to management and treatment of primary threat to life. As a preventative measure, isolation and the provi-
immunodeficiencies involves prevention and treatment of infec- sion of an aseptic environment are recommended and have been
tions, and when attainable, restoration of a functional immune shown to protect against infections for extended periods. The

504 ParT fOur Immunological Deficiencies


76
prevention and successful treatment of infections are strong (VOD). Alternative conditioning agents include treosulfan
2
determinants of HSCT outcome and is associated with decreased (1-treitol-1,4-bis-methanesulfonate), which has both myeloabla-
frequency of GvHD. In particular, infection prevention is critical tive and immunosuppressive properties, as well as an improved
in patients with SCID receiving matched unrelated HSCT, where patient safety profile.
the risk of GvHD has been reported to be >70% (the main cause Reduced intensity conditioning (RIC) involving incomplete
of morbidity and mortality). 68 ablation of the bone marrow may also be beneficial in permitting
engraftment and immune reconstitution. However, where such
Hematopoietic Stem Cell Transplantation regimens may offer improved survival and reduced toxicity, there
HSCT is the only potentially curative therapeutic approach for have also been reports of increased incidences of mixed donor
69
patients SCID and various forms of CID. The replacement of chimerism and graft failure. In these instances, repeat HSCT or
defective HSCs with cells from a healthy donor, typically bone donor lymphocyte infusions may be necessary, which may pose
marrow, allows T-cell precursors to repopulate the native thymus further risk to patients. 77
and permits reconstitution of a functional immune system. As HSCT without conditioning has been attempted in patients
a result of advancements made in preparing the host, donor who are too sick to tolerate pre-transplant chemoablation,
cells, conditioning regimens, and supportive therapy, HSCT however, this is associated with a high frequency of complications
78
survival rates have markedly improved since the early 1980s and mortality. In such circumstances, it is recommended that
(Chapter 82). the patient be stabilized until a full protocol can be implemented.
Donor Source Prophylaxis and Treatment of Graft versus Host Disease
Transplantation involving related HLA-identical donors (RID), GvHD is caused by T cell mediated attack of the host tissue by
usually a sibling, carry the most favorable prognosis, with survival the graft, and is a significant cause of morbidity and mortality
rates of 90 to 100%. Complete immune reconstitution occurs to allogeneic HSCT recipients. The principal affected organs are
rapidly and carries a low risk of GvHD. However, since such skin, gastrointestinal tract and liver, with the current grading
donors are available in less than 20% of cases, donor sources system (grades I-IV) based upon the extent of organ involve-
79
including HLA-matched unrelated donors (MUD) or HLA- ment. Risk factors for GvHD include donor-host incompatibility
mismatched related donors (MMRD) can be considered. as well as the source of stem cells, and can be significantly reduced
70
The survival rates for MUD HSCT are greater than 70%, by introducing prophylactic immunosuppression and depletion
with some centers reporting rates of up to 83% 68,71 and low of donor T cells before infusion. The primary response to such
72
incidences of GvHD. This modality has proven especially first-line treatment is the most important predictor of long term
effective in cases with CID. Experience with MMRD HSCT in survival in patients with acute GvHD.
the past has been disappointing, 73,74 but recent reports suggest Options for pharmacologic prophylaxis include monotherapy
improved survival rates for these transplants, although follow-up with a calcineurin inhibitor (such as cyclosporine or tacrolimus),
2
in many of the cases is still too short. Such transplants involving or in combination with steroids, methotrexate or mycopholate
haploidentical donors require the marrow to be depleted of T mofetil. The efficacy of steroids in improving the outcome and
cells, and immune reconstitution may be prolonged. Rates of probability of survival is well documented. 80,81
graft failure necessitating a second transplant have been high, T cell depletion is recommended for HSCT involving HLA-
72
along with incomplete immune reconstituation. Complications mismatched donors. However, while depletion of donor T cells
include opportunistic infections, chronic GVHD, autoimmunity using physical separation techniques, monoclonal antibodies or
and late deaths. anti-thymocyte globulin can reduce GvHD, it is also associated
Nevertheless, regardless of donor source, HSCT prior to 3.5 with delayed immune reconstitution and an increased incidence of
months of age or before the onset of infection is associated with post-transplant lymphoproliferative disorders and life-threatening
high rates of survival (95% and 90% respectively) when compared infections. 79
to older children (76%). 2
Gene Therapy
Conditioning Gene therapy represents a therapeutic option for patients with
62
Pre-transplant conditioning helps to prepare the recipient marrow primary immunodeficiency who lack a HLA-identical donor
for optimal engraftment of donor stem cells and T cell reconstitu- (Chapter 85). By using retroviruses to introduce a functional
tion, and plays an important role in the long-term outcome of copy of the defective gene into the patient’s own HSCs, this
75
HSCT. Whether conditioning is necessary depends in part on technique negates the need for a donor and is not associated
the type of immunodeficiency. For example, whereas myeloabla- with complications normally arising from HLA-incompatibility.
tion is necessary for HSCT in patients with sufficient immune To date, gene therapy has been demonstrated to be extremely
cells to reject a graft (as in CID), it may not be indicated for effective in treating patients with ADA deficiency, resulting in a
patients with SCID receiving HLA-matched stem cells from a variable increase in T and B cell numbers as well as significant
sibling donor. However, it is worth noting that donor B cells improvement of immune function. Importantly, there have been
rarely engraft in the absence of conditioning regimens, and many no reports of serious adverse events or malignancy to this
patients remain on lifelong immunoglobulin replacement with indication. 23
increased risk of infective lung damage and T lymphocyte However, early attempts to utilize gene therapy in other forms
senescence. of primary immunodeficiency were met with mixed results, and
83
Myeloablative conditioning with busulfan and cyclophospha- highlighted various pitfalls related to the first-generation vectors.
mide was once commonly used for HSCT in patients with SCID A number of serious adverse events, including leukemia, were
and CID, although a protocol including busulfan and fludarabine caused by preferential integration of retroviral vectors in the
is currently proposed due to risk of veno-occlusive disease proximity of transcription initiation sites, leading to increased

CHaPTEr 35 Primary T-Cell Immunodeficiencies 505


and deregulated expression of oncogenes. Use of a γ-retrovirus lymphoma, have also been reported recently as sole manifestations
vector in patients with Wiskott-Aldrich syndrome resulted in of T-cell immunodeficiencies. With the increased recognition of
partial or complete resolution of immunodeficiency, however 7 genetic aberrations linked to these diseases, we are likely to see
84
of the 10 patients receiving gene therapy developed malignancy. a great expansion of novel phenotypes associated with known
Furthermore, in patients with chronic granulomatous disease, genotypes, although not necessarily with identical mutations.
long term immune reconstitution was variable and myelodys-
plastic syndrome was reported in 3 of 10 patients. Between 1999 ON THE HOrIZON
and 2006, trials for IL2RG deficiency initially reported successful
immune reconstitution in 18 of 20 recipients; however clonal • Whole exome sequencing can be technically performed using DNA
derived from a dried blood spot. Implementing this technology to
proliferation caused by insertional mutagenesis occurred in 5 newborn screening will immensely improve the outcome of patients.
85
recipients after 2 to 5 years. Taken together, these results • In the future, closer attention will be paid to family members of patients
prompted a discontinuation of these trials, and a call to develop with overt immunodeficiency to better understand the clinical impact
novel and much safer vector constructs, including self-inactivating of monoallelic/carrier genetic aberrations.
γ-retrovirus and lentiviral vectors. To date, follow-up studies in • Whole exome sequencing is widely reported to be successful in only
patients with IL2RG deficiency utilizing a self-inactivating 40% of cases. Whole-genome sequencing and development of new
bioinformatics algorithms would likely yield better results.
γ-retrovirus vector have so far been encouraging, with reports • Although hematopoietic stem cell transplantation can cure patients
of excellent immune reconstitution and no evidence of insertional with T-cell deficiency, in many cases, it remains a high-risk procedure
48
83
mutagenesis. In an ongoing study, the application of lentiviral and may not be optimal therapy for a growing number of newly defined
vectors in Wiskott-Aldrich syndrome have demonstrated multi- combined immunodeficiencies. New developments in gene therapy
lineage engraftment of corrected cells, both in the bone marrow and gene editing are likely to expand as alternative treatments.
and peripheral blood, with no reports of clonal expansion or
leukemia. This expansion in diagnosis of profound T-cell deficiencies
With the advancement in technology and progress made in raises new opportunities to study mechanisms underlying
vector design, gene therapy is a viable option for challenging autoimmunity as well as lymphoid malignancies. However, these
forms of primary immunodeficiency, in which current available cases may pose new challenges, such as choice of HSC therapy.
treatments are insufficient. Further prospective trials should help to determine the validity
of transplantation compared with conservative immunosuppres-
Gene Editing sive therapy or innovative new biological treatments.
Gene editing technologies allow precise correction of the defective With challenges come opportunities, and we are living in an
genomic DNA site and are thus a promising alternative to HSCT exciting era of improved tools to enhance the understanding
(Chapter 85). Using engineered endonucleases, such CRISPR/ of the molecular changes and mechanisms leading to profound
Cas9, zinc finger nucleases, and transcription activator-like T-cell deficiency and associated autoimmunity and malignancy.
effector nucleases, double-stranded breaks are introduced into This wealth of knowledge should help advance novel treatments.
specific sequences of the genomic DNA and repaired through
homology-directed repair. In the presence of a DNA repair Please check your eBook at https://expertconsult.inkling.com/
template containing a functional version of the defective gene, for self-assessment questions. See inside cover for registration
the double-stranded break is accurately repaired with the cor- details.
rected sequence incorporated. While gene editing provides greater
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combined immune deficiency. J Allergy Clin Immunol [Letter]. [Comparative Study Research Support, Non-U.S. Gov’t Review].
2008;122(6):1215–16. 2012;24(5):580–4.
82. Fischer A, Hacein-Bey Abina S, Touzot F, et al. Gene therapy for primary 86. Genovese P, Schiroli G, Escobar G, et al. Targeted genome editing in
immunodeficiencies. Clin Genet [Review]. 2015;88(6):507–15. human repopulating haematopoietic stem cells. Nature [Research
83. Hacein-Bey-Abina S, Pai SY, Gaspar HB, et al. A modified gamma- Support, Non-U.S. Gov’t]. 2014;510(7504):235–40.
retrovirus vector for X-linked severe combined immunodeficiency. N 87. Urnov FD, Miller JC, Lee YL, et al. Highly efficient endogenous human
Engl J Med [Clinical Trial, Phase I Clinical Trial, Phase II Multicenter gene correction using designed zinc-finger nucleases. Nature
Study Research Support, N.I.H., Extramural Research Support, Non-U.S. 2005;435(7042):646–51.
Gov’t]. 2014;371(15):1407–17.
84. Braun CJ, Boztug K, Paruzynski A, et al. Gene therapy for Wiskott-
Aldrich syndrome—long-term efficacy and genotoxicity. Sci Transl Med

CHaPTEr 35 Primary T-Cell Immunodeficiencies 508.e1


M u LTIPLE-CHOICE Q u ESTIONS

1. Each of these comments about T-cell deficiencies (severe B. In vitro responses to mitogens can be normal in some
combined immunodeficiency/combined immunodeficiency cases.
[SCID/CID]) are TRUE, except: C. Evaluation of natural killer (NK) cell numbers and function
A. Patients may present in infancy with failure to thrive. can be beneficial for diagnosis.
B. The thymus always appears dysplastic. D. Serum immunoglobulin levels can be normal.
C. Malignancy could be the sole presenting feature. E. CH50 does not contribute to the diagnosis.
D. Clinical manifestations may first arise during late childhood 3. For which of the following conditions is hematopoietic stem
or adolescence. cell transplantation not recommended?
E. Patients may present with severe hypocalcaemia.
A. FOXP3 deficiency
2. Which of the following is INCORRECT? B. Ataxia telangiectasia
A. All patients who present with a SCID phenotype can be C. Major histocompatibility complex (MHC) class II deficiency
detected at birth by T-cell receptor excision circle (TREC) D. Adenosine deaminase (ADA) deficiency
analysis E. DOCK2 deficiency

36






Immunodeficiencies at the Interface of Innate

and Adaptive Immunity



Jacinta Bustamante, Shen-Ying Zhang, Bertrand Boisson, Michael Ciancanelli,
Emmanuelle Jouanguy, Stéphanie Dupuis-Boisson, Anne Puel, Capucine Picard,
Jean-Laurent Casanova






