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Primary Defects of Antibody Production
Of the primary immunodeficiency diseases, those affecting antibody production are the most prevalent. Selective absence of IgA is the most common defect, with rates ranging from 1 in 333 to 1 in 18,000 persons among different races and ethnicities. Patients with antibody deficiency are usually recognized because they have recurrent infections with encapsulated bacteria, predominantly in the upper and lower respiratory tracts. Some individuals with selective IgA deficiency or infants with transient hypogammaglobulinemia may have few or no infections. These conditions have a complex and likely polygenic inheritance, as do the common variable immunodeficiency (CVID) syndromes. The gene defects for many primary antibody deficiency disorders have been identified ( Table 150.1 ) and localized ( Fig. 150.1 ). Sometimes the defect is not in the B cell itself but in T cells, which are required for complete B-cell function. Some disorders are caused by unknown factors or are secondary to an underlying disease or its treatment ( Table 150.2 ).
Table 150.1
Genetic Basis of the Most Common Primary Antibody Deficiency Disorders
| GENE | PHENOTYPE | DISORDER |
|---|---|---|
| BAFFR | CVID | Hypogammaglobulinemia |
| CD19 | CVID | Hypogammaglobulinemia |
| CD20 | CVID | Hypogammaglobulinemia |
| CD21 | CVID | Hypogammaglobulinemia |
| CD81 | CVID | Hypogammaglobulinemia |
| CTLA4 | CVID | Hypogammaglobulinemia, pronounced lymphoproliferation and autoimmunity |
| ICOS | CVID | Hypogammaglobulinemia, autoimmunity, neoplasia |
| LRBA | CVID | Hypogammaglobulinemia, pronounced lymphoproliferation and autoimmunity |
| NFKB2 | CVID | Hypogammaglobulinemia, autoimmunity |
| NFKB1 | CVID | Hypogammaglobulinemia, autoimmunity |
| PIK3CD | CVID | Hypogammaglobulinemia, adenopathy |
| PI3KR1 (AD) | CVID | Hypogammaglobulinemia |
| TNFRSF13B | CVID | Hypogammaglobulinemia, low penetrance of disease |
| Unknown | CVID | Hypogammaglobulinemia, autoimmunity Majority of patients with CVID have no known gene defect. |
| Unknown | IgG subclass deficiency | Variable association with infection |
| Unknown | Specific antibody deficiency | Normal immunoglobulin levels with poor vaccine responses |
| Unknown | Transient hypogammaglobulinemia of infancy | Vaccine responses are usually preserved, and most children outgrow this by age 3 yr. |
| Unknown | Selective IgA deficiency | Low or absent IgA; low concentrations of all immunoglobulins and of switched memory B cells in CVID |
| BLNK | Agammaglobulinemia | Absence of antibody production, lack of B cells |
| BTK | Agammaglobulinemia | Absence of antibody production, lack of B cells, X-linked agammaglobulinemia |
| CD79A | Agammaglobulinemia | Loss of the Igα required for signal transduction, absence of antibody production, lack of B cells |
| CD79B | Agammaglobulinemia | Loss of the Igβ required for signal transduction, absence of antibody production, lack of B cells |
| IGHM | Agammaglobulinemia | Loss of the Ig heavy chain, absence of antibody production, lack of B cells |
| IGLL1 | Agammaglobulinemia | Loss of the surrogate light chain, absence of antibody production, lack of B cells |
| PI3KR1 (AR) | Agammaglobulinemia | Loss of signal transduction through the B-cell receptor, absence of antibody production, lack of B cells |
| TCF3 | Agammaglobulinemia | Loss of a key transcription factor for B-cell development, absence of antibody production, lack of B cells |
| AID | Class switch defect | Failure to produce IgG, IgA, and IgE antibodies |
| CD40 | Class switch defect | Failure to produce IgG, IgA, and IgE antibodies, Pneumocystis and Cryptosporidium susceptibility |
| CD154 | Class switch defect | Failure to produce IgG, IgA, and IgE antibodies, Pneumocystis and Cryptosporidium susceptibility |
| INO80 | Class switch defect | Failure to produce IgG, IgA, and IgE antibodies |
| MSH6 | Class switch defect | Failure to produce IgG, IgA, and IgE antibodies, malignancy |
| UNG | Class switch defect | Failure to produce IgG, IgA, and IgE antibodies |
| SH2D1A | X-linked lymphoproliferative disease | Various phenotypes including hypogammaglobulinemia |
| XIAP | X-linked lymphoproliferative disease | Various phenotypes including hypogammaglobulinemia |
| CD27 | EBV lymphoproliferation | Memory B-cell deficiency Hypogammaglobulinemia |
| NEMO | Anhidrotic ectodermal dysplasia with immunodeficiency | Phenotype highly variable but includes specific antibody deficiency and CVID |
CVID, Common variable immunodeficiency; EBV, Epstein-Barr virus.
