T cell differentiation, effector pathways, and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which, in turn, give rise to the T cell precursors that migrate to the thymus. The development of CD4+ and CD8+ T cells is shown. Known T cell effector pathways are indicated, i.e., γδ cells, cytotoxic T cells (Tc), TH1, TH2, TH17, TFh (follicular helper) CD4 effector T cells, regulatory T cells (Treg), and natural killer T cells (NKTs); abbreviations for PIDs are contained in boxes. Vertical bars indicate a complete deficiency; broken bars a partial deficiency. SCID, severe combined immunodeficiency; ZAP 70, zeta-associated protein deficiency, MHCII, major histocompatibility complex class II deficiency; TAP, TAP1 and 2 deficiencies; Orai1, Stim1 deficiencies; HLH, hematopoietic lymphohistiocytosis; MSMD, Mendelian susceptibility to mycobacterial disease; Tyk2, DOCK8, autosomal recessive form of hyper-IgE syndrome; STAT3, autosomal dominant form of hyper-IgE syndrome; CD40L, ICOS, SAP deficiencies; IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome; XLP, X-linked proliferative syndromes.
T cell differentiation and severe combined immunodeficiencies (SCIDs). The vertical bars indicate the six mechanisms currently known to lead to SCID. The names of deficient proteins are indicated in the boxes adjacent to the vertical bars. A broken line means that deficiency is partial or involves only some of the indicated immunodeficiencies. HSCs, hematopoietic stem cells; CLPs, common lymphoid progenitors; ADA, adenosine deaminase deficiency; NKs, natural killer cells; TCR, T cell receptor; DNAL4, DNA ligase 4.
Given the central role of T lymphocytes in adaptive immune responses (Chap. 314), PIDs involving T cells generally have severe pathologic consequences; this explains the poor overall prognosis and the need for early diagnosis and the early intervention with appropriate therapy. Several differentiation pathways of T cell effectors have been described, one or all of which may be affected by a given PID (Fig. 316-2). Follicular helper CD4+ T cells in germinal centers are required for T-dependent antibody production, including the generation of Ig class-switched, high-affinity antibodies. CD4+ TH1 cells provide cytokine-dependent (mostly interferon-γ-dependent) help to macrophages for intracellular killing of various microorganisms, including mycobacteria and Salmonella. CD4+ TH2 cells produce IL-4, IL-5, and IL-13 and thus recruit and activate eosinophils and other cells required to fight helminth infections. CD4+ TH17 cells produce IL-17 and IL-22 cytokines that recruit neutrophils to the skin and lungs to fight bacterial and fungal infections. Cytotoxic CD8+ T cells can kill infected cells, notably in the context of viral infections. In addition, certain T cell deficiencies predispose affected individuals to Pneumocystis jiroveci lung infections early in life and to chronic gut/biliary duct/liver infections by Cryptosporidia and related genera later on in life. Lastly, naturally occuring or induced regulatory T cells are essential for controlling inflammation (notably reactivity to commensal bacteria in the gut) and autoimmunity. The role of other T cell subsets with limited T cell receptor (TCR) diversity [such as γδTCR T cells or natural killer T (NKT) cells] in PIDs is less well known; however, these subsets can be defective in certain PIDs and this finding can sometimes contribute to the diagnosis (e.g., NKT cell deficiency in X-linked proliferative syndrome). T cell deficiencies account for approximately 20% of all cases of PID.