In the last 20 years, new primary immunodeficiencies (PIDs) initially thought to be rare, but they have since been diagnosed
affecting the immunity mediated by interferon (IFN)- γ, IFN- in about 800 patients around the world (see Table 36.1).
α/β-λ, Toll and interleukin-1 receptor (TIR) domain nuclear
factor (NF)-κB, Toll-like receptor (TLR)-3 pathway, and inter-
leukin (IL)-17 have been identified. Some of these genetic defects MENDELIAN SUSCEPTIBILITY TO
are “conventional” PIDs, associated with a broad range of MYCOBACTERIAL DISEASE: GENETIC
infections, but others provide a molecular explanation for severe DISORDERS OF THE IFN-γ CIRCUIT
pediatric infectious diseases previously thought to be idiopathic
(Table 36.1). These “nonconventional” PIDs may be associated Genetic disorders of the IFN-γ circuit are associated with a
with severe and/or recurrent infections caused by a single family selective susceptibility to weakly pathogenic mycobacteria, such
of microorganisms, a situation strongly contrasting with that as environmental mycobacteria (EM) and/or Bacille Calmette-
for “conventional” PIDs. Standard immunological explorations Guérin (BCG) vaccines, and Salmonella (MSMD, Online
21
are generally normal in these patients, whether they are susceptible mendelian Inheritance in Man [OMIM]: 209950) (Fig. 36.1).
to one or many infectious agents. Despite the lack of a clear These PIDs are caused by mutations in 10 genes involved in
immunological abnormality, infections in these patients are IFN-γ–mediated immunity: IFNGR1 and IFNGR2, encoding the
typically severe, and often fatal. This chapter is devoted to the two chains of the receptor for IFN-γ, a pleiotropic cytokine
description of these PIDs. They include disorders of the IFN-γ secreted by natural killer (NK) and T cells; STAT1, encoding a
circuit associated with the syndrome of mendelian susceptibility transcription factor essential to the IFN-γR signaling pathway;
1,2
to mycobacterial disease (MSMD). Combined disorders of IL12B, encoding the p40 subunit of IL-12 and IL-23, IFN-γ–
IFN-γ- and IFN-α/β-λ-mediated immunity are associated with induced cytokines secreted by macrophages and dendritic cells
mycobacterial and viral diseases. We also describe genetic defects (DCs); IL12RB1, encoding the β 1 chain of the receptor for IL-12
3-9
affecting primarily the TLR-3 pathway. The predominant and IL-23, which is expressed on NK and T cells; NEMO, encoding
infectious phenotype of patients with these defects is herpes NF-κB essential modulator (NEMO), which is involved in the
simplex virus (HSV)-1 encephalitis (HSE) in childhood. We CD40-dependent induction of IL-12; IRF8, encoding an IFN
discovered the first genetic defect associated with severe isolated regulatory factor inducible by IFN-γ; TYK2, which is involved
10
influenza, and mutation of IRF7. We describe four PIDs associ- in IL-12–dependent IFN-γ immunity; and ISG15, encoding an
1,2
ated with impaired signaling downstream from or via the TIR IFN-γ-inducing molecule that acts in synergy with IL-12. The
canonical pathway as a result of mutations of IRAK4, MYD88, MSMD-causing mutations in CYBB affect the respiratory burst
22
NEMO, and NFKBIA. 11-15 Mutations of NEMO and NFKBIA selectively in macrophages. Some mutations of STAT1 and most
also impair the alternative, Toll/IL-1R homologous region (TIR) mutations of NEMO are associated with a much broader range
domain–containing adapter-inducing IFN-β (TRIF)–dependent of infectious diseases (see below), and complete interferon regula-
16
pathway. The principal infectious phenotype of patients with tory factor-8 (IRF8) deficiency is associated with a lack of circulat-
any of these defects is the occurrence of pyogenic bacterial ing monocytes and DCs, and severe clinical disease, mimicking
infections. Finally, we have described a new group of defects combined immunodeficiency (CID). 1,23,24 The molecular and
affecting IL-17 pathways and conferring predisposition to chronic clinical features of MSMD have been reviewed elsewhere. 1
mucocutaneous candidiasis (CMC). 17-20 All these disorders were
Complete IFN-γR1 and IFN-γR2 Deficiencies
KEY CONCEPTS Autosomal recessive (AR) complete IFN-γ receptor 1 (IFN-γR1)
deficiency (OMIM 107470) is caused by recessive null IFNGR1
• New primary immunodeficiencies (PIDs) should be sought in patients mutations precluding the expression of IFN-γR1 on the cell
with unexplained infectious diseases. surface or the recognition of its ligand, IFN-γ, by surface-expressed
• Children with severe infectious diseases should be repeatedly receptors. Affected patients fail to respond to IFN-γ and have
investigated for known and unknown immunodeficiency conditions. high serum concentrations of IFN-γ after infection. Mutations
1
• The exploration of idiopathic infections leads to the discovery of new
PIDs and to a better understanding of immunity to pathogens. of the IFNGR2 gene encoding IFN-γR2 lead to a complete loss
of cellular responsiveness to IFN-γ because of a lack of receptor
509

510 ParT fOur Immunological Deficiencies



TABLE 36.1 New Inherited Disorders
INfECTIONS Inflammatory
Gene form Inheritance Mycobacteria Salmonella Viruses HSE Pyogenic Bacteria fungi EDa Signs
IFNRG1 Amorphic AR ++ + + − − − − N
Hypomorphic AR ++ + − − + − − N
Hypomorphic AD ++ + − − − +/− a − N
IFNGR2 Amorphic AR ++ − + − − − − N
Hypomorphic AR ++ − − − − − − N
IRF8 Amorphic AR ++ − − − − − − N
Hypomorphic AD ++ − − − − − − N
IL12RB1 Amorphic AR ++ ++ − − − +/− b − N
IL12B Amorphic AR ++ ++ − − − − − N
STAT1 Hypomorphic AD ++ − − − − − − N
Hypomorphic AR ++ − + − − − − N
Amorphic AR ++ − ++ + − − − N
Hypermorphic AD − − − − − ++ − N
ISG15 Amorphic AR ++ − − − − − − N
TYK2 Amorphic AR ++ − + − − − − N
+
CYBB Hypomorphic XR ++ − − − − − − N
TLR3 Hypomorphic AD − − + ++ − − − N
UNC93B1 Amorphic AR − − + ++ − − − N
TRAF3 Hypomorphic AD − − + ++ − − − N
TRIF Amorphic AR − − − ++ − − − N
Hypomorphic AD − − − ++ − − − N
TBK1 Hypomorphic AD − − − ++ − − − N
IRF3 Hypomorphic AD − − − ++ − − − N
IRF7 Amorphic AR − − Flu − − − − N
NEMO Hypomorphic XR + + + + ++ + +/− Weak
NFKBIA Hypermorphic AD − + + + ++ + + Weak
IRAK4 Amorphic AR − − − − ++ − − Weak
MyD88 Amorphic AR − − − − ++ − − Weak
HOIL Amorphic AR − − + − ++ − − Strong
HOIP Hypomorphic AR − − + − ++ − − Strong
IL17RA Amorphic AR − − − − + ++ − N
IL17RC Amorphic AR − − − − − ++ − N
IL17F Hypomorphic AD − − − − + ++ − N
ACT1 Amorphic AR − − − − + ++ − N
RORC Amorphic AR ++ − − − − + − N

HSE, herpes simplex encephalitis; EDA, ectodermal anhidrotic dysplasia; AR, autosomal recessive; N, normal; AD, autosomal dominant; VZV, varicella-zoster virus; HSV-1, herpes
simplex virus type 1; XR, X-recessive.
a one patient with AD IFN-γR1 deficiency presented one episode of Histoplasma capsulatum infection, and another patient presented coccidioidomycosis.
b one patient with IL-12Rβ1 deficiency presented one episode of Paracoccidioides brasiliensis infection, and some patients display forms of chronic mucocutaneous candidiasis.


expression or the expression on the cell surface of nonfunctional HSCT is the only curative treatment for these patients but has
receptors (OMIM 147569). All known patients have suffered proven to be associated with an unusually high rate of graft
from disseminated infections caused by EM and/or BCG, with rejection, making transplantation particularly difficult. 1
impaired granuloma formation, all requiring continuous mul-
tidrug therapy (Fig. 36.2A). 1,25 Infections usually began early in Autosomal Recessive Partial IFN-γR1 and
life, often before the age of 3 years. The immunological features IFN-γR2 Deficiencies
of patients with IFN-γR2 deficiency are essentially indistinguish- Fifteen patients from 12 unrelated kindred with AR partial
27
able from those of patients with AR complete IFN-γR1 deficiency. IFN-γR1 deficiency (OMIM 107470) have been identified.
A few of these patients have presented with nontyphoidal sal- Two mutations affecting the extracellular domain of IFN-γR1
monellosis, and one presented with recurrent invasive infections have been identified: V63G and I87T. Founder effects accounted
25
with Listeria monocytogenes. Viral infections caused by cyto- for the recurrence of both mutations. Patients with AR partial
megalovirus (CMV), human herpes virus 8 (HHV-8), respiratory IFN-γR1 deficiency have a less severe clinical phenotype than
syncytial virus (RSV), pseudorabies virus 3 (PRV-3), and varicella- patients with AR complete IFN-γR1 deficiency. Disseminated
zoster virus (VZV) have been described in some patients. One BCG was observed in five patients. One patient, who had not
patient had a fatal HHV-8–driven Kaposi sarcoma, a second had been vaccinated with BCG, had curable symptomatic primary
a pineal germinoma, and a third had a cutaneous squamous cell tuberculosis (TB). Mycobacterium abscessus caused a disseminated
1
carcinoma. Multiple antibiotics against mycobacteria should infection in one patient. Other nonmycobacterial infections caused
be administered without interruption. Vaccination with live BCG by bacteria (Salmonella, Shigella sonnei, Haemophilus influenzae,
is contraindicated. The prognosis is very poor in the absence of Legionella spp., Mycoplasma pneumoniae, and Klebsiella spp.),
25
hematopoietic stem cell transplantation (HSCT). HSCT is best viruses (VZV, RSV, Molluscum contagiosum), and parasites
26
carried out once mycobacterial disease has been controlled. (Toxoplasma gondii, Cryptosporidium) have been reported. The

CHaPTEr 36 Immunodeficiencies at the Interface of Innate and Adaptive Immunity 511


ISG15


p19 IL-12Rβ1 TYK2
Mycobacteria IL-23R JAK2
p40 IL-12Rβ1 TYK2

gp91phox IL-12 p35 IL-12Rβ2 JAK2
NF-κB NEMO
CD40 CD40L
IRF-8 IRF-1
IFNγR1 IFNγ

STAT1 IFNγR2 IFNγR1
IFNγ IFNγR2

Antigen presenting cell T lymphocyte and NK cell
fIG 36.1 Genetic Etiologies of Mendelian Susceptibility to Mycobacterial Disease (MSMD). IL-12 is secreted principally by phagocytes
and dendritic cells (DCs) and binds to a receptor consisting of a heterodimer of β 1 and β 2 chains that is expressed specifically on natural
killer (NK) and T lymphocytes. IFN-γ is secreted by NK and T lymphocytes and binds to a ubiquitous receptor consisting of two chains,
a ligand-binding (IFN-γR1) and a signaling-associated chain (IFN-γR2). Signal transducer and activator of transcription 1 is phosphorylated
in response to IFN-γ and is translocated to the nucleus as a homodimer. Nuclear factor (NF)-κB essential modulator (NEMO) is a
regulatory protein in the NF-κB pathway. The engagement of CD40 signaling via the NF-κB pathway is important for IL-12 production
and for protective immunity against mycobacterial infection. Interferon regulatory factor-8 (IRF8) is an IFN-γ–inducible transcription factor
required for the induction of various target genes, including IL-12. TYK2 is necessary for the response to IL-12 in T lymphocytes and
NK cells. Gp91 phox is a key component of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.

25
affected patients had well circumscribed and differentiated suggestive of AD IFN-γR1 deficiency. Only 5% of the patients
tuberculoid granulomas (Fig. 36.2B). The cellular phenotype is in the largest cohort of patients with heterozygous 818del4 ever
characterized by an impaired response to high concentrations published have presented with nontyphoidal salmonellosis, one
of IFN-γ, with receptor expression on the cell surface. Five has presented a single episode of infection with Histoplasma
mutations in six patients with PR IFN-γR2 deficiency (OMIM capsulatum, eight are asymptomatic, and two died of disseminated
1
147569) have also been reported. Patients have had BCG, M. mycobacterial infection at the ages of 17 and 27 years, respectively.
abscessus, M. bovis, M. elephantis, M. fortuitum, and M. simiae Antimycobacterial antibiotic treatment could be combined with
infections. The patients had high plasma IFN-γ concentrations, IFN-γ injection in cases of disseminated infection. Antibiotics
and various cell types displayed an impaired response to IFN-γ. All can be stopped, but not within the first year after the infection
hypomorphic mutations of IFNGR2 lead to abnormally high levels is brought under control. Vaccination with live BCG is contra-
of N-glycosylation of the corresponding protein and its retention indicated. The clinical outcome of patients with AD IFN-γR1
28
in the endoplasmic reticulum (ER). Thus a diagnosis of PR deficiency, like that of patients with AR partial IFN-γR1 and
IFN-γR1 or IFN-γR2 deficiency should be considered in children IFN-γR2 deficiencies, is much better than that of children with
and adults with mycobacterial infections and a mild clinical and AR complete IFN-γR deficiency because there is some residual
histological phenotype. 1,28 For these patients, antimycobacterial IFN-γ signaling. There is, therefore, a strict correlation between
treatment can eventually be stopped, but not within the first year IFNGR1 genotype and cellular and clinical phenotype. 25
after the infection is brought under control. Recombinant IFN-γ One heterozygous mutation of IFNGR2 has been reported
29
is indicated for the treatment of PR IFN-γR deficiencies. Patients to contribute to an AD form of partial IFN-γR2 deficiency.
should then be closely monitored. HSCT is not indicated, given This mutation, 186delC, creates a premature codon stop upstream
the relatively mild infectious phenotype. 1 from the segment encoding the transmembrane domain. The
affected patient had a mild form of mycobacterial infectious
Autosomal Dominant Partial IFN-γR1 and disease, and her father was asymptomatic. Haploinsufficiency
IFN-γR2 Deficiencies of the IFNGR2 locus was observed in Epstein-Barr virus (EBV)
More than 70 patients were found to have autosomal dominant B cells and T lymphocytes. 29
1
(AD) partial IFN-γR1 deficiency (OMIM 107470). These patients
have a heterozygous small frameshift deletion in IFNGR1, most Complete IL-12Rβ1 and IL-12P40 Deficiencies
bearing the same 818del4 heterozygous mutation (or another More than 200 patients with AR complete IL-12 receptor β1
mutation in the same region), downstream from the segment (IL-12Rβ1) deficiency (OMIN 601604), with no cellular expression
encoding the transmembrane domain, but upstream from the or with expression of the mutated form, have been identified. 1,30
recycling motif and JAK1 and STAT1 docking sites. This hetero- The cellular phenotype of patients with IL-12Rβ1 deficiency is
zygous mutation defines the first hotspot for small deletions. It a lack of response of natural killer (NK) and T lymphocytes to
is dominant negative and decreases cellular responses to IFN-γ IL-12 and IL-23, resulting in low levels of IFN-γ production.
in heterozygous cells and patients. The clinical phenotype is The clinical phenotype is characterized by EM/BCG infections,
characterized by EM and BCG infections, often affecting the with half the patients also presenting nontyphoidal salmonel-
30
bones. 1,25 A diagnosis of mycobacterial osteomyelitis is highly losis. Most of the children inoculated with live BCG vaccine