The pre-B cell receives proliferation and differentiation signals through the pre–B-cell receptor (BCR) and the co-receptors Igα and Igβ. Signaling from the pre-BCR involves the immunoreceptor tyrosine-based activation motifs (ITAMs) of the co-receptors Igα and Igβ, which scaffold and activate the tyrosine kinase SYK. SYK either activates the extracellular signal–regulated kinase (ERK) pathway or phosphorylates (P) (together with LYN) the adaptor protein B-cell linker (BLNK) and Bruton tyrosine kinase (BTK), leading to the activation of phospholipase Cγ2 (PLCγ2) and the phosphoinositide-3 kinase (PI3K) pathway. Defects in this pathway affect the pre-BCR (in Cµ or pseudo light-chain λ5), the pre-BCR signal transduction molecules Igα and Igβ, the downstream molecules BTK, BLNK, and PI3K, components of the co-stimulatory CD19 complex (CD19, CD21, and CD81), and the B-cell marker CD20. The BCR triggers the canonical nuclear factor-κB (NF-κB) pathway through the scaffolding protein CARD11 and activation of the IκB kinase (IKK) complex (comprising IKKα, IKKβ, and NEMO [NF-κB essential modulator]). IKK activation leads to the phosphorylation and degradation of NF-κB inhibitor-α (IκBα) and the subsequent release of the p50-p65 NF-κB heterodimer, which then translocates to the nucleus to regulate gene transcription ( not shown ). Following antigen binding to antigen receptors (e.g., BCR), endoplasmic reticulum Ca 2+ stores are depleted, STIM1 is activated, and ORAI1 Ca 2+ release-activated Ca 2+ channels open, resulting in store-operated Ca 2+ entry. This influx results in activation of the transcription factor NFAT (nuclear factor of activated T cell). The dashed arrows indicate downstream signaling events. ER, Endoplasmic reticulum; PAD, primary antibody deficiency; PtdIns(4,5)P 2 , phosphatidylinositol-4,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol-3,4,5-trisphosphate.
(From Durandy A, Kracker S, Fischer A. Primary antibody deficiencies. Nat Rev Immunol 13:521, 2013).
Table 150.2
Other Conditions Associated With Humoral Immunodeficiency
| GENETIC DISORDERS | |
| T-cell defects | Most T-cell defects can have a secondary deficit in immunoglobulin. |
| Complex syndromes | Transcobalamin II deficiency and hypogammaglobulinemia, Wiskott-Aldrich syndrome, ataxia telangiectasia, etc. |
| Chromosomal anomalies | Chromosome 18q− syndrome 22q11.2 deletion Trisomy 8, trisomy 21 |
| SYSTEMIC DISORDERS | |
| Malignancy | Chronic lymphocytic leukemia Immunodeficiency with thymoma T-cell lymphoma |
| Metabolic or physical loss | Immunodeficiency caused by hypercatabolism of immunoglobulin |
| Immunodeficiency caused by excessive loss of immunoglobulins and lymphocytes | |
| ENVIRONMENTAL EXPOSURES | |
| Drug induced | Antimalarial agents Captopril Carbamazepine Glucocorticoids Fenclofenac Gold salts Imatinib Penicillamine Phenytoin Sulfasalazine |
| Infectious diseases | Congenital rubella Congenital infection with cytomegalovirus Congenital infection with Toxoplasma gondii Epstein-Barr virus Human immunodeficiency virus |
X-Linked Agammaglobulinemia
Patients with X-linked agammaglobulinemia ( XLA ), or Bruton agammaglobulinemia , have a profound defect in B-lymphocyte development resulting in severe hypogammaglobulinemia, an absence of circulating B cells, small to absent tonsils, and no palpable lymph nodes.