Severe Combined Immunodeficiencies
Severe combined immunodeficiencies (SCIDs) constitute a group of rare PIDs characterized by a profound block in T cell development and thus the complete absence of these cells. The developmental block is always the consequence of an intrinsic deficiency. The incidence of SCID is estimated to be 1 in 50,000 to 100,000 live births. Given the severity of the T cell deficiency, clinical consequences occur early in life (usually within 3 to 6 months of birth). The most frequent clinical manifestations are recurrent oral candidiasis, failure to thrive, and protracted diarrhea and/or acute interstitial pneumonitis caused by Pneumocystis jiroveci (although the latter can also be observed in the first year of life in children with B cell deficiencies). Severe viral infections or invasive bacterial infections can also occur. Patients may also experience complications related to infections caused by live vaccines (notably bacille Calmette-Guérin; BCG) that may lead not only to local and regional infection but also to disseminated infection manifested by fever, splenomegaly, and skin and lytic bone lesions. A scaly skin eruption can be observed in a context of maternal T cell engraftment (see below). A diagnosis of SCID can be suspected on the basis of the patient's clinical history and, possibly, a family history of deaths in very young children (suggestive of either X-linked or recessive inheritance). Lymphocytopenia is strongly suggestive of SCID in more than 90% of cases (Table 316-2). The absence of a thymic shadow on a chest x-ray can also be suggestive of SCID. An accurate diagnosis relies on precise determination of the number of circulating T, B, and NK lymphocytes and their subsets. T cell lymphopenia may be masked in some patients by the presence of maternal T cells (derived from maternal-fetal blood transfers) that cannot be eliminated. Although counts are usually low (<500/μL of blood), higher maternal T cell counts may, under some circumstances, initially mask the presence of SCID. Thus, screening for maternal cells by using adequate genetic markers should be performed whenever necessary. Inheritance pattern analysis and lymphocyte phenotyping can discriminate between various forms of SCID and provide guidance in the choice of accurate molecular diagnostic tests (see below). To date, six distinct causative mechanisms for SCID (Fig. 316-3) have been identified:
Severe Combined Immunodeficiency Caused by a Cytokine-Signaling Deficiency
The most frequent SCID phenotype (accounting for 40–50% of all cases) is the absence of both T and NK cells. This outcome results from a deficiency in either the common γ chain (γc) receptor (γc) that is shared by several cytokine receptors (the IL-2, -4, -7, -9, -15, and -21 receptors) or Jak-associated kinase (JAK) 3 that binds to the cytoplasmic portion of the γc chain receptor and induces signal transduction following cytokine binding. The former form of SCID (γc deficiency) has an X-linked inheritance mode, while the second is autosomal recessive. A lack of the IL-7Rα chain (which, together with γc, forms the IL-7 receptor) induces a selective T cell deficiency.
Purine Metabolism Deficiency
Ten to 20% of SCID patients exhibit a deficiency in adenosine deaminase (ADA), an enzyme of purine metabolism that deaminates adenosine (ado) and deoxyadenosine (dAdo). An ADA deficiency results in the accumulation of ado and dAdo metabolites that induce premature cell death of lymphocyte progenitors. The condition results in the absence of B and NK lymphocytes as well as T cells. The clinical expression of complete ADA deficiency typically occurs very early in life. Since ADA is a ubiquitous enzyme, its deficiency can also cause bone dysplasia with abnormal costochondral junctions and metaphyses (found in 50% of cases) and neurologic defects. The very rare purine nucleoside phosphorylase (PNP) deficiency causes a profound although incomplete T cell deficiency that is often associated with severe neurologic impairments.
Defective Rearrangements of T and B Cell Receptors
A series of SCID conditions are characterized by a selective deficiency in T and B lymphocytes with autosomal recessive inheritance. These conditions account for 20–30% of SCID cases and result from mutations in genes encoding proteins that mediate the recombination of V(D)J gene elements in T and B cell antigen receptor genes (required for the generation of diversity in antigen recognition). The main deficiencies involve RAG-1, RAG-2, DNA-dependent protein kinase, and Artemis. A less severe (albeit variable) immunologic phenotype can result from other deficiencies in the same pathway, i.e., DNA ligase 4 and Cernunnos deficiencies. Given that these latter factors are involved in DNA repair, these deficiencies also cause developmental defects.
Defective (Pre-)T Cell Receptor Signaling in the Thymus
A selective T cell defect can be caused by a series of rare deficiencies in molecules involved in signaling via the pre-TCR or the TCR. These include deficiencies in CD3 subunits associated with the (pre)TCR (i.e., CD3δ, ε, and ζ) and CD45.
Reticular dysgenesis is an extremely rare form of SCID that causes T and NK deficiencies with severe neutropenia and sensorineural deafness. It results from an adenylate kinase 2 deficiency.