512 ParT fOur Immunological Deficiencies


produce abnormally low levels of IFN-γ because of a lack of
stimulation through the IL-12R. This defect can be partially
corrected, in a dose-dependent manner, with exogenous recom-
binant IFN-γ. 1,33 All children inoculated with live BCG vaccine
developed clinical infection, and infections caused by EM or M.
tuberculosis have also been reported. Other infections, such as
salmonellosis, klebsiellosis, and nocardiosis, have been described.
Five of the reported patients are asymptomatic. Thirteen of the
50 patients died before the age of 8 years, and one patient died
at the age of 34 years. 1,33
For IL-12p40 and IL-12Rβ1 deficiencies, antibiotic treatment
can be combined with IFN-γ injection in cases of disseminated
1
infection. Antibiotics can be stopped, but not within the first
year after the infection is brought under control. Infectious
Salmonella disease should be treated with antibiotics or with
IFN-γ and antibiotics in patients with recurrent salmonellosis.
Thus a diagnosis of IL-12p40 or IL-12Rβ1 deficiency should be
considered in children and adults with mycobacterial and Sal-
A
monella infections or mycobacterial infections and CMC with
a mild clinical and histological phenotype. The vaccination of
1,33
these patients with live BCG is contraindicated. The prognosis
is, nevertheless, good, partly because of the incomplete clinical
penetrance of primary mycobacterial infection, the favorable
response of infections to treatment, and the rarity of recurrent
or multiple mycobacterial infections. Indeed, children with
primary mycobacterial disease can mount a fully protective
immune response against a secondary mycobacterial disease.
THEraPEuTIC PrINCIPLES
Treatment of Mendelian Susceptibility to
Mycobacterial Disease (MSMD) Patients
• Vaccination with live Bacille Calmette-Guérin (BCG) is contraindicated.
• Multiple antibiotics against mycobacteria should be administered
without interruption in patients with complete interferon (IFN)-γR1 or
B IFN-γR2 deficiency.
• Antimycobacterial antibiotics may be associated with IFN-γ injections
fIG 36.2 Two Types of Granuloma. (A) The lepromatous-like in selected patients with partial IFN-γR1, IFN-γR2, IRF8, CYBB, or
type consists of poorly defined, poorly differentiated granulomas, signal transducer and activator of transcription 1 (STAT1) deficiency,
with few, if any giant cells and lymphocytes, but widespread complete interleukin (IL)-12p40, IL-12Rβ1, or ISG15 deficiency.
macrophages loaded with acid-fast bacilli. (B) The tuberculoid • Hematopoietic stem cell transplantation (HSCT) should be considered
type consists of well circumscribed and differentiated granulomas, in selected patients with complete IFN-γR1 or IFN-γR2 deficiency.
with epithelioid and multinucleated giant cells containing very
few acid-fast rods, surrounded by lymphocytes and fibrosis, Autosomal Dominant Partial STAT1 Deficiency
occasionally with central caseous necrosis. Nine kindreds with 21 genetically affected cases have been reported
to have heterozygous mutations in STAT1 causing AD partial
STAT1 deficiency (OMIM 600555). 1,24 STAT1 is a critical trans-
developed clinical infection, and other mycobacterial infections ducer of IFN-mediated signals, either as STAT1 homodimers
are caused by EM (alone or associated with other infections) or (γ-activating factor [GAF]) or as STAT1/ STAT2/IRF9 trimers
by M. tuberculosis. The low penetrance for the case-definition (IFN-stimulated gene factor 3 or ISGF3) (Fig. 36.3). These
phenotype of BCG/EM disease led to the discovery of tuberculosis heterozygous STAT1 mutations reduce the cellular response to
24
as the sole infectious phenotype in several patients, providing IFN-γ, but not that to IFN-α. Mycobacterial infections caused
the first cases of mendelian predisposition to tuberculosis. by BCG, EM, or TB are observed, ranging from local to dis-
Infections caused by Paracoccidioides brasiliensis, Coccidioides seminated disease. Osteomyelitis is frequent in these patients
1
spp., Histoplasma spp., Cryptococcus neoformans, Toxoplasma (eight of 15 patients). The other six patients are asymptomatic.
spp., and Leishmania spp. have been reported in a few cases. A All patients were well at their last evaluations and were between
substantial fraction of patients with IL-12Rβ1 deficiency present four and 38 years old in 2005. Antimycobacterial treatment can
mild forms of CMC, 30-32 an observation probably related to the be stopped, but not during the first year after the infection is
impairment of the IL-23–IL-17 circuit in these patients. All the brought under control. Vaccination with live BCG is contrain-
survivors were well in 2010, when the oldest of these patients dicated. Observations of affected patients have suggested that
was 51 years old. 1,30 STAT1 and GAF are required for human IFN-γ-mediated
Fifty patients with AR complete IL-12p40 deficiency (OMIM mycobacterial immunity. In conclusion, patients with AD STAT1
161561) have been reported. 1,33 Children with this deficiency deficiency have clinical and cellular phenotypes (i.e., susceptibility

CHaPTEr 36 Immunodeficiencies at the Interface of Innate and Adaptive Immunity 513


IFN-γ IFN-α/β other infectious agents. In two other patients with a history of
pure MSMD, the same heterozygous mutation, T80A, was found
23
in IRF8, defining an AD IRF8 deficiency. The mutation was
severely hypomorphic and dominant negative. Interestingly, the
IFN-γ circuit did not appear to be disrupted in tests on whole
blood. Nevertheless, the two unrelated patients with AD IRF8
23
cytoplasmic deficiency lacked circulating CD1c CD11c DCs. This population
membrane of cells produces large amounts of IL-12 in normal individuals,
and its absence therefore probably contributed to the MSMD
phenotype.
AR Complete ISG15 Deficiency
STAT-1/STAT-1 STAT-1/STAT-2/IRF-9 Recently, six patients with complete AR ISG15 deficiency have
(GAF) (ISGF-3) nucleus been identified (OMIM 616126). 34,35 Three of the six patients
membrane
suffered from clinical disease caused by BCG vaccine. The only
features common to all patients were calcifications of the basal
ganglia in the brain. The cellular phenotype was characterized
by an impaired, but not abolished, IFN-γ production upon whole
GAS ISRE blood activation by BCG plus IL-12, as seen in patients with
antimycobacterial immunity antiviral immunity IL-12p40 or IL-12Rβ1 deficiency. 1,34,35 The addition of recom-
binant ISG15 rescued the production of IFN-γ by T and NK
fIG 36.3 STAT-1 Pathway. The binding of homodimeric IFN-γ
to its tetrameric receptor leads to activation of the constitutively cells of the patients. A high level of ISG mRNA was detected in
associated JAK kinases JAK1 and JAK2, which then phosphorylate all patients with ISG15 deficiency. The absence of intracellular
tyrosine residues in the intracellular part of interferon (IFN)-γR1. ISG15 in the patients’ cells prevents the accumulation of USP18,
Upon IFN-γ stimulation, unphosphorylated signal transducer and a potent regulator of IFN-α/β signaling, and amplifies the IFN-α/β
activator of transcription 1 (STAT1) molecules are directly recruited induced responses. This novel MSMD-causing gene acts like
to IFN-γR1 docking sites. They are then phosphorylated and both an IFN-γ–inducing secreted cytokine and an intracellular
34,35
released into the cytosol as phosphorylated STAT1 homodimers. negative regulator of IFN-α/β. These patients display not
These homodimers form γ-activating factor (GAF), which is only MSMD but also a novel form of type I interferonopathy
translocated to the nucleus. GAF binds γ-activating sequences because intracellular human (but not mouse) ISG15 is paradoxi-
(GAS) present in the promoters of target genes. Following cally a negative regulator of IFN immunity.
monomeric IFN-α/β stimulation, STAT2 is recruited to the AR Complete TYK2 Deficiency
phosphorylated IFN-αR1 chain of the heterodimeric IFN-αR, which
is in turn phosphorylated by JAK1 and TYK2. This leads to the AR complete TYK2 deficiency was first described in a Japanese
phosphorylated STAT2-mediated recruitment of STAT1, which patient as a genetic etiology of hyper-immunoglobulin E (IgE)
is then phosphorylated. Active phosphorylated STAT1/STAT2 syndrome in 2006 (OMIM 176941). However, five more families
2
heterodimers are released into the cytosol and translocated to and seven more patients have since been described. The patients
the nucleus with interferon regulatory factor-9 (IRF-9), to form harbor homozygous nonsense mutations, deletions, or insertions
interferon-stimulated gene factor-3 (ISGF-3) heterotrimers. ISGF-3 generating a premature stop codon and resulting in undetectable
2,36
binds IFN-α/β sequence response elements (ISRE) in the promot- levels of the TYK2 protein. Clinically, all the patients display
ers of target genes via the DNA-binding domains of STAT1 and mycobacterial and/or viral diseases, which appear to be the main
IRF9. In humans, recessive complete STAT1 deficiency results clinical features of AR complete TYK2 deficiency. One patient
in impaired responses to both IFN-γ and -α/β. It is associated suffered only from BCGosis, two only from tuberculosis, one
with a specific syndrome, different from mendelian susceptibility only from HSV meningitis, three had mycobacterial and viral
to mycobacterial disease (MSMD), of susceptibility to both diseases, and one had meningitis of unknown origin, although
mycobacteria (impaired IFN-γ-mediated immunity) and viruses all were vaccinated with BCG and had probably encountered
2
(impaired IFN-α/β-mediated immunity). the common viruses of childhood. The patients’ cells display
an impaired, but not abolished response to IL-12/IL-23 and
IFN-α/β, almost certainly accounting for their susceptibility to
to mycobacterial disease, osteomyelitis in particular, and impaired mycobacteria and viruses, respectively. The response to IL-10 is
GAF activation) similar to those of patients with AD IFN-γR1 weak, but with no overt clinical manifestations. An impaired
deficiency. These patients should be treated in a similar manner. 1 response to IL-23 is also observed, preventing the differentiation
of abolished CD4 T cell response into Th17 cells in vitro, but
Complete and Partial IRF8 Deficiency the patients have normal levels of circulating IL-17 T cells,
+
2
Two types of IRF8 deficiency have been reported in the last few probably accounting for their lack of CMC. An intact response
23
years (OMIM 601565). Disseminated BCG disease in a child to IL-6 has been observed in all patients except for the first
born to consanguineous parents led to the discovery of a lack patient described, who displayed the symptoms of hyper-IgE
of circulating monocytes and DCs. The severity of the disease, syndrome. The impaired response to IL-6 in this patient was
mimicking CID, rendered HSCT necessary. 1,23 Candidate gene found to be independent of WT-TYK2 expression, potentially
studies showed that the child had AR complete IRF8 deficiency. accounting for some of the unusual clinical features in this patient.
The IFN-γ circuit was, therefore, profoundly disrupted. Other Overall, AR complete TYK2 deficiency leads to isolated or
mechanisms may account for BCG disease and vulnerability to combined mycobacterial and viral diseases. 2

514 ParT fOur Immunological Deficiencies


and possibly antiviral treatment directed against herpes viruses
NEMO and CYBB Deficiencies should be administered without interruption, and HSCT should
An X-linked recessive (XR) form of MSMD (XR-MSMD) (OMIM be considered for these patients. Vaccination with live BCG is
300248) was discovered in three unrelated kindreds. This condition contraindicated. Partial, as opposed to complete, AR STAT1
24
was caused by two neighboring mutations (E315A and R319Q) deficiency has also been described in three unrelated kindreds.
in NEMO. 1,37 These two missense mutations, which affect two These patients suffered from mild mycobacterial and viral diseases.
neighboring residues in the leucine zipper domain that normally Their responses to IFN-γ and IFN-α were impaired, but not
form a salt bridge, were entirely responsible for impairment of abolished, in terms of GAF- and ISGF3-mediated immunity. AR
the CD40-triggered induction of IL-12 production by monocyte- complete and partial STAT1 deficiencies constitute an innate
derived cells following stimulation with CD40L-expressing T immunodeficiency, ranging from lethal to moderate clinical
cells. Four maternally related male patients from two successive disease, and a diagnosis of STAT1 deficiency should be considered
generations presented M. avium infection only, and the other two, in infants and children with infectious diseases, particularly (but
unrelated patients presented only mycobacterial disease. These not exclusively) if mycobacterial and viral in nature. 24
patients had a purely mycobacterial infectious phenotype, with
no sign of anhidrotic ectodermal dysplasia (EDA). 1,37 GENETIC DISORDERS OF THE TLR3–IFN-α, IFN-β,
A second form of XR MSMD has been reported (OMIM AND IFN-λ PATHWAY
22
300645) in seven patients from two unrelated French families.
The CYBB or gp91 phox mutations identified in these patients were This group of genetic disorders leads to impaired TLR3 signaling
previously unknown and affect the transmembrane domain and and susceptibility to HSE in childhood. The affected patients bear
an extracellular loop. CYBB encodes the major component of mutations of TLR3, UNC93B1, TRIF, TRAF3, TBK1, or IRF3
the nicotinamide adenine dinucleotide phosphate (NADPH) (Fig. 36.4). The TLR3 signaling pathway is mediated exclusively
22
oxidase complex. Mutations in any of the genes encoding by the TRIF adapter and leads to activation of the transcription
39
molecules from this complex generally result in chronic granu- factors IRF3 and NF-κB (see Fig. 36.4). TRIF recruits TNF
lomatous disease (CGD). However, unlike the cells of patients receptor–associated factor 6 (TRAF6) and activates TAK1 for
with CGD, neutrophils, monocytes, and monocyte-derived NF-κB activation. TRIF also recruits a signaling complex involving
39
dendritic cells (MDDCs) from these seven patients with XR TBK1 and IKKε via TRAF3 for IRF3 activation. This signaling
MSMD displayed perfectly normal levels of NADPH oxidase pathway induces the production of type I and type III IFNs and
39
22
activity. These patients produce only small amounts of neu- inflammatory cytokines and is important in antiviral immunity.
trophil and monocyte gp91 phox protein, but normal amounts of UNC-93B is a 12-transmembrane domain protein present in
cytochrome b 558 . However, monocyte-derived macrophages and the ER that delivers the nucleotide-sensing receptors TLR3, -7,
EBV-B cells display much more profound defects of gp91 phox -8, and -9 from the ER to endolysosomes. TRAF-3, TBK1, and
expression, resulting in impaired cytochrome b 558 assembly and IRF3 have functions downstream from multiple tumor necrosis
22
low levels of NADPH oxidase activity. Thus NADPH oxidase factor (TNF) receptors and the receptors inducing IFN-α, -β,
activity in human macrophages is a crucial effector mechanism and -λ production, including TLR3.
for protective immunity to tuberculous mycobacteria. None of
the seven patients suffered from any other infectious diseases. TLR3 Deficiency
These patients are all adults and are currently well. Vaccination AD and AR forms of TLR3 deficiency caused by heterozygous,
with live BCG is contraindicated in patients with these deficiencies. compound heterozygous, or homozygous mutations of TLR3
4,8
None of the patients described, to date, has had prophylactic were first identified in 2007 (OMIM 613002). Six patients from
treatment. Infections can be treated with multiple antibiotics. 1 six unrelated kindreds have been reported, and each of these
patients developed childhood HSE as a result of AR or AD,
INHERITED DISORDERS OF IFN-γ– AND complete or partial TLR3 deficiency. There is a high degree of
IFN-α/β–MEDIATED IMMUNITY allelic heterogeneity, with three AD partial defects resulting from
negative dominance or haploinsufficiency, and two AR defects
AR Complete and Partial STAT1 Deficiency resulting from complete or partial deficiency. Some subsets of
Nine children from six unrelated kindreds with AR complete blood leukocytes (MDDCs, NK cells, and CD8 T cells) from
24
STAT1 deficiency (OMIM 600555) have also been identified patients with TLR3 deficiency have an impaired response to
8,40
(unpublished data). These patients carried homozygous mutations stimulation with TLR3 agonist. The fibroblasts of the patients
that completely abolished cellular responses to both IFN-γ and produce low levels of the antiviral molecules IFN-β/-λ in response
IFN-α/β. Responses to IL-27 and IL-29 (IFN-λ) were abolished, to TLR3 agonist and HSV-1, leading to higher levels of viral
potentially accounting for the susceptibility of these children to replication and virus-induced cell death than for healthy control
bacteria and viruses, respectively. All patients had disseminated cells. Only one child from each of the kindreds identified
BCG disease. One patient died from recurrent encephalitis caused developed HSE. The patients with TLR3 deficiency developed
by HSV, a second died from an undocumented illness thought HSE upon primary infection with HSV-1 during childhood. Four
to be of viral origin, and a third died 3 months after HSCT, from (66%) of the six patients with TLR3 deficiency had at least one
EBV-induced lymphoproliferative disorder. The principal causes late relapse of HSE, whereas relapse generally occurs in only
8
of death in children with AR complete STAT1 deficiency are about 10% of HSE patients. All patients with HSC who had
38
viral diseases or disseminated infection with BCG (unpublished TLR3 deficiency were exposed to other viruses during many
data). The outcome of viral illnesses in children with AR complete years of follow-up, as shown by the positive serological results
STAT1 deficiency suggests that the STAT1-dependent response obtained for other herpes viruses, with no subsequent acute
8
to human IFN-α/β is necessary for viral immunity. The patients events. None of the other individuals from the six kindreds
with AR complete STAT-1 deficiency had multiple, severe, early- with dominant or homozygous hypomorphic TLR3 mutations
onset viral infections. Multiple antibiotics against mycobacteria developed HSE despite serologically documented HSV-1 infection.

