TABLE 49.2.
Predominant Antibody Deficiencies
| Disease | Mode of Inheritance/Genetic Locus | Clinical Features | |
|---|---|---|---|
| Severe reduction in all serum immunoglobulin isotypes with absent B cells |
Bruton tyrosine kinase deficiency | XL/Xq21.3–22 | Severe bacterial infections (especially of the respiratory tract), absent lymphoid tissue |
| µ heavy chain deficiency | AR/14q32.3 | Severe bacterial infections | |
| λ5 deficiency | AR/22q11.21 | Severe bacterial infections | |
| Igα deficiency | AR/19q13.2 | Severe bacterial infections | |
| Igβ deficiency | AR/17q23 | Severe bacterial infections | |
| BLNK deficiency | AR/10q23.2 | Severe bacterial infections | |
| SP110 deficiency | AR/2q37.1 | Hepatic veno-occlusive disease, some with frequent infection | |
| LRRC8A deficiency | AD/9q34.11 | Facial anomalies | |
| PIK3R1 | AR/5q13.1 | Recurrent bacterial infection | |
| Thymoma with immunodeficiency (Good syndrome) | None | Recurrent infection with encapsulated bacteria and diarrhea, autoimmune phenomena | |
| Myelodysplasia | Variable/monosomy 7, trisomy 8, dyskeratosis congenita | Recurrent infections and pancytopenia | |
| Severe reduction in at least two serum immunoglobulin isotypes with low or normal B-cell numbers |
Common variable immunodeficiency syndromes | ≈10% with family history AR or AD | Recurrent respiratory tract infections leading to chronic sinusitis, hearing loss, bronchiectasis, autoimmune disease, lymphoproliferation, malignancy (especially non-Hodgkin lymphoma and gastric carcinoma) |
| TACI alterations | AD and AR/17p11.2 | ||
| BAFFR alterations | AR/22q13 | ||
| MSH5 alterations | Unk/6p22.1-p21.3 | ||
| ICOS deficiency | AR/2q33 | Recurrent infections | |
| CD19 deficiency | AR/16p11.2 | Recurrent infections | |
| X-linked lymphoproliferative disease (mutation in SH2 domain protein 1A) | XL/Xq25–q26 | Fulminant infection with EBV, lymphoma, dysgammaglobulinemia | |
| CD81 deficiency | AR/11p15.5 | Recurrent infections | |
| CD20 deficiency | AR/11q12.2 | Recurrent infections | |
| CD21 deficiency | AR/1q32.2 | Recurrent infections | |
| LRBA deficiency | AR/4q31.3 | Recurrent infections, inflammatory bowel disease, EBV infection | |
| TNSF12 deficiency | AD/17p13.1 | Recurrent bacterial infections, thrombocytopenia, neutropenia | |
| NFKB2 deficiency | AD/10q24.32 | Recurrent infections | |
| CXCR4 activation | AD gain of function/2q22.1 | WHIM syndrome | |
| Severe reduction in serum IgG and IgA with increased IgM and normal B-cell numbers (disorders of immunoglobulin class switching) |
CD40 ligand deficiency | XL/Xq26.3-Xq27.1 | Recurrent infections with bacteria and opportunistic pathogens, neutropenia, autoimmune disease |
| CD40 deficiency | AR/20q11-20q13.2 | Recurrent infections with bacteria and opportunistic pathogens, neutropenia, autoimmune disease | |
| NEMO hypomorphic mutations | XL/Xq28 | Recurrent infections with bacteria and opportunistic pathogens, neutropenia, autoimmune disease | |
| AID deficiency | AR/12p13 | Recurrent bacterial infections and diarrhea, marked enlargement of lymphoid organs | |
| UNG deficiency | AR/12q23–q24.1 | Recurrent bacterial infections and diarrhea, marked enlargement of lymphoid organs | |
| Isotype or light-chain deficiencies with normal B-cell numbers |
Ig heavy-chain deficiency | AR/14q32 | Most patients are healthy |
| κ-chain deficiency | AR/2p11.2 | Most patients are healthy | |
| Isolated IgG subclass deficiency | Variable/unknown | Most patients are healthy | |
| IgA deficiency associated with IgG subclass deficiency | Variable/unknown | Most patients are healthy | |
| Selective IgA deficiency | Variable/unknown | Most patients asymptomatic, but increased prevalence of infections, autoimmune disease, atopy, and celiac disease | |
| PRKCδ deficiency | AR/3p21.1 | Recurrent infection, autoimmunity, and chronic EBV infection | |
| Activated PI3K-γ | AD gain of function/1p36.22 | Recurrent infection, autoimmunity, chronic EBV, and CMV infection | |
| Specific antibody deficiency with normal immunoglobulin level and B-cell number | Inability to make antibodies to specific antigens | Variable/unknown | Recurrent sinopulmonary infection, bronchiectasis, diarrhea, autoimmune disease |
| Transient hypogammaglobulinemia of infancy | IgG and IgA deficiency | Variable/unknown | More likely to be male (60%–80%), mild infections and diarrhea, atopy |
λ5, Immunoglobulin lambda-like polypeptide (a surrogate light chain subunit that is part of the pre–B-cell receptor); AID, activation-induced cytidine deaminase (thought to be essential for initiation of the DNA cleavage required for class-switch recombination and somatic hypermutation); BAFF-R, B-cell–activating factor receptor; BLNK, B linker (a cytoplasmic linker or adaptor protein that plays a critical role in B-cell development); CMV, cytomegalovirus; CXCR4, CXC-chemokine receptor 4 (mediates migration of resting leukocytes and hematopoietic progenitors in response to its ligand, stromal cell–derived factor 1 [SDF1]); EBV, Epstein–Barr virus; ICOS, inducible T-cell costimulator (belongs to CD28 family of costimulatory surface molecules); Ig, immunoglobulin; Igα, immunoglobulin-associated α (necessary for expression and function of the B-cell antigen receptor); Igβ, immunoglobulin-associated β (necessary for expression and function of the B-cell antigen receptor); LRBA, lipopolysaccharide-responsive, beige-like anchor protein (implicated in regulating endosomal trafficking, particularly endocytosis of ligand-activated receptors); MSH5, mutS homolog 5 (a protein involved with DNA mismatch repair and meiotic recombination); NEMO, NFκB essential modulator; NFκB, nuclear factor kappa-B; PRKCD, member of the protein kinase c family (involved in B-cell receptor-mediated signaling); PI3K-γ, protein kinase C family member (critical for regulation of cell survival, proliferation, and apoptosis); TACI, transmembrane activator and CAML-interactor; TNSF12, tumor necrosis factor ligand superfamily, member 12 (weak inducer of apoptosis); UNG, uracil DNA glycosylase (allows creation of single-stranded breaks essential to class switch recombination and somatic hypermutation); WHIM syndrome, warts, hypogammaglobulinemia, infections, and myelokathexis.