Common variable immunodeficiency (CVID) covers a variety of different primary antibody deficiencies (PIDD) with specific clinical manifestations and immunological phenotypes. The first genetic defect correlating with CVID was discovered in 2002. Since then, there has been a steadily increasing number of yearly publications on CVID (Pubmed graph, http://www.medscape.com/viewarticle/733149_10).
Typical pattern of immunoglobulin levels (IgG, IgA, IgM) in humoral immunodeficiency. Click here to enlarge the table.
New gene defects associated with a CVID phenotype have been described in BAFF-receptor (BAFF-R), CD81, and CD20 in single consanguineous families.
New genetic defects in CVID:
- BAFF-receptor Deficiency
BAFF-receptor (BAFF-R), TACI, and BCMA are members of the TNF-R family, which regulate the survival and homeostasis of B cells. All three receptors bind a TNF-like ligand, termed BAFF or BLyS. TACI and BCMA also bind the BAFF-related ligand APRIL.
So far, only mutations in the TACI and in the BAFF-R gene have been associated with CVID.
BAFF-R and BCR are the most important survival receptors of B cells. Nevertheless, the lack of BAFF-R function can be compensated to some extent by the plasticity of the immune system, thus allowing protective immune responses in spite of BAFF-R deficiency.
- CD20 Deficiency
CD20 is a multimeric protein complex expressed on the cell surface of B cells. CD20 is involved in the regulation of Ca2+ transport across the cell membrane.
- CD81 Deficiency
CD19 forms a complex together with CD21, CD81, and CD225. The complex lowers the B-cell receptor-signaling threshold by amplifying the BCR signal in response to antigens.
TLR signaling defects in CVID
TLR signaling defects also play a role in the etiology of CVID. TLR7/8 function is even more impaired in CVID patients than TLR9 function.
CD21-low B Cells and calcium signaling in CVID
The CD21-low B-cell subpopulation in CVID is somewhat better understood now but still leaving their origin obscure. Complement receptor 2 (CR2/CD21) is part of the B-cell coreceptor and expressed by mature B cells and follicular dendritic cells. CD21 is a receptor for C3d-opsonized immune complexes and enhances antigen-specific B-cell responses. Viruses, such as HIV and EBV, use the complement receptors (CR2) to the enter the cell. Genetic CD21 deficiency is associated with hypogammaglobulinemia (JACI, 2011).
T cells in CVID
Further immunophenotypic analysis of T and B cells in large CVID patient cohorts revealed subgroups with signs of severely disturbed cellular immunity.
Several trials described the reduction of regulatory T cells in a subgroup of CVID patients. There is an association between low numbers of regulatory T cells and an autoimmune manifestation, granulomatous disease and splenomegaly.
Common Variable Immunodeficiency at the End of a Prospering Decade: Towards Novel Gene Defects and Beyond. Curr Opin Allergy Clin Immunol. 2010;10(6):526-533, Medscape, 2011.