CHaPTEr 36 Immunodeficiencies at the Interface of Innate and Adaptive Immunity 515


TLR-1, 2, 5, 6, 10 IL-1Rs
RANK/ TLR-4
VEGFR3/ TNFR-S
EDAR TCR/BCR
MD2







TLR-7,
8, 9
MyD88
TRIF
TLR-3
UNC-93B
TRAF3
IRAK4 UNC-93B
IRAK1 IKK
NEMO TBK1
IKK
αβ
p p Iκ Bα
Iκ Bα
Iκ Bα Iκ Bα MAPK IRF3
κ
B
α
I
Iκ Bα
NF-κB p50 p65 p50 p65
p50 p65 AP1 IRF3
IL-6, IL-1, TNFα IL-6, IL-1, TNFα IFNβ

fIG 36.4 Human Defects Involving the Interferon (IFN)-α/-β, IFN-λ and Nuclear Factor (NF)-κB
Pathways. Immune receptor signaling pathways leading to NF-κB activation can be grouped into
four categories on the basis of the surface receptors involved: the developmental receptors
RANK, VEGFR3, and EDAR; antigen receptors (T-cell receptor [TCR] and B-cell receptor [BCR]);
members of the tumor necrosis factor (TNF) receptor superfamily (TNF-Rs) and members of the
TIR superfamily (IL-1Rs/TLRs). The two proteins of the Toll/IL-1R (TIR) signaling pathway (MyD88,
IRAK-4) and the two proteins of the NF-κB signaling pathway (NEMO and IκBα) responsible for
primary immune deficiencies (PIDs) are shown in red. UNC-93B defects abolish cellular responses
to TLR3 and 7–9 agonists. TNF receptor–associated factor 3 (TRAF3) defects impair the cellular
responses to TLR3 and other pathways. The three proteins of the TLR3 signaling pathway (TLR3,
UNC-93B, and TRAF3) responsible for PIDs are shown in red.

Childhood-onset HSE is, therefore, caused by TLR3 deficiency deficiency developed HSE. The first patient presented recurrent
in an identifiable fraction of patients, particularly those displaying episodes of HSE at the ages of 11 months, 14 months, and 3 2
1
HSE recurrence. Treatment with recombinant IFN-α, in parallel years. During 14 years of follow-up, this patient has experienced
with acyclovir, may help improve the outcome in patients with no subsequent acute events. The second patient presented recur-
TLR3 deficiency and HSE. TLR3 deficiency displayed complete rent episodes of HSE at the ages of 5 and 17 years. She is now
penetrance at the cellular level but incomplete penetrance at the 21 years old, and her clinical status has not worsened since the
clinical level. Multiple factors may affect clinical penetrance, second episode of HSE. One sibling of the second patient, who
including age at infection with HSV-1, the viral inoculum, and carries the same homozygous mutation in UNC93B1, is now 30
human modifier genes. 8 years old and has not developed HSE, despite serologically
documented HSV-1 infection. The two patients with UNC-93B
UNC-93B Deficiency deficiency and HSE have been exposed to other viruses with no
3
AR complete UNC-93B deficiency was identified, in 2006, as the evident clinical manifestations. Treatment with recombinant
3
first genetic etiology of isolated HSE (OMIM 610551). Three IFN-α may also be considered, in parallel with acyclovir, in
individuals from two consanguineous kindreds were found to patients with UNC-93B deficiency and HSE.
carry homozygous mutations of UNC93B1. UNC-93B-deficient
fibroblasts and leukocytes did not respond to TLR3, or to TLR7-9 TRIF Deficiency
agonists, respectively, in terms of IFN-α, -β, and -λ production. The subsequent discovery of AR and AD TRIF deficiencies in
Fibroblasts from patients with UNC-93B deficiency displayed children with HSE completely validated the essential role of
abnormally high levels of viral replication and cell death after human TLR3 immunity in anti-HSV-1 defense in the central
3
7
infection with HSV-1. Two of the three individuals with UNC-93B nervous system (CNS). A patient with AR TRIF deficiency, born

516 ParT fOur Immunological Deficiencies


to consanguineous Saudi parents, suffered from HSE at the age fibroblasts from both patients displayed normal IFN responses
6
of 2 years. A homozygous nonsense mutation, R141X, was to the TLR3-independent agonists and viruses tested. AD TBK1
7
identified as the cause of her AR TRIF deficiency. Another patient, deficiency, therefore, confers narrow, partial cellular phenotypes,
with AD TRIF deficiency, of mixed European descent (French, probably accounting for the narrow clinical phenotype of
Portuguese, and Swiss), suffered from HSE at the age of 21 months. these patients, which is limited to HSE. The two patients with
A heterozygous missense mutation, S186L, led to AD TRIF TBK1 deficiency suffered from HSE at the ages of 7 years and
7
deficiency in this girl. . The two patients with TRIF deficiency 11 months, respectively. During subsequent follow-up over a
have displayed no other unusually severe infectious diseases period of years, they have suffered no other unusual infectious
during follow-up to date. The TLR3 signaling pathway was found diseases, including viral diseases, in the absence of prophylaxis.
to be impaired in cells from patients with both AR and AD TRIF As in other HSE patients with genetic deficiencies of the TLR3
deficiencies, whereas the TRIF-dependent TLR4 pathway was pathway, treatment with recombinant IFN-α, in parallel with
affected only in patients with AR TRIF deficiency. Interestingly, acyclovir, may be considered in patients with TBK1 deficiency
abnormally weak responses to stimulation of the DExD/H-box and HSE.
helicase pathway have been observed in both AR and AD TRIF-
deficient fibroblasts. These results demonstrate the importance IRF3 Deficiency
of TRIF for the TLR3-dependent production of antiviral IFNs IRF3 is a transcription factor that controls multiple IFN-inducing
7
in the CNS during primary infection with HSV-1. However, pathways, including the TLR3 pathway, which can be triggered
they also suggest that the TRIF-dependent TLR4 and, probably, by dsRNA, and the pathways triggered by other RNA and DNA
the DExD/H-box helicase pathways, are largely redundant in sensors. IRF3 is normally activated by TBK1 and/or IKKε kinases.
host defense in humans. A missense IRF3 mutation has been identified in a 15-year-old
9
patient with HSE. The resulting mutant IRF3 protein could not
TRAF3 Deficiency activate transcription and was dominant through haploinsuf-
A French patient with AD TRAF3 deficiency and HSE has recently ficiency. In heterozygous cells, haploinsufficiency for IRF3 impairs
5
been identified. The de novo germline heterozygous missense the induction of antiviral IFN-α/β in leukocytes following
mutation in this patient is loss-of-expression, loss-of-function, stimulation with various agonists. Moreover, the induction of
and dominant-negative. Fibroblasts from the patient displayed IFN-β in fibroblasts stimulated with poly(I:C), which mimics
impaired responses to TLR3 agonist stimulation, in terms of viral dsRNA and activates TLR3, was also impaired. Finally, IFN-β
IFN-β and -λ production. Various TRAF3-dependent pathways induction by HSV1 was impaired in fibroblasts. Overall, consistent
were impaired in the patient’s cells, including the IFN-α/β-, and with the key role of IRF3 in inducing IFN-α/β, a profound,
IFN-λ–inducing and TNF-R–responsive pathways. However, broad cellular phenotype was observed in patients with AD IRF3
there was sufficient residual TRAF3-dependent signaling for most deficiency. Despite the broad impact of AD IRF3 deficiency, in
defects to remain clinically silent. By contrast, the impaired TLR3 terms of both the pathways and cell types affected, its clinical
response was symptomatic and caused HSE, implying that the phenotype in the single patient identified to date is surprisingly
9
TLR3 pathway is critically dependent on TRAF3 and essential narrow, restricted to HSE. Moreover, clinical penetrance is
for immunity to HSV-1 in the CNS. The first clinical signs of incomplete, as a heterozygous relative of the patient is healthy.
HSE in the patient with TRAF3 deficiency appeared at the age Overall, the discovery of IRF3 deficiency in a patient with HSE
of 4 years. The patient with TRAF3 deficiency and HSE described suggests that IRF3 is a key component in TLR3-dependent,
here is now 18 years old and has otherwise remained healthy IFN-mediated, CNS-intrinsic immunity to HSV-1. It also adds
5
with no prophylaxis. She shows normal resistance to other weight to the emerging notion that impaired TLR3-IFN immunity
5
infectious diseases, including viral diseases, in particular. We can underlie HSE of childhood, suggesting that IFN treatment
cannot yet exclude the possibility that other forms of human may be beneficial to patients. 9
TRAF3 deficiency are involved in other human diseases, including
viral diseases, but TRAF3 deficiency should be sought in other IRF7 Deficiency
children with HSE. AR complete IRF7 deficiency was identified, in 2015, as the first
10
genetic etiology of severe isolated influenza (OMIM 616345).
TBK1 Deficiency A 30-month-old girl born to nonconsanguineous French parents
The identification of AD TBK1 deficiency as a new genetic was admitted to intensive care for 3 weeks and required respiratory
etiology of isolated childhood HSE was probably the greatest support for 10 days because of pandemic H1N1 (pH1N1) 2009
6
surprise to come out of human studies to date. TBK1 is a kinase influenza A virus (IAV)–induced acute respiratory distress
at the crossroads of multiple IFN-inducing signaling pathways, syndrome. This patient carries compound heterozygous mutations,
10
including those mediated by TLR3, cytosolic double-stranded RNA p.F410V and p.Q421X, in IRF7, encoding IRF7. Each of her
(dsRNA) sensors, and dsDNA sensors. Two unrelated children parents has a single heterozygous mutation, and neither has any
with HSE were found to carry different heterozygous missense significant infectious disease history. IRF7 is required for the
mutations in the gene encoding TBK1. Both mutations underlie production and amplification of the antiviral type I (IFN-α/β)
a phenotype that is dominant, but presumably by different and III (IFN-λ) IFNs. The patient’s fibroblasts displayed impaired
mechanisms: negative dominance (G159A) and haplotype insuf- IFN-β and IFN-λ1 production in response to various stimuli,
ficiency (D50A). A defect in poly(I:C)–induced TLR3 responses including IAV. Consequently, IAV replication resulted in titers
was detected only in fibroblasts from the patient carrying the 100 times higher in the patient’s fibroblasts than in fibroblasts
6
dominant-negative TBK1 mutation. Nevertheless, levels of viral from a healthy donor. Furthermore, type I IFN production was
replication and cell death caused by two TLR3-dependent viruses abolished in the patient’s plasmacytoid DCs, a cell type that
(HSV-1 and VSV) were high in fibroblasts from both patients. normally produces constitutively high levels of IRF7 and, therefore,
However, the peripheral blood mononuclear cells (PBMCs) and large amounts of type I IFN. Moreover, pulmonary epithelial

CHaPTEr 36 Immunodeficiencies at the Interface of Innate and Adaptive Immunity 517


cells differentiated in vitro from patient-specific induced plu-
ripotent stem cells displayed uncontrolled virus replication and
impaired IFN-β production. The patient had no other serious
viral infections despite being seropositive for a myriad respiratory
10
viruses and is currently healthy at the age of 8 years. Thus the
IRF7-dependent IFN amplification pathway is crucial for the
mounting of antiviral responses to influenza virus but may be
redundant for other viruses.