Defective Egress of Lymphocytes
Defective egress of lymphocytes from the thymus has been found in a patient with very low T cell counts but a normal thymic shadow. This condition was found to result from a deficiency in coronin-1A.
Patients with SCID require appropriate care with aggressive anti-infective therapies, immunoglobulin replacement, and (when necessary) parenteral nutrition support. In most cases, curative treatment relies on HSCT. Today, HSCT provides a very high curative potential for SCID patients who are otherwise in reasonably good condition. In this regard, the feasibility of neonatal screening is now being evaluated. Gene therapy has been found to be successful for cases of X-linked SCID (γc deficiency) and SCID caused by an ADA deficiency, although toxicity has become an issue in the treatment of the former disease. Lastly, a third option for the treatment of ADA deficiency consists of enzyme substitution with a pegylated enzyme.
A profound T cell defect can also result from faulty development of the thymus, as is most often observed in rare cases of DiGeorge syndrome—a relatively common condition leading to a constellation of developmental defects. In approximately 1% of such cases, the thymus is completely absent, leading to virtually no mature T cells. However, expansion of oligoclonal T cells can occur and is associated with skin lesions. Diagnosis (using immunofluorescence in situ hybridization) is based on the identification of a hemizygous deletion in the long arm of chromosome 22. To recover the capability for T cell differentiation, these cases require a thymic graft. CHARGE (coloboma of the eye, heart anomaly, choanal atresia, retardation, genital and ear anomalies) syndrome (CHD7 deficiency) is a less frequent cause of impaired thymus development. Lastly, the very rare "nude" defect is characterized by the absence of both hair and the thymus.
Omenn syndrome consists of a subset of T cell deficiencies that present with a unique phenotype, including early-onset erythrodermia, alopecia, hepatosplenomegaly, and failure to thrive. These patients usually display T cell lymphocytosis, eosinophilia, and low B cell counts. It has been found that the T cells of these patients exhibit a low TCR heterogeneity. This peculiar syndrome is the consequence of hypomorphic mutations in genes usually associated with SCID, i.e., RAG-1, RAG-2, or (less frequently) Artemis or IL-7Rα. The impaired homeostasis of differentiating T cells thus causes this immune system–associated disease. These patients are very fragile, requiring simultaneous anti-infective therapy, nutritional support, and immunosuppression. HSCT provides a curative approach.
Functional T Cell Defects (Fig. 316-2)
A subset of T cell PIDs with autosomal inheritance is characterized by partially preserved T cell differentiation but defective activation resulting in abnormal effector function. There are many causes of these defects, but all lead to susceptibility to viral and opportunistic infections, chronic diarrhea, and failure to thrive, with onset during childhood. Careful phenotyping and in vitro functional assays are required to identify these diseases, the best characterized of which are the following.
Zeta-Associated Protein 70 (ZAP70) Deficiency
Zeta-associated protein 70 is recruited to the TCR following antigen recognition. A ZAP70 deficiency leads typically to an almost complete absence of CD8+ T cells; CD4+ T cells are present but cannot be activated in vitro by TCR stimulation.
Calcium Signaling Defects
A small number of patients have been reported who exhibit a profound defect in in vitro T and B cell activation as a result of defective antigen receptor-mediated Ca2+ influx. This defect is caused by a mutation in the calcium channel gene (ORAI-) or its activator (STIM-1). It is noteworthy that these patients are also prone to autoimmune manifestations (blood cytopenias) and exhibit a nonprogressive muscle disease.
Human Leukocyteantigen (HLA) Class II Deficiency
Defective expression of HLA class II molecules is the hallmark of a group of four recessive genetic defects all of which affect molecules (RFX5, RFXAP, RFXANK, and CIITA) involved in the transactivation of the genes coding for HLA class II. As a result, low but variable CD4+ T cell counts are observed in addition to defective antigen-specific T and B cell responses. These patients are particularly susceptible to herpesvirus, adenovirus, and enterovirus infections and chronic gut/liver Cryptosporidium infections.