Genetics and Pathogenesis
The abnormal gene in XLA maps to q22 on the long arm of the X chromosome and encodes the B-cell protein tyrosine kinase Btk (Bruton tyrosine kinase). Btk is a member of the Tec family of cytoplasmic protein tyrosine kinases and is expressed at high levels in all B-lineage cells, including pre-B cells. Some pre-B cells are found in the bone marrow, but the percentage of peripheral blood B lymphocytes is <1%. The percentage of T cells is increased, ratios of T-cell subsets are normal, and T-cell function is intact. The thymus is normal.
Seven autosomal recessive defects have also been shown to result in agammaglobulinemia with an absence of circulating B cell s (see Table 150.1 ), including mutations in the genes encoding (1) the µ heavy chain gene; (2) the Igα and (3) Igβ signaling molecules; (4) B-cell linker adaptor protein (BLNK); (5) the surrogate light chain, λ5/14.1; (6) leucine-rich repeat-containing 8 (LRRC8); and (7) the p85α subunit of phosphatidylinositol-3 kinase. These are rare but are clinically indistinguishable from the X-linked form.
Clinical Manifestations
Most boys afflicted with XLA remain well during the first 6-9 mo of life by virtue of maternally transmitted IgG antibodies. Thereafter, they acquire infections with extracellular pyogenic organisms, such as Streptococcus pneumoniae and Haemophilus influenzae, unless they are given prophylactic antibiotics or immunoglobulin therapy. Infections include sinusitis, otitis media, pneumonia, or, less often, sepsis or meningitis. Infections with Mycoplasma are also particularly problematic. Chronic fungal infections are seen; Pneumocystis jiroveci pneumonia rarely occurs. Viral infections are usually handled normally, with the exceptions of hepatitis viruses and enteroviruses. There were several examples of paralysis when live polio vaccine was administered to these patients, and chronic, eventually fatal, central nervous system (CNS) infections with various echoviruses and coxsackieviruses have occurred in a significant number of patients. An enterovirus-associated myositis resembling dermatomyositis has also been observed. Neutropenia , typically seen at diagnosis when infected, can be associated with Pseudomonas or staphylococcal infections.
Diagnosis
The diagnosis of XLA should be suspected if lymphoid hypoplasia is found on physical examination (minimal or no tonsillar tissue and no palpable lymph nodes), and serum concentrations of IgG, IgA, IgM, and IgE are far below the 95% confidence limits for appropriate age- and race-matched controls; total immunoglobulins are usually <100 mg/dL. Levels of natural antibodies to type A and B red blood cell polysaccharide antigens (isohemagglutinins) and antibodies to antigens given during routine immunizations are abnormally low in XLA, whereas they are typically normal in transient hypogammaglobulinemia of infancy. Flow cytometry is an important test to demonstrate the absence of circulating B cells , which will distinguish XLA from most types of CVID, the hyper-IgM syndrome, and transient hypogammaglobulinemia of infancy.
Common Variable Immunodeficiency
CVID is a syndrome characterized by hypogammaglobulinemia. Serum IgG must be <2 standard deviations below the age-adjusted norms, with low IgA and or IgM levels. CVID patients may appear similar clinically to those with XLA in the types of infections experienced and bacterial etiologic agents involved, except that enterovirus meningoencephalitis is rare in patients with CVID ( Table 150.3 ). In contrast to XLA, the sex distribution in CVID is almost equal, the age at onset is later, and infections may be less severe. CVID is the most common of the antibody defects.
