TNFRSF13B
The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells.
The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TNFRSF13B (TACI) and BCMA is crucial for development and maintenance of humoral immunity in mice and humans.
Pathology
germline mutations of TNFRSF13B in
- common variable immune deficiency (CVID) (MIM.240500)
- IgA deficiency
TACI deficient B cells are resistant to IgG production, even in the presence of CD40L, demonstrating the complex pathway of isotype switching.
This may help explain the variability of disease, as different mutations anywhere along the sequence of B-cell activation and maturation can cause a similar phenotypic picture.
In addition, the expression of mutations in TACI may be affected by environmental or genetic factors, akin to other immune disorders such as celiac disease.
A viral trigger may be responsible in a genetically susceptible host. This is not unreasonable considering that Epstein-Barr virus (EBV) has been shown to bypass T-cell signaling, and itself activate the CD40 signal involved in class switching, a pathway that is closely related to TACI and BAFF/APRIL.
Though genetic mutations are currently being discovered, a complex interaction between a virus and immune system may still be a factor.
Maternal antibodies to IgA seem to correlate with IgA deficiency development in a child, and a similar mechanism may be behind the development of some cases of CVID, especially in a genetically susceptible host.
A subset of CVID patients display homozygous loss of the inducible costimulator on activated T cells.
As more is discovered about the mutations that may result in dysregulation of B-cell maturation and isotype switching, CVID may be relegated to an umbrella diagnosis embracing the clinical phenotypes of TACI deficiency (TNFRSF13B MIM.604907), BAFF deficiency (TNFSF13B MIM.603969), APRIL deficiency (TNFSF13 MIM.604472), loss of inducible costimulator, etc.
The potential is that each of the receptors (and ligands) in these pathways has its own set of mutations that cause CVID, resulting is a heterogeneous clinical picture.
References
Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schaffer AA, Hammarstrom L, Grimbacher B. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005 Aug;37(8):820-8. PMID: #16007087#
Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, Geha RS. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005 Aug;37(8):829-34. PMID: #16007086#