Defective expression of molecules involved in antigen presentation by HLA class I molecules (i.e., TAP-1, TAP-2, and Tapasin) leads to reduced CD8+ T cell counts, loss of HLA class I antigen expression, and a particular phenotype consisting of chronic obstructive pulmonary disease and severe vasculitis.
A variety of other T cell PIDs have been described, some of which are associated with a precise molecular defect [e.g., IL-2-inducible T cell kinase (ITK) deficiency]. These conditions are also characterized by profound vulnerability to infections, such as severe Epstein-Barr virus (EBV)–induced B cell proliferation and autoimmune disorders in ITK deficiency. Milder phenotypes are associated with CD8 and CD3γ deficiencies.
HSCT is indicated for most of these diseases, although the prognosis is worse than in SCID because many patients are chronically infected at the time of diagnosis. Fairly aggressive immunosuppression and myeloablation may be necessary to achieve engraftment of allogeneic stem cells.
T Cell Primary Immunodeficiencies with DNA Repair Defects
This is a group of PIDs characterized by a combination of T and B cell defects of variable intensity, together with a number of nonimmunologic features resulting from DNA fragility. The autosomal recessive disorder ataxia-telangiectasia (AT) is the most frequently encountered condition in this group. It has an incidence of 1:40,000 live births and causes B cell defects (low IgA, IgG2 deficiency, and low antibody production), which often require immunoglobulin replacement. Ataxia telangiectasia is associated with a progressive T cell immunodeficiency. As the name suggests, the hallmark features of AT are telangiectasia and cerebellar ataxia. The latter manifestations may not be detectable before the age of 3–4 years, so that AT should be considered in young children with IgA deficiency and recurrent and problematic infections. Diagnosis is based on a cytogenetic analysis showing excessive chromosomal rearrangements (mostly affecting chromosomes 7 and 14) in lymphocytes. Ataxia telangiectasia is caused by a mutation in the gene encoding the ATM protein—a kinase that plays an important role in the detection and repair of DNA lesions (or cell death if the lesions are too numerous) by triggering several different pathways. Overall, AT is a progressive disease that carries a very high risk of lymphoma, leukemia, and (during adulthood) carcinomas. A variant of AT ("AT-like disease") is caused by mutation in the MRE11 gene.
Nijmegen breakage syndrome (NBS) is a less common condition that also results from chromosome instability (with the same cytogenetic abnormalities as in AT). NBS is characterized by a severe T and B cell combined immune deficiency with autosomal recessive inheritance. Individuals with NBS exhibit microcephaly and a bird-like face, but have neither ataxia nor telangiectasia. The risk of malignancies is very high. Nijmegen breakage syndrome results from a deficiency in Nibrin (NBSI, a protein associated with MRE11 and Rad50 that is involved in checking DNA lesions) caused by hypomorphic mutations.
Severe forms of dyskeratosis congenita (also known as Hoyeraal-Hreidarsson syndrome) combine a progressive immunodeficiency that can also include an absence of B and NK lymphocytes, progressive bone marrow failure, microcephaly, in utero growth retardation, and gastrointestinal disease. The disease can be X-linked or, more rarely, autosomal recessive. It is caused by the mutation of genes encoding telomere maintenance proteins, including dyskerin (DKC1).
Finally, the immunodeficiency with centromeric and facial anomalies (ICF) is a complex syndrome of autosomal recessive inheritance that variably combines a mild T cell immune deficiency with a more severe B cell immune deficiency, coarse face, digestive disease, and mild mental retardation. A diagnostic feature is the detection by cytogenetic analysis of multiradial aspects in multiple chromosomes (most frequently 1, 9, and 16) corresponding to an abnormal DNA structure secondary to defective DNA methylation. It is the consequence of a deficiency in the DNA methyltransferase DNMT3B.
T Cell Primary Immunodeficiencies with Hyper-IgE
Several T cell PIDs are associated with elevated serum IgE levels (as in Omenn syndrome). A condition sometimes referred to as autosomal recessive hyper-IgE syndrome is notably characterized by recurrent bacterial infections in the skin and respiratory tract and severe skin and mucosal infections by pox viruses and human papillomaviruses, together with severe allergic manifestations. T and B lymphocyte counts are low. Mutations in the DOCK8 gene have been found in a subset of these patients.