Table 150.3
Main Phenotypes of Primary Antibody Deficiencies
| PHENOTYPE | MAIN CLINICAL FEATURES | MAIN B-CELL FEATURES |
|---|---|---|
| Agammaglobulinemia | Bacterial infections (in respiratory tract) and enterovirus infections | Absence of CD19 B cells |
| Combined variable immunodeficiency (CVID) | Bacterial infections (in respiratory tract and gut), autoimmunity, cancer, and increased risk of granuloma | Highly variable; may see decreased memory B cells |
| Class switch defects | Bacterial and opportunistic infections | Decreased frequency of memory B cells |
| Selective IgA deficiency | Most often asymptomatic | Normal |
| IgG subclass deficiency | Frequent bacterial infections; diagnosis after age 2 yr | B-cell subsets normal |
| Selective polysaccharide antibody deficiency | Bacterial infections (after age 2 yr) | Normal IgG (including IgG2 and IgG4) levels, normal B-cell subsets |
Genetics and Pathogenesis
CVID is a phenotypic diagnosis with a polygenic inheritance in most cases. Genes known to produce the CVID phenotype when mutated include ICOS (inducible co-stimulator) deficiency, SH2DIA (responsible for X-linked lymphoproliferative disease [XLP]), CD19, CD20, CD21, CD81, BAFF-R (B-cell–activating factor of the tumor necrosis factor family of receptors), TACI (transmembrane activator, calcium modulator, and cyclophilin ligand interactor). These mutations in aggregate account for <10% of all cases of CVID. With rare exceptions, management of CVID does not depend on a genetic diagnosis. In the setting of atypical infections or autoimmunity, pursuing a genetic diagnosis can be useful because some genetic etiologies can have a poor prognosis and transplantation should be considered.
Despite normal numbers of circulating B cells in many patients and the presence of lymphoid cortical follicles, blood B cells from CVID patients do not differentiate normally into immunoglobulin-producing cells. They may have a deficiency of switched memory B cells.
Clinical Manifestations
The serum immunoglobulin and antibody deficiencies in CVID are associated with recurrent sinopulmonary infections. Repeated pulmonary infections may produce bronchiectasis. Sepsis and meningitis with encapsulated bacteria occur more frequently than in the general population. Patients with recurrent infections as their only manifestation typically have a normal life expectancy and do well with immunoglobulin replacement. The presence of autoimmune disease or lymphoproliferation confers a poor prognosis. Patients with CVID often have autoantibody formation and normal-sized or enlarged tonsils and lymph nodes; about 25% of patients have splenomegaly. CVID has also been associated with a spruelike enteropathy with or without nodular lymphoid hyperplasia of the intestine. Other autoimmune diseases include alopecia areata, hemolytic anemia, thrombocytopenia, gastric atrophy, achlorhydria, and pernicious anemia. Lymphoid interstitial pneumonia, intestinal lung disease, pseudolymphoma, B-cell lymphomas, amyloidosis, and noncaseating sarcoid-like granulomas of the lungs, spleen, skin, and liver also occur. There is an increased risk of lymphomas.
Selective IgA Deficiency
An isolated absence or near absence (<5 mg/dL) of serum and secretory IgA is the most common well-defined immunodeficiency disorder, with a disease frequency as high as 0.33% in some populations. Patients may be asymptomatic or may develop sinopulmonary or gastrointestinal (GI) infections (especially Giardia ). IgA deficiency is also associated with celiac disease and autoimmune disorders. The diagnosis cannot be made until about 4 yr of age, when IgA levels should be matured to adult levels.
The basic defect resulting in IgA deficiency is unknown. Phenotypically normal blood B cells are present. This defect also often occurs in pedigrees containing individuals with CVID. Indeed, IgA deficiency may evolve into CVID. IgA deficiency is noted in patients treated with the same drugs associated with producing CVID (phenytoin, d -penicillamine, gold, and sulfasalazine), suggesting that environmental factors may trigger this disease in a genetically susceptible person.
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