GENETIC DISORDERS OF
NF-κB–MEDIATED IMMUNITY A

This group of inherited disorders leads to impaired NF-κB signal-
ing and strong susceptibility to pyogenic bacteria. Affected patients
bear mutations of NEMO, NFKBIA, IRAK4, MYD88, HOIL1, or
HOIP (see Fig. 36.4). 16,41,42 Patients with ectodermal dysplasia,
anhidrotic (EDA) and immunodeficiency (EDA-ID) syndrome
carry either XR hypomorphic mutations of NEMO, AD hyper-
morphic mutations of NFKBIA, or AR amorphic mutations of
43
IKKB. Diverse mutations have been found in NEMO, associated B
with various cellular and clinical phenotypes (see above and fIG 36.5 Patients With Anhidrotic Ectodermal Dysplasia and
44
below). Patients with AR amorphic mutations of IRAK4 or Immunodeficiency (EDA-ID). Two patients with EDA-ID, one
MyD88 present a more restricted, purely immunological defect, with widely spaced cone- or peg-shaped teeth (A), the other
with specific impairment of the TIR-IL receptor–associated kinase having conical incisors (B).
13
(IRAK) signaling pathway. Patients with NEMO, IκBα, IKKB,
HOIL1, or HOIP deficiencies are susceptible to multiple infectious
agents, including pyogenic bacteria, mycobacteria, and viruses. of patients with NEMO deficiency do not display any of the
By contrast, patients with IRAK-4 or MyD88 deficiencies seem classic features of the EDA phenotype. 16
to be specifically prone to pyogenic bacterial diseases. Prophylactic trimethoprim–sulfamethoxazole and/or penicillin
V treatment should be considered and IgG substitution should
NEMO Deficiency be carried out in patients with NEMO deficiency presenting an
XR-EDA-ID is a rare PID associated with a developmental disorder impairment of B-cell immunity. Patients with functional B-cell
(OMIM 300291). Patients with XR-EDA-ID carry hypomorphic immunity should be immunized with S. pneumoniae conjugated
mutations of IKBKG, which encodes IKK-γ/NEMO, a protein and nonconjugated vaccines, H. influenzae conjugated vaccine,
essential for activation of the ubiquitous transcription factor and N. meningitidis conjugated and nonconjugated vaccines.
NF-κB. Up to 100 patients with NEMO deficiency have been Vaccination with live BCG is contraindicated. It is important to
reported. 16,43 The only known consistent immunological abnor- initiate empiric parenteral antibiotic treatment against S. pneu-
mality in patients with NEMO deficiency is an absence of serum moniae, Staphylococcus aureus, Pseudomonas aeruginosa, and H.
antibodies against carbohydrates, which has been found in most influenzae as soon as infection is suspected or the patient develops
of the patients described to date. Some patients have hyper-IgM a moderate fever, without taking inflammatory parameters into
syndrome, and a few have NK-cell abnormalities. Most patients account, as patients may die of rapid invasive bacterial infection
with NEMO deficiency fail to produce IL-10 in response to despite appropriate prophylaxis. HSCT should be considered for
16
activation with TNF-α in whole-blood assays. 16 patients with severe infectious and cellular phenotypes (Picard
The infectious phenotype of the other NEMO-deficient unpublished).
patients is characterized mostly by infections caused by encap-
sulated pyogenic bacteria, such as H. influenzae and Streptococcus IκBα Deficiency
pneumoniae. Infections caused by weakly pathogenic microorgan- Ten patients with three different hypermorphic mutations of
isms, such as M. avium and M. kansasii, have also been diagnosed NFKBIA, which encodes an inhibitor of NF-κB (OMIM 164008),
16
in patients. Other infectious diseases, including salmonellosis, have been identified since 2003, one of whom displays complex
Pneumocystis pneumonia, and viral illnesses caused by HSV and partial mosaicism. 15,16 IκBα deficiency can lead to an impairment
CMV, have been reported. Infectious episodes were marked by of T-cell receptor (TCR) signaling in 70% of patients, and all
44
a poor clinical and biological inflammatory response. One-third have impaired TNF receptor (TNFR) and IL1R/TLR responses.
of the patients with NEMO deficiency died from invasive infection, Patients with IκBα deficiency have dysgammaglobulinemia and
44
demonstrating the severity of this disorder. About 80% of the impaired production of specific antibodies. Some also have low
patients with NEMO deficiency described to date have had proportions of memory CD4 or CD8 T cells or both, excess
EDA-ID, which is characterized by hypohidrosis, widely spaced naïve T cells, or an absence of TCRγ/δ T cells. With the exception
16
cone-shaped or peg-shaped teeth, and hypotrichosis (Fig. 36.5). of two patients with IκBα deficiency, one with complex mosaicism
These features result from defective signaling via the ectodysplasin and one with S36Y mutation, all patients have been found to
16
receptor signaling pathway. In some other patients with NEMO have the features of EDA. All 10 patients with IκBα deficiency
deficiency, osteopetrosis (O) and lymphedema (L) have been have developed recurrent bacterial infections: pneumonia in five
16
found associated with the EDA phenotype. Some patients also cases, sepsis or meningitis in three cases, and arthritis in one
have dysmorphia with mild frontal bossing. However, about 10% case. They are also prone to opportunistic infections, six of these

518 ParT fOur Immunological Deficiencies


patients having had Pneumocystis pneumonia and CMC. Finally, disease, resulting in the deaths of 20 of the 49 known patients,
some patients presented with recurrent diarrhea and/or colitis. all of whom died before the age of 8 years. Eleven of these patients
Thus a diagnosis of IκBα deficiency should be considered in died from invasive pneumococcal disease. There is an overall
children with EDA and CID with impaired T-cell immunity. A trend toward improvement with age, as shown by the seven adult
preventive treatment, including antibiotic prophylaxis with patients doing well with no treatment at ages of 18 to 37 years.
trimethoprim–sulfamethoxazole and/or penicillin V, should be Patients with IRAK-4 deficiency should also be immunized
proposed and IgG substitution should be carried out in patients with S. pneumonia, H. influenzae, N. meningitidis conjugated
with IκBα deficiency. The recommendations for febrile patients vaccine (and also nonconjugated vaccine when available). A
with NEMO deficiency should also be applied to patients with preventive treatment, including antibiotic prophylaxis with
IκBα deficiency. HSCT has been reported in four patients with cotrimoxazole plus penicillin V, should be administered through-
severe IκBα deficiency causing CID. 45,46 out the life of the patient. Given the severity of bacterial infection
during childhood and the defective antibody production found
IL-1 Receptor–Associated Kinase-4 Deficiency in some patients with IRAK-4 deficiency, we also recommend
Inherited IRAK-4 deficiency (OMIM 607676) is an AR disorder the administration of empiric IgG replacement until the patient
11
first described in 2003. In total, 49 patients have since been is at least 10 years old. This prophylaxis seems to decrease the
13
identified, from 32 kindreds. 13,16 The blood cells of the patients incidence of invasive bacterial infections. It is important to
fail to produce the proinflammatory cytokines IL-1β and IL-18 initiate empiric parenteral antibiotic treatment against S. pneu-
upon stimulation with all known TLR agonists (with the exception moniae, S. aureus, and P. aeruginosa as soon as an infection is
of TLR3 agonists). Patients with IRAK-4 deficiency seem to have suspected or if the patient develops a moderate fever, without
normal antigen-specific T- and B-cell responses, as shown in taking inflammatory parameters into account because patients
routine immunological investigations, with two notable excep- may die of rapid invasive bacterial infection despite appropriate
47
tions. First, the glycan-specific IgG and IgM antibody responses prophylaxis. A diagnosis of IRAK-4 deficiency should be con-
to pneumococcal and AB glycans (allohemagglutinins of the sidered in children presenting with recurrent pyogenic infection
ABO system) are impaired in up to one-third of the cases and poor inflammatory responses.
13
explored. Second, serum IgE and IgG4 concentrations are high
in up to two-thirds and one-third, respectively, of patients tested. 13 MYD88 Deficiency
MyD88 deficiency is an AR disorder recently described in 22
THEraPEuTIC PrINCIPLES patients (OMIM 612260). 12,13,16 Patients with MyD88 deficiency
Patients with Inherited Disorders of Toll and IL-1 display a lack of production of IL-6 by whole blood and no
CD62L shedding from granulocytes following activation with
Receptor (TIR)-Mediated Immunity most of the TLR and IL-1R agonists tested, with the exception
12
• Patients should receive conjugated and nonconjugated vaccines against of TLR3, which signals through a MyD88-independent pathway.
encapsulated bacteria (Pneumococcus, H. influenzae, Thus there seems to be no overt defect of leukocyte development
Meningococcus). in patients with MyD88 deficiency, and antigen-specific T- and
• A preventive treatment, including antibiotic prophylaxis with cotri- B-cell responses appear to be normal, as shown by routine
moxazole plus penicillin V, should be administered throughout the life immunological analyses, in most cases. Serum IgE and IgG4
16
of the patient. concentrations were high in up to one-half and one-third,
• Monthly prophylactic administrations of intravenous or subcutaneous 13
immunoglobulins should be considered in selected patients. respectively, of the patients tested. Some of the modest, subclini-
• Empiric parenteral antibiotic treatment against Streptococcus pneu- cal abnormalities of B-cell responses observed, such as the
moniae, Staphylococcus aureus, and Pseudomonas aeruginosa should production of low levels of antibodies against carbohydrates in
be initiated as soon as an infection is suspected or if the patient some patients, may thus reflect impaired TACI responses, rather
develops a moderate fever, without taking inflammatory parameters than impaired TLR and IL-1R responses. MyD88 deficiency, like
into account. IRAK-4 deficiency, confers a predisposition to severe bacterial
• Hemopoietic stem cell transplantation (HSCT) should be considered infection, with impairment of the ability to increase plasma
in selected patients with NEMO and IκBαα deficiency.
C-reactive protein (CRP) concentrations and to mount fever at
the beginning of infection. However, pus formation has been
IRAK-4–deficient patients suffer from recurrent infections observed at various sites of infection.
caused by pyogenic bacteria, mostly S. pneumoniae, S. aureus, Patients with MyD88 deficiency present a narrow susceptibility
16
and P. aeruginosa, with little or no fever or inflammatory to invasive pyogenic bacterial infections. S. pneumoniae was
13
response. The leading pathogen responsible for infections in involved in 41% of the documented invasive episodes in patients
these patients is S. pneumoniae, which was found in half the with MyD88 deficiency, whereas S. aureus and P. aeruginosa
cases of documented invasive infection (septicemia, meningitis, were found in 20% and 16% of such episodes, respectively.
abscesses, or arthritis), whereas S. aureus and P. aeruginosa were Most patients with MyD88 deficiency suffered from their first
found in 14% and 19% of such episodes, respectively. Patients bacterial infection before the age of 2 years. Nine patients died
with IRAK-4 deficiency also suffer from noninvasive pyogenic from invasive bacterial infections, all before the age of 4 years,
16
bacterial infections, mostly affecting skin and upper respiratory and most before the age of 1 year. Seven of these patients died
tract, with necrotizing infections particularly common. The from invasive pneumococcal disease. However, MyD88 deficiency
principal bacterial strains isolated during noninvasive infections seems to improve with age, and none of the patients has presented
13
in patients with IRAK-4 deficiency are S. aureus in 43% of invasive bacterial infection after adolescence. MyD88 deficiency
episodes, P. aeruginosa in 22% of episodes, and S. pneumonia in also confers a predisposition to noninvasive pyogenic bacterial
16% of episodes. All reported sudden invasive infections occurred infections, mostly affecting skin and the upper respiratory tract.
before the age of 14 years. IRAK-4 deficiency is a life-threatening The principal bacterial strains found during noninvasive infections

CHaPTEr 36 Immunodeficiencies at the Interface of Innate and Adaptive Immunity 519