A very rare, related condition with autosomal recessive inheritance that causes a similar susceptibility to infection with various microbes (see above), including mycobacteria, reportedly results from a deficiency in Tyk-2, a JAK family kinase involved in the signaling of many different cytokine receptors.
Autosomal Dominant Hyper-IgE Syndrome (Hies)
This unique condition, the autosomal dominant hyper-IgE syndrome, is usually diagnosed by the combination of recurrent skin and lung infections that can be complicated by pneumatoceles. Infections are caused by pyogenic bacteria and fungi. Several other manifestations characterize HIES, including facial dysmorphy, defective loss of primary teeth, hyperextensibility, scoliosis, and osteoporosis. Elevated serum IgE levels are typical of this syndrome. Recently, defective TH17 effector responses have been shown to account at least in part for the specific patterns of susceptibility to particular microbes. This condition is caused by a heterozygous (dominant) mutation in the gene encoding the transcription factor STAT3 that is required in a number of signaling pathways following binding of cytokine to cytokine receptors (such as that of IL-6 and the IL-6 receptor).
Cartilage Hair Hypoplasia
The autosomal recessive cartilage hair hypoplasia (CHH) disease is characterized by short-limb dwarfism, metaphyseal dysostosis, and sparse hair, together with a combined T and B cell PID of extremely variable intensity (ranging from quasi-SCID to no clinically significant immune defects). The condition can predispose to erythroblastopenia, autoimmunity, and tumors. It is caused by mutations in the RMRP gene for a noncoding ribosome-associated RNA.
CD40 Ligand and CD40 Deficiencies
Hyper-IgM syndrome (HIGM) is a well-known PID that is usually classified as a B cell immune deficiency (see Fig. 316-4 and below). It results from defective immunoglobulin class switch recombination (CSR) in germinal centers and leads to profound deficiency in production of IgG, IgA, and IgE (although IgM production is maintained). Approximately half of HIGM sufferers are also prone to opportunistic infections, e.g., interstitial pneumonitis caused by Pneumocystis jiroveci (in young children), protracted diarrhea and cholangitis caused by Cryptosporidium, and infection of the brain with Toxoplasma gondii.
B cell differentiation and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which give rise to pre-B cells. The B cell differentiation pathway goes through the pre–B cell stage (expression of the μ heavy chain and surrogate light chain), the immature B cell stage (expression of surface IgM), and the mature B cell stage (expression of surface IgM and IgD). The main phenotypic characteristics of these cells are indicated. In lymphoid organs, B cells can differentiate into plasma cells and produce IgM or undergo (in germinal centers) Ig class switch recombination (CSR) and somatic mutation of the variable region of V genes (SHM) that enable selection of high-affinity antibodies. These B cells produce antibodies of various isotypes and generate memory B cells. PIDs are indicated in the purple boxes. CVID: common variable immunodeficiency.
In the majority of cases, this condition has an X-linked inheritance and is caused by a deficiency in CD40 ligand (L). CD40L induces signaling events in B cells that are necessary for both CSR and adequate activation of other CD40-expressing cells that are involved in innate immune responses against the above-mentioned microorganisms. More rarely, the condition is caused by a deficiency in CD40 itself. The poorer prognosis of CD40L and CD40 deficiencies (relative to most other HIGM conditions) implies that (1) thorough investigations have to be performed in all cases of HIGM and (2) potentially curative HSCT should be discussed on a case-by-case basis for this group of patients.
