What causes common variable immunodeficiency (CVID)?

Updated: Oct 16, 2018
  • Author: C Lucy Park, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Answer

This disorder likely has various causes, and a single etiology is unlikely. The search for gene(s) that underlie common variable immunodeficiency has been difficult, partly because of the heterogeneity. Although most cases are sporadic, at least 10% are familial with autosomal dominant inheritance more common than autosomal recessive inheritance.

The following genetic defects have been described in patients with common variable immunodeficiency: TACI (transmembrane activator and calcium-modulating cyclophilin ligand interactor, TNFRSF13B), ICOS (inducible costimulator of activated T cells), CD19 deficiency, BAFFR (B-cell activating factor of the TNF family receptor, TNFRSF13C), CD81, CD20, and CD21. [7]

Table 1. Genetic Defects in Common Variable Immunodeficiency (Open Table in a new window)

Genetic defect

Chromosomal location

Inheritance

Phenotype

B cells

TNFRSF13B (TACI); approximately 10% of cases

17p11.2

Autosomal dominant (AD)

Common variable immunodeficiency, selective immunoglobulin A deficiency (SIgAD)

< 5% of cases involve absent TACI expression; 95% of cases have normal TACI expression on B cells; low-to-absent IgA levels; autoimmune disease; lymphoproliferative disease; splenomegaly; reduced class-switched memory B cells

TNFRSF13C (BAFF-R); < 1% of cases

22q13.2

Autosomal recessive (AR)

Late-onset, incomplete penetrance

Absent BAFF-R on B-cell surface; reduced class-switched and non–class-switched memory B cells; increased transitional B cells; impaired response to polysaccharide antigen

ICOS; approximately 2% of cases

2q33

AR

Early and late onset

Absent ICOS on activated T cells; reduced class-switched memory B cells; nodular lymphoid hyperplasia; autoimmunity; predisposition to neoplasm

CD19; < 1% of cases

16p11.2

AR

Early and late onset

Low-to-absent CD19 on B cells; reduced class-switched memory B cells; low CD21+ expression on B cells; normal number of CD20+ cells in peripheral blood

CD81; < 1% of cases

 

AR

Unclear

Impaired Ca++ flux after BCR stimulation; autoimmunity; impaired response to protein and polysaccharide antigens; nearly absent CD19 expression

CD20; < 1% of cases

 

AR

Unclear

Reduced switched memory B cells; impaired somatic hypermutation; impaired response to pneumococcal polysaccharide antigens

CD21; < 1% of cases

 

AR

Unclear

Reduced class-switched memory B cells; hypogammaglobulinemia; reduced binding of C3d-containing immune complexes and EBV-gp350 to B cells; impaired response to pneumococcal polysaccharide antigens

Mutations in the gene that encodes TACI were reported in 10–15% of patients with common immunodeficiency and in a smaller number of patients with IgA deficiency. TACI is one of 3 tumor necrosis factor (TNF)–receptor family members and mediates isotype switching in B cells. TACI mutations were associated with both familial and sporadic forms of common variable immunodeficiency. TACI deficiency phenotype varies from asymptomatic hypogammaglobulinemia and SIgAD to full-blown common variable immunodeficiency. This variable penetrance may reflect the ability of BCMA and BAFFR to substitute for TACI functions.

A common genetic basis for common variable immunodeficiency and SIgAD has been suspected because these disorders occur in first-degree relatives of patients. Families of both types of patients have high incidences of abnormal Ig concentrations, autoantibodies, autoimmune diseases, and malignancies. Familial occurrences of SIgAD and common variable immunodeficiency have been observed in approximately 20% of cases, including reported cases of SIgAD developing into common variable immunodeficiency over time and, occasionally, vice versa, which suggests these conditions are closely linked and can be progressive or reversible.

Other gene mutations reportedly associated with common variable immunodeficiency include ICOS on chromosome 2q, CD19 on 16p, and BAFFR on 22q.

Multiple allelic DNA and protein markers were used to examine the extended HLA-DR3, HLA-B8, and HLA-A1 haplotypes in a large American family with several members affected with SIgAD/CVID. [8] This examination identified a susceptibility locus in the class III region within a fragment that contains 21 known genes, including the genes for TNF-alpha, lymphotoxin (LT)-alpha, and LT-beta. This area, the so-called class IV region, contains a heavy concentration of genes that may play important roles in stress, inflammation, or infection. Others reported that certain major histocompatibility complex (MHC) haplotypes, which were found in abnormally high frequency in immunodeficient patients, were also found in normal members of the pedigree. These findings suggest that the presence of these MHC haplotypes alone is not sufficient for expression of the defects.

Common variable immunodeficiency and SIgAD have been associated with anti-rheumatic or anti-epileptic drugs, including azathioprine, cyclosporine, D-penicillamine, gold, sulfasalazine, carbamazepine, levetiracetam, oxcarbazepine, and phenytoin. Immunoglobulin may be normalized after months to years of medication avoidance. Drug-associated common variable immunodeficiency or SIgAD suggests that a pathogenetic process may involve common key steps in individuals with the permissive genetic background.

Each BAFF-R, CD20, and CD81 gene defects is represented by only one consanguineous family and is proof of a definite causal relationship requires for identification of additional affected families.


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