were S. aureus in 53% of patients, S. pneumoniae in 20% of
patients, and P. aeruginosa in 13% of patients. Most patients with HOIP Deficiency
MyD88 deficiency have had noninvasive bacterial infections, with AR HOIP (HOIP is also known as RNF31, OMIM 612487)
half of the patients suffering from their first noninvasive bacterial deficiency caused by a homozygous mutation has also been
infection before the age of 2 years. Patients with MyD88 deficiency identified in one patient. This patient displayed an autoinflam-
continue to suffer from skin infections, sinusitis, or pneumonia, matory syndrome, pyogenic bacterial diseases, amylopectinosis,
42
even after reaching adolescence. Treatment recommendations and lymphangiectasia. At the cellular level, HOIP deficiency
for patients with MyD88 deficiency are identical to those for causes the same impaired responses to TNF and IL-1β agonists
those with IRAK-4 deficiency (see above). A diagnosis of MyD88 found in patients with AR HOIL-1 deficiency. Systemic inflam-
deficiency should be considered in children presenting with mation results from the overactivation of monocytes in response
recurrent pyogenic infection with poor inflammatory responses. to stimulation with IL-1β. Immunological investigations showed
T-cell lymphopenia, an impaired proliferative response to
THEraPEuTIC PrINCIPLES anti-CD3, and hypogammaglobulinemia associated with non-
Treatment of Patients with HSE Susceptibility protective antibody responses to S. pneumoniae and H. influenzae,
but with a good antibody response to tetanus toxoid. In addition
• Treatment with interferon (IFN)-α, in parallel with acyclovir, may help to recurrent autoinflammation, this patient developed generalized
to improve disease outcome in patients with Toll-like receptor 3 (TLR3) lymphadenopathy after immunization with BCG. She also had
pathway deficiencies, in particular. recurrent episodes of diarrhea, amyotrophy, muscle weakness,
• Serological monitoring for herpes simplex virus 1 (HSV-1) infection and failure to thrive, partly because of muscle amylopectinosis.
42
should be considered in individuals carrying mutations of TLR3 pathway
genes but with no anti-HSV-1 antibody detectable in serum. Patients with HOIP deficiency should be treated in the same
• In the absence of an effective vaccine against HSV-1, acyclovir may way as those with HOIL-1 deficiency.
be considered an appropriate prophylactic treatment in individuals
carrying mutations of TLR3 pathway genes, even if serologically negative GENETIC DISORDERS OF
for HSV-1.
TH17-MEDIATED IMMUNITY
CMC is characterized by persistent or recurrent infections of
HOIL1 Deficiency skin (intertrigo, angular cheilitis), mucous membranes (oral,
The linear ubiquitination chain assembly complex (LUBAC) is esophageal, genital), and nails (onychomycosis) caused by Candida
48
assembled by a complex containing HOIL1 (also known as (C. albicans in particular). CMC was first described in the 1960s
RBCK1), SHARPIN, and HOIP (also known as RNF31). LUBAC and was reported to display AD heritance. Isolated CMC usually
adds head-to-tail linear polyubiquitin chains to substrate protein begins early in infancy and affects otherwise healthy individuals.
and has been implicated in NF-κB signaling, together with NEMO, Invasive candidiasis, dermatophytosis, bacterial infections of the
RIPK1, and ASC1. AR HOIL1 (HOIL1/RBCK1, OMIM# 610924) respiratory tract, and cutaneous infections caused by Staphylococ-
deficiency, caused by homozygous or compound heterozygous cus have been reported in some patients. In rare cases, an associa-
mutations of the HOIL1 gene, has been identified in three patients. tion with cerebral aneurysm or oral/esophageal squamous cell
These patients had a paradoxical clinical phenotype combining carcinoma, and thyroid autoimmunity has also been described.
an autoinflammatory syndrome with pyogenic bacterial diseases, These PIDs are caused by mutations of the IL17RA, IL17RC,
41
which led to their death. LUBAC deficiency results in an impaired IL17F, ACT1, and STAT1 genes (Fig. 36.6). 17-20 Some patients
49
response to TNF and IL-1β in fibroblasts or to CD40L in B cells, with invasive candidiasis carry mutations of the CARD9 gene.
but hyperresponsiveness to IL-1β in monocytes. All three patients The molecular and clinical features of CMC have been reviewed
had recurrent systemic inflammatory symptoms, present from elsewhere. In particular, this condition is reported in patients
the first few months of life, as a result of monocyte overactivation. with AR autoimmune polyendocrinopathy syndrome type 1
They also developed recurrent pyogenic bacterial infections caused (APS-1 or APECED) (OMIM 240300). APS-1 is caused by
by S. pneumoniae, H. influenzae, Escherichia coli, Staphylococcus mutations of the AIRE gene resulting in impaired T-cell tolerance,
spp., and Enterococcus, partly because of their inability to produce with 88% of patients developing CMC. High levels of neutralizing
antipolysaccharide antibodies. One patient also had chronic CMV autoantibodies against IL-17A, IL-17F, and/or IL-22 have been
41
infection and another had Giardia intestinalis infection. All detected in the serum of patients with APS-1. 50
three patients also had amyotrophy, muscle weakness, and failure AR complete IL-17RA deficiency (OMIM 613953) was first
to thrive, partly as a result of muscular amylopectinosis com- identified in 2011 (see Fig. 36.6). A patient from a consanguineous
41
plicated by myopathy and cardiomyopathy. More recently, 14 family from Morocco was found to suffer from recurrent CMC
patients with HOIL1 deficiency from 10 unrelated kindreds have (resistant to local antifungal treatment), cutaneous abscesses
been reported, with identification on the basis of neuromuscular and folliculitis caused by S. aureus, acute otitis media, and lower
17
and cardiac involvement secondary to amylopectinosis. Patients respiratory tract infections. No invasive bacterial infectious
with HOIL1 deficiency should be immunized (with S. pneumoniae disease was reported in this patient. A homozygous premature
conjugated and nonconjugated vaccines, H. influenzae conjugated stop codon was found to prevent production of the protein in
vaccine, and N. meningitidis conjugated and nonconjugated this patient. The cellular phenotype was characterized by an
vaccines). Prophylactic penicillin V treatment and IgG substitution absence of response to IL-17A and IL-17F homo- and heterodi-
17
should also be considered. Heart transplantation should be mers and to IL-17E (IL-25), in the patient’s fibroblasts. Seventeen
considered for patients with heart failure. The autoinflammation other patients from nine unrelated kindreds have since been
is more difficult to control. One patient underwent HSCT, which identified (Puel A).
corrected the autoinflammation and the predisposition to infec- AD IL-17F deficiency (OMIM 613956) was also first described
17
tious disease. in 2011 (see Fig. 36.6). Patients from a multiplex kindred from

520 ParT fOur Immunological Deficiencies




C. albicans IL-17A
IL-17F
IL-17RA
PRR
IL-17RC

CARD9 ACT1

RORyt




NF-κB MAPK
STAT-3 STAT1
IL-6R IFN-R

IL-6
IL-23
IL-23R IL-27R

Phagocytes, epithelial cells T lymphocytes
fIG 36.6 Genetic Etiologies Affecting the Interleukin (IL)-17 Pathway. Schematic representation
of IL-17 immunity and cooperation between cells recognizing Candida albicans (phagocytes and
epithelial cells) and cells producing IL-17 cytokines (T and innate [NK] lymphocytes). CMCD-causing
mutations (in blue) of IL-17F, IL-17RA, IL17RC, CARD9, and ACT1 impair IL-17 function or response.
CMCD-causing gain-of-function mutations (also shown in blue) in STAT1 impair the development
of IL-17–producing T cells.


Argentina displayed isolated CMC (see Fig. 36.6). A monoallelic and resulting in impaired T-cell tolerance, 88% of patients develop
mutation of IL17F was detected and found to have no impact CMC. High levels of neutralizing autoantibodies against IL-17A,
on protein production. However, this mutation greatly decreased IL-17F, and/or IL-22 have been detected in the serum of patients
the activity of homo- and heterodimers (IL-17F/IL-17F or IL-17A/ with APS-1. 50
IL-17F) by affecting binding of the complex to the receptor. AR complete ACT1 deficiency has been reported in two patients
19
Another patient with a monoallelic mutation of IL-17F has been from a consanguineous family from Algeria. These two siblings
reported, but no cellular characterization was carried out. 17 developed CMC. However, one of them presented recurrent
AR complete IL-17RC deficiency has been reported in three episodes of folliculitis decalvans and bilateral blepharitis caused
18
unrelated patients from Turkey and Argentina. All patients by S. aureus. Their cellular phenotypes are characterized by
suffered from CMC, and none presented invasive or recurrent impaired responses to IL-17A and IL-17F in fibroblasts and
bacterial infections. The clinical manifestations of infectious impaired responses to IL-17E in T lymphocytes. 19
diseases in this group of patients resembled those in patients with
18
AD IL-17 deficiency. The three homozygous mutations identified, THEraPEuTIC PrINCIPLES
Q138X, R376X and R378X, confer a loss of IL-17RC protein Treatment of Chronic Mucocutaneous
expression in transfected HEK293T cells, with complete abolition Candidiasis (CMC)
of the response to IL-17A and IL-17 homo- and heterodimers. 18
Genome-wide approaches led to the discovery of heterozygous • A preventive antifungal treatment, (principally fluconazole) should be
STAT1 missense mutations in patients with CMC disease (D) administered in the long term, followed by other antifungal drugs,
20
(OMIM 614162). These mutations, unlike the previously such as itraconazole or posaconazole.
reported mono- or biallelic STAT1 loss-of-function mutations • Antibiotic prophylaxis should be considered in selected patients with
cutaneous staphylococcal disease.
associated with susceptibility to mycobacterial, intracellular • Monthly prophylactic administration of intravenous immunoglobulin
bacterial, and viral infections, were shown to be gain of function should be considered in selected patients with recurrent pneumonia.
24
(GOF). A recent study from the International STAT GOF group • Granulocyte–colony-stimulating factor (G-CSF), the JAK inhibitor
described 274 patients from 167 kindreds from 40 countries on ruxolitinib, or hemopoietic stem cell transplantation (HSCT) may also
20
five continents. In total, 76 mutations of the STAT1 gene have be considered.
been identified and characterized in vitro. CMCD-causing STAT1
mutations enhance the responses of STAT1 to IFN-α/β, IFN-γ, AR complete ROR-γ/ROR-γT RORC deficiency has recently
and IL-27 and of the repressors of IL-17 T-cell development, been identified in three unrelated consanguineous families from
51
probably accounting for the low IL-17 T-cell counts in these Israel, Chile, and Saudi Arabia. RORC is a DNA-binding
20
patients, resulting in CMCD. In AR APS-1 (APECED;)(OMIM transcription factor that plays an important role in thymopoiesis.
240300), caused by autoimmune regulator (AIRE) deficiency The patients suffered from an unusual combination of BCGosis

CHaPTEr 36 Immunodeficiencies at the Interface of Innate and Adaptive Immunity 521


51
and mild CMC in the absence of other clinical manifestations. this chapter. We thank all the members of the Human Genetics
The three homozygous mutations identified, S38L, Q329X, and of Infectious Diseases Laboratory for helpful discussions. The
Q441X, affect both IL-17 and IFN-γ immunity. As predicted by Laboratory of Human Genetics of Infectious Diseases is supported
studies in mice, the lack of functional ROR-γT protein prevents by grants from the Rockefeller University Center for Clinical
the development of IL-17-producing T cells, accounting for the and the Rockefeller University. The Laboratory of Human Genetics
chronic candidiasis observed in these patients. Surprisingly, the of Infectious Diseases is supported by the March of Dimes, the
patients also lacked mucosal-associated invariant T (MAIT) cells ANR, the INSERM, the FRM, and the PHRC.
and invariant natural killer T cells (iNKT), which normally
produce IFN-γ and can inhibit intracellular mycobacterial replica- Please check your eBook at https://expertconsult.inkling.com/
tion. Moreover, their conventional CD8 α/β and γ/δ T cells, for self-assessment questions. See inside cover for registration
unlike their CD4 α/β T and NK cells, produced only very small details.
amounts of IFN-γ. ROR-γ/ROR-γT thus plays a critical role in
MAIT and iNKT development, and in the capacity of CD8 and
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CHaPTEr 36 Immunodeficiencies at the Interface of Innate and Adaptive Immunity 522.e1


M u LTIPLE-CHOICE Q u ESTIONS

1. A 2-year-old patient was diagnosed of disseminated osteo- 3. Patients with defect in interleukin-17 (IL-17) immunity are
myelitis caused by atypical mycobacteria. Immunophenotyping characterized by which of the following infectious phenotype?
of T, B, and natural killer (NK) cells are normal. Respiratory A. Patients present with persistent mucocutaneous candidiasis
burst excludes chronic granulomatous disease. What is the B. Patients present susceptibility to herpes virus
correct procedure in the investigation? C. Patients present with recurrent bacterial pneumonia
A. Mitogen-induced T-cell proliferation
B. Test of interferon (IFN)-γ pathway and treatment with
multiple antimycobacterial antibiotics.
C. Observation for 2 weeks while performing an evaluation
2. A 3-year-old boy was diagnosed of herpes simplex encephalitis,
but no cutaneous lesion of herpes virus infection was observed.
Immunophenotyping of lymphocytes was normal. To inves-
tigate the causal immune defect, what would be the best study
to undertake?
A. Observation during 1 week while treating with antibiotics.
Acyclovir should be used if no sign of clinical recover.
B. Test Toll-like receptors (TLR) response to multiple ligands
using peripheral blood mononuclear cells.
C. Test TLR3 responsiveness using dermal fibroblasts.

37









Infections in the Immunocompromised Host



Alexandra F. Freeman, Jennifer M. Cuellar-Rodriguez







As a result of improvements in antimicrobials and immunosup- clear infection, such as in the gastrointestinal (GI) and genito-
1,2
pressant agents, there are increasing numbers of hosts with urinary tract, but also in response to infection. Therefore
immune deficiencies, either acquired primarily through genetic although necrotic and purulent centers may form in liver and
defects or acquired secondarily, for example, through treatment lymph node infections, the yield with drainage may be poor
for malignancy and autoimmune disease, or after solid or because of the thicker consistency of granulomatous inflamma-
hematopoietic stem cell transplantation (HSCT). Understanding tion. At times, the infected lymph nodes may need resection to
both the genetic defects and the immunological targets of cure infections. Likewise, in lung infections, fine-needle aspiration
immunosuppressant agents will help further the knowledge of frequently provides a higher yield than bronchoscopy because
host control of infection. In this chapter, we review the infection of the nature of inflammation. In addition, it is important to
spectrum of some of the major classes of primary immunode- alert the microbiology laboratory when G. bethesdensis is sus-
ficiencies, as well as acquired immunodeficiency, opportunistic pected, such as with lymphadenitis, as growth requires special
infections in patients with human immunodeficiency virus (HIV) media.
and acquired immunodeficiency syndrome (AIDS) are described The granulomatous inflammation seen in CGD infections
separately in Chapter 39. may be intense enough to impede successful treatment of infection
solely with antimicrobials and necessitate corticosteroid addition
PRIMARY IMMUNODEFICIENCIES to appropriate antimicrobials. For instance, “mulch pneumonitis”
occurs with large inhalations of decaying organic matter, such
Phagocyte Defects (Chapter 22) as mulch. A diffuse pneumonitis associated with Aspergillus
4
Phagocytic neutrophils and monocytes are key members of the results and can be quite fulminant, with a high mortality if the
primary immune response. Neutrophils are essential in the initial inflammatory response is not treated (e.g., with corticosteroids)
host defense against microbes. Antimicrobial peptides, cytokines, in addition to antifungals. There is suggestion that the addition
and chemokines released at the site of microbial entry cause of corticosteroids may help with other infections in CGD, such
neutrophils to migrate to the site of inflammation (chemotaxis), as Nocardia pneumonia and S. aureus liver abscesses. 5,6
ingest, and then kill the microbe through oxygen-dependent or Trimethoprim–sulfamethoxazole (TMP-SMX) is effective
oxygen-independent mechanisms. Defects in quantity or quality against the majority of bacterial pathogens in CGD and thus is
of neutrophils can predispose to infection, which is primarily an ideal prophylactic antibiotic and has been shown to signifi-
7
with fungi and bacteria (Table 37.1). Defects in monocytes are cantly decrease bacterial infections. Itraconazole was shown to
7
less frequent and contribute to control of intracellular bacteria, be effective in preventing some of the fungal infections. The
mycobacteria, and fungi. newer triazoles, including voriconazole and posaconazole, have
not been studied as prophylactic antimicrobials in this setting
Chronic Granulomatous Disease but have an extended spectrum and would likely be effective as
Chronic granulomatous disease (CGD) causes the most common well. Toxicities of extended use with certain antimicrobials need
qualitative neutrophil immunodeficiency. Defects in the nico- to be considered; for instance, voriconazole is associated with
tinamide adenine dinucleotide phosphate (NADPH) oxidase photosensitivity and increased skin cancers with prolonged use,
cause an abnormal neutrophil respiratory burst, leading to as well as fluoride toxicity in rare cases. 8,9
recurrent bacterial and fungal infections. However, it is interesting
that the spectrum of infections is fairly limited, with the most Leukocyte Adhesion Deficiencies
common pathogens being Staphylococcus aureus, Burkholderia Leukocyte adhesion deficiencies (LADs) result from the inability
1-3
2
cepacia, Serratia marcescens, Nocardia spp., and Aspergillus spp. of neutrophils to migrate to the site of infection. LAD-1 is
Other infecting organisms occur less frequently but are rare most frequent, resulting from a defect in β 2 integrin and pre-
outside of CGD, and these include Chromobacterium violaceum, senting typically with failure of umbilical cord separation and
Aspergillus nidulans, and Granulibacter bethesdensis. 3 omphalitis. The spectrum of infection is not as specific as with
Infections in CGD are typically of the lung, lymph nodes, CGD but is limited typically to bacterial infections. Gingivitis
liver, and bone (Fig. 37.1). and periodontitis lead to frequent oral bacterial infections, and
Identification of the infecting organism is essential in CGD necrotizing ulcerative skin infections are common, typically with
to guide antimicrobial therapy. CGD is not only characterized S. aureus or gram-negative bacteria (GNB). Although primarily
by exuberant granulomatous inflammation, both in areas without a defect of neutrophils resulting in bacterial infections, viral