Wiskott-Aldrich syndrome (WAS) is a complex, recessive, X-linked disease with an incidence of approximately 1 in 200,000 live births. It is caused by mutations in the WASP gene that affect not only T lymphocytes but also the other lymphocyte subsets, dendritic cells, and platelets. WAS is typically characterized by the following clinical manifestations: recurrent bacterial infections, eczema, and bleeding caused by thrombocytopenia. However, these manifestations are highly variable—mostly as a consequence of the many different WASP mutations that have been observed. Null mutations predispose affected individuals to invasive and bronchopulmonary infections, viral infections, severe eczema, and autoimmune manifestations. The latter include autoantibody-mediated blood cytopenia, glomerulonephritis, skin and visceral vasculitis (including brain vasculitis), erythema nodosum, and arthritis. Another possible consequence of WAS is lymphoma, which may be virally induced (e.g., by EBV or Kaposi's sarcoma–associated herpesvirus). Thrombocytopenia can be severe and compounded by the peripheral destruction of platelets associated with autoimmune disorders. Hypomorphic mutations usually lead to milder outcomes that are generally limited to thrombocytopenia. It is noteworthy that even patients with "isolated" X-linked thrombocytopenia can develop severe autoimmune disease or lymphoma later in life. The immunologic workup is not very informative; there can be a relative CD8+ T cell deficiency, frequently accompanied by low serum IgM levels and decreased antigen-specific antibody responses. A typical feature is reduced-sized platelets on a blood smear. Diagnosis is based on intracellular immunofluorescence analysis of WAS protein (WASp) expression in blood cells. WASp regulates the actin cytoskeleton and thus plays an important role in many lymphocyte functions, including cell adhesion and migration and the formation of synapses between antigen-presenting and target cells. Predisposition to autoimmune disorders may (at least in part) be related to defective regulatory T cells. The treatment of WAS should match the severity of disease expression. Prophylactic antibiotics, immunoglobulin G (IgG) supplementation, and careful topical treatment of eczema are indicated. Although splenectomy improves platelet count in a majority of cases, this intervention is associated with a significant risk of infection (both pre- and post-HSCT). Allogeneic HSCT is curative, with fairly good results overall. Gene therapy trials are also under way.
A few other complex PIDs are worth mentioning. Sp110 deficiency causes a T cell PID with liver venoocclusive disease and hypogammaglobulinemia. Chronic mucocutaneous candidiasis (CMC) is probably a heterogeneous disease, considering the different inheritance patterns that have been observed. In some cases, chronic candidiasis is associated with late-onset bronchopulmonary infections, bronchiectasis, and brain aneurysms. Moderate forms of CMC are related to autoimmunity and AIRE deficiency (see below). In this setting, predisposition to candida infection is associated with the detection of autoantibodies to TH17 cytokines. Recently, innate immunodeficiencies (CARD9 and possibly Dectin-1) have been found in a few families with CMC.
Deficiencies that predominantly affect B lymphocytes are the most frequent PIDs and account for 60–70% of all cases. B lymphocytes make antibodies. Pentameric IgMs are found in the vascular compartment and are also secreted at mucosal surfaces. IgG antibodies diffuse freely into extravascular spaces, whereas IgA antibodies are produced and secreted predominantly from mucosa-associated lymphoid tissues. Although Ig isotypes have distinct effector functions, including Fc receptor–mediated and (indirectly) C3 receptor–dependent phagocytosis of microorganisms, they share the ability to recognize and neutralize a given pathogen. Defective antibody production therefore allows the establishment of invasive, pyogenic bacterial infections as well as recurrent sinus and pulmonary infections (mostly caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and, less frequently, by gram-negative bacteria). If left untreated, recurrent bronchial infections lead to bronchiectasis and, ultimately, cor pulmonale and death. Parasitic infections such as caused by Giardia lambliasis as well as bacterial infections caused by Helicobacter and Campylobacter of the gut are also observed. A complete lack of antibody production (namely agammaglobulinemia) can also predispose affected individuals to severe, chronic, disseminated enteroviral infections causing meningoencephalitis, hepatitis, and a dermatomyositis-like disease.
Even with the most profound of B cell deficiencies, infections rarely occur before the age of 6 months; this is because of transient protection provided by the transplacental passage of immunoglobulins during the last trimester of pregnancy. Conversely, a genetically nonimmunodeficient child born to a mother with hypogammaglobulinemia is, in the absence of maternal Ig substitution, usually prone to severe bacterial infections in utero and for several months after birth.
