Identifying New Genetic Defects in Common Variable Immunodeficiency (CVID)

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,

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.

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