523

524 Part four Immunological Deficiencies



TABLE 37.1 Infection Susceptibility of Select Primary Immunodeficiencies
Immunodeficiency Genetic Defect functional Defect Infection Susceptibility
Chronic granulomatous disease Gp91 phox , p22 phox , p40 phox , Defect in nicotinamide adenine Catalase positive bacteria (e.g.,
p47 phox , p67 phox dinucleotide phosphate (NADPH) Staphylococcus aureus, Burkholderia,
oxidase leading to abnormal serratia, Nocardia) and filamentous molds
superoxide production
Leukocyte adhesion disorder-1 β 2 integrin Neutrophil migration Bacteria, typically S. aureus, gram-negative
(LAD-1)
Severe congenital neutropenia HAX1, ELANE Neutropenia Bacteria, typically streptococci, S. aureus,
gram-negative
X-linked agammaglobulinemia Bruton tyrosine kinase (BTK) Absence of B cells, antibody Encapsulated bacteria, enterovirus,
production Helicobacter, and related species
CD40 ligand deficiency CD40 ligand Impaired B-cell class switching Encapsulated bacteria, Pneumocystis
jiroveci, Cryptosporidium
Severe combined Multiple genes, such as IL2RG, T-cell lymphopenia, variable B- and Bacteria, virus, P. jiroveci, Candida, Bacille
immunodeficiency (SCID) RAG1/2, ADA, JAK3, etc. natural killer (NK)-cell expression Calmette-Guérin (BCG)
DiGeorge syndrome Deletion of chromosome 22q11 Thymic hypoplasia or aplasia Viruses, opportunists infrequent
in majority
Autosomal dominant hyper-IgE Signal transducer and activator Impaired T-helper-17 (Th17) cell S. aureus, Candida, dimorphic fungi;
syndrome (Job’s syndrome; of transcription 3 (STAT3) differentiation secondary infection of pneumatoceles
AD-HIES) with molds, gram-negative bacteria and
nontuberculous mycobacteria
Dedicator of cytokinesis 8 DOCK8 T-cell lymphopenia, defect still S. aureus, Candida, Molluscum
(DOCK8) deficiency being delineated contagiosum, human papillomavirus
(HPV), herpes viruses
Interleukin-12 (IL-12)/interferon IFN-γR1, IFN-γR2, IL-12, IL-12R, Failure of signal transducer and Mycobacteria, Salmonella, dimorphic fungi
(IFN)-γ axis defects NEMO, STAT1 activator of transcription 1 (STAT1)
activation, intracellular killing
Complement C5–9 defects Specific complements Impaired membrane attack complex Neisseria species
killing



KEY CoNCEPtS
Infection Risks in Primary Immunodeficiencies

• Neutrophil defects present primarily with bacterial and fungal
infections.
• Humoral immunodeficiencies present with impaired antibody formation
and primarily sinopulmonary infections with encapsulated
organisms.
• Severe primarily T-cell defects usually present with opportunists, such
as Pneumocystis.
fIG 37.1 Chest computed tomography (CT) scan of a Nocardia • Abnormalities of the interleukin-12 (IL-12)/interferon (IFN)-γ axis com-
monly present with nontuberculous mycobacteria (NTM) infections.
pneumonia in a 17-year-old man with chronic granulomatous • Cytokine autoantibody syndromes are being increasingly recognized
disease. with infection susceptibility dependent on the involved cytokine.





warts are not infrequent. Fungal infections are unusual. Little is neutropenia. Benign ethnic neutropenia is seen primarily in
known about antimicrobial prophylaxis for LAD-1, but typically individuals of African descent and is usually asymptomatic.
prophylaxis with some coverage for oral flora, S. aureus, and Secondary causes of neutropenia also include antineutrophil
7
GNB is provided, such as with amoxicillin/clavulanate. Other antibodies and hypersplenism with sequestration.
rare neutrophil defects, including Chediak-Higashi and Griscelli Infections associated with neutropenia relate to the etiology as
syndromes, also are characterized by recurrent pyogenic infections. well as the degree and duration of neutropenia. Cyclic neutropenia
may be largely asymptomatic, with self-limited fevers and oral
Quantitative Phagocyte Defects ulcers or cervical lymphadenopathy, as opposed to the severe
Neutropenia is the most common quantitative defect of phago- chronic neutropenia of infancy that has more serious infections.
cytes and typically results from cytotoxic agents, as discussed Neutropenia is most frequently associated with bacterial infections,
later in this chapter. Autosomal recessive defects in HAX1 cause often localized to the mouth, cervical lymph nodes, lungs, and
Kostmann syndrome, a type of severe congenital neutropenia, perianal area, with both gram-positive bacteria (GPB) and GNB.
which typically presents in infancy with recurrent bacterial Fungal infections are more frequent in the prolonged and severe
10
infections. Autosomal dominant defects in the neutrophil elastase neutropenias associated with hematological malignancies and
gene ELANE cause severe congenital neutropenia and cyclic hematopoietic transplantation. Fever in the setting of neutropenia

CHaPtEr 37 Infections in the Immunocompromised Host 525


requires rapid assessment, with particular focus on physical
examination of areas with high bacterial colonization, such as PRIMARY CELLULAR AND COMBINED
the oral cavity and perianal region, as well as sites of indwelling IMMUNODEFICIENCIES (Chapter 35)
intravenous catheters. Empiric broad-spectrum antibiotics after
obtaining appropriate cultures are often prudent. Severe Combined Immunodeficiency
Monocytopenia has been described in GATA2 deficiency and Severe combined immunodeficiency (SCID) results from a severe
associated with disseminated Bacille Calmette-Guérin (BCG) deficiency in the number or function of T cells. Depending on
with interferon (IFN) regulatory factor 8 (IRF8) deficiency. 11,12 the genetic defect, B and/or natural killer (NK) cells are affected
The described spectrum of GATA2 deficiency is increasing and as well. Presentation is typically very early in life, with significant
includes MonoMAC syndrome, Emberger syndrome with compromise within the first few months of life. In recent years,
lymphedema and myelodysplasia, familial leukemia, aplastic there has been more recognition of “leaky” forms of SCID, in
11
anemia, and childhood-onset neutropenia. The predominant which the defects are not complete and presentation can be later
clinical findings are disseminated mycobacteria; fungal infections, and more variable. 16
such as disseminated histoplasmosis; warts with cervical and SCID is associated with recurrent and persistent viral, bacterial,
vulvar dysplasia; pulmonary alveolar proteinosis (PAP); myelo- and fungal infections. PJP frequently occurs in early infancy,
dysplasia; and leukemia. Onset is typically in later childhood and prophylaxis should be provided. Chronic mucocutaneous
and adulthood, and in addition to monocytopenia, lymphocy- candidiasis (CMC) is frequent and may require antifungal sup-
topenia may be present. When the patient is symptomatic, pressive therapy. Diarrhea from viral and other etiologies fre-
treatment is typically with HSCT. quently leads to failure to thrive. Severe respiratory viral infections
and CMV also occur. In countries where BCG vaccine is given,
HUMORAL IMMUNODEFICIENCIES (Chapter 34) disseminated infection may result; transplantation may lead to
an immune reconstitution syndrome in which sites of BCG
Humoral immunodeficiencies are characterized by absent or infection become inflamed and abscesses may form.
defective B cells with resultant lack of specific antibody responses,
leading predominantly to infections with encapsulated bacteria. DiGeorge Syndrome
There is a spectrum of severity with X-linked agammaglobulin- Immune deficiency in DiGeorge syndrome results from varying
17
emia (XLA) characterized by a total absence of B cells and degrees of thymic hypoplasia or aplasia. Other manifestations
presentation in the first years of life and the later presentations include congenital heart disease, characteristic facies and palate
of common variable immunodeficiency (CVID). 13 anomalies, hypocalcemia, and learning disabilities. With the
Humoral immunodeficiencies are characterized by recurrent exception of severe cases in which there is thymic aplasia and
ear, sinus, and lung infections, with typical bacterial etiologies severe T-cell lymphopenia, opportunistic infections (OIs) are
being Streptococcus pneumoniae and Haemophilus influenzae. infrequent. Upper respiratory tract infections predominate, and
Despite immunoglobulin (Ig) replacement, bronchiectasis may prophylactic antibiotics may not be necessary. With the more
occur, and with it, the spectrum of pulmonary infections may mild defects, live viral vaccination may be considered safe. 18
broaden requiring careful microbiological monitoring. Neutro-
penia may occur with XLA and CD40 ligand deficiency, frequently Autosomal Dominant Hyper-IgE Syndrome
when replacement Ig is not provided, and may be associated (Job’s Syndrome)
with a broader spectrum of infection, with more severe S. aureus Autosomal dominant hyper-IgE syndrome (Job’s syndrome;
and Pseudomonas infections. Chronic Mycoplasma and Ureaplasma AD-HIES), resulting from STAT3 mutations, has been frequently
spp. infections can occur leading to lung disease and arthritis. characterized as a phagocytic defect. However, in recent years,
Giardia can be a source of GI disease. In severe humoral defects, it has been recognized that the immune defects center around
such as XLA, persistent Helicobacter, Flexispira, and Campylobacter the failure of T-helper 17 (Th17) cell differentiation and a decrease
spp. infections are infrequent and are characterized by ulcerative in memory T and B cells. 19,20 A lack of Th17 cells resulting in
skin lesions. 14,15 These infections require a high index of suspicion impaired interleukin-17 (IL-17) and IL-22 signaling and dimin-
to be identified, as special microbiology media with longer lengths ished antimicrobial peptide upregulation appears to at least
of incubation may be required. Eradication of infection, even explain some of the infection susceptibility.
with a combination of intravenous antibiotics, is often difficult. AD-HIES is characterized by recurrent skin and lung bacterial
Severe meningoencephalitis with enteroviral infections may occur infections, CMC, eczema, and a variety of connective tissue,
20
and can be quite devastating and difficult to treat. Replacement skeletal, and vascular abnormalities. S. aureus skin abscesses
Ig therapy, given intravenously or subcutaneously, is used to start early in life, and S. aureus colonization appears to drive the
minimize the recurrent encapsulated bacterial infections and eczema. S. aureus, S. pneumoniae, and H. influenzae pneumonias
diminish the risk of enterovirus infection. The role of prophylactic typically start in the first few years of life, and prophylactic
antibiotics is not well studied and varies among centers. antimicrobials, such as TMP-SMX, can be useful in reducing
CD40 ligand deficiency (X-linked hyper-IgM) is the most the frequency. Healing of pneumonias appears aberrant, and
13
common of the Ig class switch defects. Sinopulmonary infections bronchiectasis and pneumatoceles frequently result. The lung
similar to XLA typically arise in early childhood. However, as with these parenchymal abnormalities is then predisposed to
opposed to XLA, Pneumocystis jiroveci pneumonia (PJP) occurs mold infections (most frequently Aspergillus and Scedosporium
and may be the initial infection. Other infections indicative of spp.) and gram-negative infections, such as with Pseudomonas
T-cell defects occur as well, including cytomegalovirus (CMV) aeruginosa and nontuberculous mycobacteria (Fig. 37.2). These
infection, toxoplasmosis, and cryptosporidiosis. Cryptosporidial secondary infections can be quite difficult to eradicate. CMC is
infection can be a chronic and severe problem and may lead to the most frequent fungal infection. PJP is much less frequent,
sclerosing cholangitis. typically occurring in infancy, potentially as the first pneumonia.

526 Part four Immunological Deficiencies



















fIG 37.2 Chest computed tomography (CT) scan of a pneumato-
cele with secondary Mycobacterium abscessus and Pseudomonas
aeruginosa infection in a 25-year-old woman with autosomal
dominant hyper-IgE syndrome (Job’s syndrome; AD-HIES).
fIG 37.3 Brain magnetic resonance imaging (MRI) scan showing
Bacille Calmette-Guérin (BCG) abscesses in a 3-year-old boy
with an interferon (IFN)-γ receptor defect.