Diagnosis of B cell PIDs relies on the determination of serum Ig levels (Table 316-2). Determination of antibody production following immunization with tetanus toxoid vaccine or nonconjugated pneumococcal polysaccharide antigens can also help diagnose more subtle deficiencies. Another useful test is B cell phenotype determination in switched μ−S− CD27+ and nonswitched memory B cells (μ+S+ CD27+). In agammaglobulinemic patients, examination of bone marrow B cell precursors (Fig. 316-4) can help obtain a precise diagnosis and guide the choice of genetic tests.
Agammaglobulinemia is characterized by a profound defect in B cell development (<1% of the normal B cell blood count). In most patients, very low residual Ig isotypes can be detected in the serum. In 85% of cases, agammaglobulinemia is caused by a mutation in the BTK gene that is located on the X-chromosome. The BTK gene product is a kinase that participates in (pre) B cell receptor signaling. When the kinase is defective, there is a block (albeit a leaky one) at the pre-B to B cell stage (Fig. 316-4). Detection of BTK by intracellular immunofluorescence of monocytes, and lack thereof in patients with X-linked agammaglobulinemia, is a useful diagnostic test. Not all of the mutations in BTK result in agammaglobulinemia, since some patients have a milder form of hypogammaglobulinemia and low but detectable B cell counts. These cases should not be confused with common variable immunodeficiency (CVID, see below). About 10% of agammaglobulinemia cases are caused by alterations in genes encoding elements of the pre-B cell receptor, i.e., the μ heavy chain, the λ5 surrogate light chain, Igα or Igβ, and the scaffold protein BLNK. In 5% of cases, the defect is unknown. It is noteworthy that agammaglobulinemia can be observed in patients with ICF syndrome, despite the presence of normal peripheral B cell counts. Lastly, agammaglobulinemia can be a manifestation of a myelodysplastic syndrome (associated or not with neutropenia). Treatment of agammaglobulinemic patients is based on immunoglobulin replacement (see below). Profound hypogammaglobulinemia is also observed in adults, in association with thymoma.
Hyper-IgM (Higm) Syndromes
Hyper-IgM syndrome is a rare B cell PID characterized by defective Ig CSR. It results in very low serum levels of IgG and IgA and elevated or normal serum IgM levels. The clinical severity is similar to that seen in agammaglobulinemia, although chronic lung disease and sinusitis are less frequent and enteroviral infections are uncommon. As discussed above, a diagnosis of HIGM involves screening for an X-linked CD40L deficiency and an autosomal recessive CD40 deficiency, which affect both B and T cells. In 50% of cases affecting only B cells, these isolated HIGM syndromes result from mutations in the gene encoding activation-induced deaminase, the protein that induces CSR in B cell germinal centers. These patients usually have enlarged lymphoid organs. In the other 50% of cases, the etiology is unknown (except for rare UNG and PMS2 deficiencies). Furthermore, IgM-mediated autoimmunity and lymphomas can occur in HIGM syndrome. It is noteworthy that HIGM can result from fetal rubella syndrome or can be a predominant immunologic feature of other PIDs, such as the immunodeficiency associated with ectodermic anhydrotic hypoplasia X-linked NEMO deficiency and the combined T and B cell PIDs caused by DNA repair defects such as ataxia-telangectasia and Cernunnos deficiency.
Common Variable Immunodeficiency (CVID)
CVID is an ill-defined condition characterized by low serum levels of one or more Ig isotypes. Its prevalence is estimated to be 1 in 20,000. The condition is recognized predominantly in adults, although clinical manifestations can occur earlier in life. Hypogammaglobulinemia is associated with at least partially defective antibody production in response to vaccine antigens. B lymphocyte counts are often normal but can be low. Besides infections, CVID patients may develop lymphoproliferation (splenomegaly), granulomatous lesions, colitis, antibody-mediated autoimmune disease, and lymphomas. A family history is found in 10% of cases. A clear-cut dominant inheritance pattern is found in some families, whereas recessive inheritance is observed more rarely. In most cases, no molecular cause can be identified. A small number of patients in Germany were found to carry mutations in the ICOS gene encoding a T cell-membrane protein that contributes to B cell activation and survival. In 10% of patients with CVID, monoallelic or biallelic mutations of the gene encoding TACI (a member of the TNF receptor family that is expressed on B cells) have been found. In fact, heterozygous TACI mutations correspond to a genetic susceptibility factor, since similar heterozygous mutations are found in 1% of controls. The BAFF receptor was found to be defective in a kindred with CVID, although not all individuals carrying the mutation have CVID.
A diagnosis of CVID should be made after excluding the presence of hypomorphic mutations associated with agammaglobulinemia or more subtle T cell defects; this is particularly the case in children. It is possible that many cases of CVID result from a constellation of factors, rather than a single genetic defect. Recently, rare cases of hypogammaglobulinemia were found to be associated with CD19 and CD81 deficiencies. These patients have B cells that can be identified by typing for other B cell markers.
Selective Ig Isotype Deficiencies
IgA deficiency and CVID represent polar ends of a clinical spectrum due to the same underlying gene defect(s) in a large subset of these patients. IgA deficiency is the most common PID; it can be found in 1 in every 600 individuals. It is asymptomatic in most cases; however, individuals may present with increased numbers of acute and chronic respiratory infections that may lead to bronchiectasis. In addition, over their lifetime, these patients experience an increased susceptibility to drug allergies, atopic disorders, and autoimmune diseases. Symptomatic IgA deficiency is probably related to CVID, since it can be found in relatives of patients with CVID. Furthermore, IgA deficiency may progress to CVID. It is thus important to assess serum Ig levels in IgA-deficient patients (especially when infections occur frequently) in order to detect changes that should prompt the initiation of immunoglobulin replacement. Selective IgG2 (+G4) deficiency (which in some cases may be associated with IgA deficiency) can also result in recurrent sinopulmonary infections and should thus be specifically sought in this clinical setting. These conditions are ill-defined and a pathophysiologic explanation has not been found.
Selective Antibody Deficiency to Polysaccharide Antigens
Some patients with normal serum Ig levels are prone to S. pneumoniae and H. influenzae infections of the respiratory tract. Defective production of antibodies against polysaccharide antigens (such as those in the S. pneumoniae cell wall) can be observed and is probably causative. This condition may correspond to a defect in marginal zone B cells, a B cell subpopulation involved in T-independent antibody responses.
IgG antibodies have a half-life of 21–28 days. Thus, injection of plasma-derived polyclonal IgG containing a myriad of high-affinity antibodies can provide protection against disease-causing microorganisms in patients with defective IgG antibody production. This form of therapy should not be based on laboratory data alone (i.e., IgG and/or antibody deficiency) but should be guided by the occurrence or not of infections; otherwise, patients might be subjected to unjustified IgG infusions. Immunoglobulin replacement can be performed by IV or subcutaneous routes. In the former case, injections have to be repeated every 3–4 weeks, with a residual target level of 800 mg/mL in patients who had very low IgG levels prior to therapy. Subcutaneous injections are typically performed once a week, although the frequency can be adjusted on a case-by-case basis. A trough level of 800 mg/mL is desirable. Whatever the mode of administration, the main goal is to reduce the frequency of the respiratory tract infections and prevent chronic lung and sinus disease. The two routes appear to be equally safe and efficacious and so the choice should be left to the preference of the patient.
In patients with chronic lung disease, chest physical therapy with good pulmonary toilet and the cyclic use of antibiotics are also needed. Immunoglobulin replacement is well tolerated by most patients, although the selection of the best-tolerated Ig preparation may be necessary in certain cases. Since IgG preparations contain a small proportion of IgAs, caution should be taken in patients with residual antibody production capacity and a complete IgA deficiency, as these subjects may develop anti-IgA antibodies that can trigger anaphylactic shock. These patients should be treated with IgA-free IgG preparations. Immunoglobulin replacement is a lifelong therapy; its rationale and procedures have to be fully understood and mastered by the patient and his or her family, in order to guarantee the strict observance required for efficacy.