Disseminated cryptococcal infection has been described causing
meningitis or GI infection. Histoplasma typically has caused
disease of the GI tract, and Coccidioides infection has caused infection, including some viral susceptibility. Death in childhood
meningitis. 21 is frequent, and HSCT is typically considered.
Compared with loss of function STAT1 mutations, which are
DOCK8 Deficiency characterized by disseminated NTM infections, gain-of-function
Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined STAT1 (GOF-STAT1) mutations have a much broader infection
25
defect that is one cause of an autosomal recessive hyper-IgE susceptibility pattern and varied presentations. Although initially
22
syndrome (AR-HIES). Compared with AD-HIES, DOCK8 described as causing CMC, GOF-STAT1 mutations are also
deficiency is characterized by severe cutaneous viral infections associated with disseminated endemic mycoses, such as Coc-
in addition to sinopulmonary infections. Recurrent cutaneous cidioides infection, viral infections including those of the herpes
infections with herpes simplex virus (HSV) and varicella-zoster family and progressive multifocal leukoencephalopathy (PML),
virus (VZV) occur, as well as severe, disfiguring warts and Mol- and bacterial infections. GOF-STAT1 mutations can also be
luscum contagiosum infection. DOCK8 deficiency has an overall associated with NTM infections.
worse prognosis than AD-HIES, with frequent occurrence of
malignancies, typically squamous cell carcinoma and lymphomas. COMPLEMENT DEFICIENCIES (Chapter 21)
Defects of the IL-12/IFN-γ Axis Infections with encapsulated organisms are the typical manifesta-
26
Defects of the IL-12/IFN-γ axis are characterized primarily by tions of complement defects. C3 deficiency is associated with
mycobacterial infections. Monocyte-derived macrophages ingest recurrent and severe infections with S. pneumoniae, H. influenzae,
intracellular bacteria, such as Mycobacterium and Salmonella, and Neisseria meningitidis, whereas deficiencies of the components
leading to IL-12 secretion. IL-12 binds to its receptor on T of the terminal pathway composing the membrane attack complex,
lymphocytes and NK cells leading to IFN-γ secretion, which C5-9, result in N. gonorrhoeae and N. meningitidis infections.
then binds to its heterodimeric receptor on macrophages, activat-
ing microbial killing through signal transducer and activator of ASPLENIA
transcription 1 (STAT1). Many defects along this pathway have
been described, including mutations in IL-12, IL-12 receptor, The spleen acts as both a source for antibody production and a
IFN-γ receptor1 and 2, STAT1, and nuclear factor (NF)-κB filter to remove pathogens through phagocytic cells. Spleens can
essential modulator operon (NEMO). 23,24 Defects along this be physically absent, either congenitally or through surgical
pathway show varying susceptibility to nontuberculous myco- resection (e.g., with intractable hemolytic anemia or thrombo-
bacteria (NTM), Salmonella, and endemic dimorphic fungal cytopenia, malignancy, trauma), or functionally absent as is seen
infection (Fig. 37.3). For example, individuals with dominant with increased age in sickle cell disease. Infections associated
IFN-γ receptor defects retain some IFN-γ signaling and tend to with asplenia include sepsis with encapsulated bacteria, namely,
have localized NTM infections, often presenting with osteomy- S. pneumoniae and H. influenzae, and with Babesia, a protozoan
elitis, and infrequently other OIs, such as disseminated histo- that infects erythrocytes and causes fever and hemolysis with
26
plasmosis. Treatment of the dominant IFN-γ receptor defects is asplenia. Similar to babesiosis, malaria infection can be more
typically successful with combination antimycobacterial agents severe in patients without a spleen. The risk of infection differs
with or without exogenous IFN-γ. In contrast, autosomal recessive with the etiology of asplenia, with splenectomy associated with
IFN-γ receptor defects, in which there is typically no residual trauma having the lowest risk as typically small amounts of
IFN-γ signaling, have much more severe disease, with earlier splenic tissue remain. In addition, infection with encapsulated
onset of disseminated NTM or BCG disease, poor response to organisms appears to be more common in children with asplenia
therapy with frequent relapse, and a greater susceptibility to than in adults with asplenia.

CHaPtEr 37 Infections in the Immunocompromised Host 527


immunomodulators in autoimmune and inflammatory disorders,
SECONDARY NON–MEDICATION-ASSOCIATED and graft-versus-host disease (GvHD). These drugs inhibit
IMMUNODEFICIENCY B-cell and T-cell proliferation and hinder cellular and humoral
33
immune responses in a dose-dependent fashion. One of the
Cytokine Autoantibodies main side effects of these agents is hematopoietic toxicity; they
In recent years, there has been greater recognition of susceptibility induce neutropenia to varying degrees. Fever occurs during
to infection associated with anticytokine autoantibodies. 27-30 chemotherapeutic-induced neutropenia in 10–50% of patients
Autoimmune polyendocrinopathy with candidiasis and ecto- with solid tumors and in >80% of those with hematologic
34
dermal dysplasia (APOCED) is a disorder caused by mutations malignancies. Common sites of infection include the intes-
in the autoimmune regulator gene (AIRE). Many autoimmune tinal tract, lungs, and skin; bacteremia occurs in up to 25% of
manifestations are seen in APOCED, including hypoparathyroid- patients. Probably because of the high incidence of indwelling
ism, diabetes, and adrenal failure as a result of persistent autoreac- catheters and widespread use of prophylactic antibiotics, currently
tive T cells caused by failure of thymic deletion. The main coagulase-negative staphylococci are the most common blood
infectious complication is severe CMC. Neutralizing autoantibod- isolates, followed by drug-resistant Enterobacteriaceae and non-
34
ies to IL-17 and IL-22 have been detected and may contribute fermenting GNB (e.g., P. aeruginosa). Invasive mold infections
to the occurrence of CMC, similar to other defects along the (e.g., aspergillosis) typically occur after prolonged neutropenia
Th17/IL-17/IL-22 pathway, such as AD-HIES. 29,30 Neutralizing (>2 weeks). Invasive yeast (usually Candida spp.) infections are
autoantibodies to IFN-γ leading most frequently to disseminated more commonly seen in patients with severe mucositis and
27
NTM infections have been described. This disorder typically neutropenia. Detailed guidelines for the use of antimicrobial
presents in adulthood and has an increased prevalence in Asians. agents in the setting of chemotherapy-induced neutropenic fever
34
Although the primary manifestation of autoantibodies against have been published. Although bacterial infections are the most
granulocyte macrophage–colony-stimulating factor (GM-CSF) common infections, when used as immunomodulators, a higher
antibodies is PAP, an increased frequency of OIs, such as with frequency of OIs, such as PJP, and infections with Listeria spp.,
Nocardia and Cryptococcus, has been described. 30 NTM, Cryptococcus, and VZV, has been described.
Glucocorticoids
tHEraPEutIC PrINCIPLES
Prevention of Infection in Patients With a Defect Depending on the dose and duration, glucocorticoids can induce
a vast range of immune defects through decreasing cytokine
in Host Defenses production (IL-1, IL-6, and tumor necrosis factor-α [TNF-α),
and impairing neutrophil and lymphocyte trafficking and func-
• Use of prophylactic antibiotics in patients at high risk for a specific
type of infection tion. Infections are a frequent complication of corticosteroid
32
• Immunization to prevent specific bacterial and viral infections: use. Bacterial infections are the most common infectious
• Active immunization, especially in patients who should be capable complication, but opportunistic fungal, viral, and mycobacterial
of mounting an effective response (e.g., before elective splenectomy infections are also seen, particularly with high doses and long
or before elective initiation of immunosuppressive therapy) duration of systemic therapy. Some associated infections include
• Passive immunization through administration of high-titer pooled GPB and GNB, superficial and invasive candidiasis, invasive
immunoglobulin to patients exposed to or at high risk of specific
viral infections. aspergillosis and nocardiosis, cryptococcosis, PJP, listeriosis,
endemic mycoses, tuberculosis (TB), and infections with NTM,
and VZV, among others. Outside of the setting of SOT and HSCT,
INFECTIONS IN PATIENTS RECEIVING routine use of antimicrobials for patients receiving corticosteroids
IMMUNOSUPPRESSIVE MEDICATIONS is not recommended, except for anti-TB treatment (e.g., isoniazid)
for those with a positive tuberculin skin test (purified protein
31
Immunosuppressive drugs have been used for over 60 years and derivative [PPD]) or a positive IFN-γ release assay, and TMP-SMX
35
are essential for the management of autoimmune/inflammatory in those receiving high-dose steroid for extended periods.
diseases and hematological and oncological malignancies and Alternate-day use of corticosteroids has been associated with a
in transplant recipients. Early immunosuppressive agents lacked lower risk of severe infection; therefore whenever possible, this
specificity and therefore led to serious and numerous adverse dosing schedule should be used. 31
effects. Newer immunosuppressive agents have revolutionized
the treatment of multiple diseases, but many of these have led Calcineurin Inhibitors and Mammalian Target of
to an increase in specific infectious complications. Knowledge of Rapamycin Inhibitors
the particular infection or treatment associations is imperative. 32 The calcineurin inhibitors, cyclosporine and tacrolimus, have
Described below are the most common classes of drugs that been cornerstones in improving the outcome of transplant
have been linked to infectious complications. Notably, immu- recipients by reducing T-cell function and thus preventing allograft
nosuppressive agents are frequently used in combination, and rejection in SOT and GvHD in HSCT. Infectious complications,
therefore establishing clear causality is challenging. typically viral, seem to be dose dependent and seen more often
when these drugs are used in combination with other immunosup-
Cytotoxic Agents (e.g., Cyclophosphamide, pressants. 32,33 The mammalian target of rapamycin (mTOR)
Methotrexate, Azathioprine) inhibitors sirolimus and everolimus have been associated with
Initially developed to control neoplastic growth in oncologi- a lower incidence of CMV infection, compared with other
32
cal and hematological malignancies, cytotoxic drugs have also immunosuppressive agents used in transplantation. Although
found their niche as an essential component of the conditioning impaired wound healing has been seen, this has not correlated
regimen for HSCT and solid organ transplantation (SOT), as with an increased incidence of infections.

528 Part four Immunological Deficiencies



Mycophenolate Mofetil Tumor Necrosis Factor-α Inhibitors
Mycophenolate mofetil (MMF) is a prodrug of mycophenolic TNF-α is a cytokine that plays a central role in macrophage and
acid, which inhibits inosine monophosphate dehydrogenase, a phagosome activation, differentiation of monocytes into mac-
key enzyme in purine synthesis. It is a cytotoxic drug with rophages, recruitment of neutrophils and macrophages, and
33
antiproliferative effect on T and B lymphocytes. In addition granuloma formation and maintenance. Blockade results in an
to its potential myelosuppressive effect, it has been associated increased risk of infection, particularly in the first few months
in SOT to a higher risk of CMV infection. 32 after treatment. 37,38 Infections characterized by granulomas have
been described most frequently, in particular TB and NTM
Antithymocyte Globulin infections, but also disseminated histoplasmosis and coccidioi-
39
Antithymocyte globulin (ATG) is a polyclonal Ig prepared by domycosis. Other notable infections are listeriosis, legionellosis,
immunizing horses or rabbits with human thymocytes and salmonellosis, recurrent or relapsing leishmaniasis, overwhelming
harvesting the IgG. These antibodies produce a profound lym- Plasmodium falciparum infection, and invasive mold infections
phopenia that can last well beyond 1 year. Used for induction or (i.e., aspergillosis and mucormycosis). Risk of certain viral
rejection therapy in transplantations, their use has been associated infections also appears to be increased, particularly VZV infection.
consistently with a greater risk of CMV and posttransplantation Several cases of severe hepatitis B virus (HBV) reactivation in
36
lymphoproliferative disease (PTLD). CMV prophylaxis or patients with positive surface antigen at the start of treatment
preemptive therapy is recommended in transplant recipients that have been reported, many of whom developed hepatic failure.
receive ATG. Because these are foreign proteins, serum sickness Patients receiving anti–TNF-α therapy should be screened for
can also develop between 1 and 2 weeks after treatment. TB (latent or active), HBV, and HCV before starting treatment,
38
and treated accordingly. Patients with latent TB should receive
Monoclonal Antibodies and Small Molecules isoniazid for 6–9 months. Ideally, patients would have received
Monoclonal antibodies (mAbs) and small molecules target specific at least 3 weeks of isoniazid before therapy with biologicals;
cellular steps, making it possible to manipulate disease pathways however, in truly urgent cases, this can be done simultaneously.
for previously untreatable illnesses. Many of these biological In patients that are hepatitis B surface antigen (HbsAg) positive,
agents interfere with specific aspects of the immune system. baseline HBV DNA levels should be obtained and antiviral
Highlighted below are those that have a key infection susceptibility prophylaxis or treatment offered. All HBV-seronegative patients
pattern. Others with more subtle increases in infections are also should be vaccinated against hepatitis B and seroconversion
included in Table 37.2. documented.




TABLE 37.2 Selected Monoclonal antibodies and Small Molecules and their risk of Infection
Drug Name target Serious Infections
Adalimumab TNF-α* TB, NTM infection, endemic mycoses, listeriosis, candidiasis, invasive mold infections,
Certolizumab pegol nocardiosis, bacterial infections, reactivation of VZV and HBV infections, severe malaria, and
Etanercept leishmaniasis
Golimumab
Infliximab
Rituximab CD20 HBV infection reactivation, PML, PCP, enteroviral meningoencephalitis, CMV disease, VZV
infection, babesiosis, parvovirus infection, nocardiosis
Anakinra IL-1 Bacterial infections (cellulitis and pneumonia)
Rilonacept
Alemtuzumab CD52 Herpes viruses reactivation (EBV, VZV, CMV, HHV-6), severe respiratory viral infections (with
adenovirus, RSV, parainfluenza virus, influenza virus), PCP, invasive mold infections,
histoplasmosis, cryptococcosis, PTLD, bacterial meningitis, toxoplasmosis, PML, parvovirus
infection, nocardiosis, TB, NTM infection, acanthamebiasis, and Balamuthia mandrillaris infection
Muromonab CD3 Bacterial infections; listeriosis; nocardiosis; aspergillosis; candidiasis; cryptococcosis;
toxoplasmosis; infections with CMV, HSV, VZV, adenovirus, RSV, and enteroviruses; and PCP
Basiliximab CD25 Bacterial infections; infections with CMV and HSV; EBV-associated PTLD; infections with RSV,
Daclizumab adenovirus, influenza, and BK virus; invasive mold infections; candidiasis; nocardiosis; TB; NTM
infection; toxoplasmosis
Natalizumab α-4 Integrin PML, respiratory viral and bacterial infections, UTI, viral meningitis and encephalitis, CMV
infection, IA, PCP, VZV infection, NTM infection, cryptosporidiosis
Abatacept T-cell costimulation blockade Bacterial infections, EBV-associated PTLD
Belatacept
Alefacept Inhibits T-cell activation 1 case of Mycobacterium avium intracellulare (MAI) bursitis, 1 case of nocardiosis when
coadministered with infliximab
Brodalumab IL 17 receptor A Mucocutaneous candidiasis
Bortezomib Proteasome inhibitor Herpes zoster
Gemtuzumab CD33 Bacteremia, bacterial pneumonia, and HSV reactivation.
*TNF-α, tumor necrosis factor-α; IL-1, interleukin-1; TB, tuberculosis; NTM, nontuberculous mycobacteria; VZV, varicella-zoster virus; HBV, hepatitis B virus; PML, progressive
multifocal leukoencephalopathy; PCP, Pneumocystis jiroveci pneumonia; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6, human herpes virus 6; RSV, respiratory syncytial
virus; PTLD, posttransplantation lymphoproliferative disease; HSV, herpes simplex virus; UTI, urinary tract infection; IA, invasive aspergillosis.