Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency.

摘要

Tumor necrosis factor (TNF)-like receptors are members of a superfamily of proteins involved in regulating maturation and survival of lymphocytes. One of these receptors, TACI (trans-membrane activator and CAML interactor; encoded by TNFRSF13B), binds two ligands, BAFF and APRIL. Deletion of Tnfrsf13b in mice results in an impaired response to thymus-independent antigens and virtually abolishes APRIL-induced switching to IgA, IgE and IgG1 (ref. 2). Conversely, lack of APRIL, owing to a targeted inactivation of Tnfsf13 in mice, results in an impaired ability to switch to IgA production. Recently, two studies have reported that sequence variants in TNFRSF13B are associated with primary immunodeficiency diseases in humans. Specifically, common variable immunodeficiency (CVID) was found to be associated with homozygosity for several coding variants (S144X, C104R and A181E); in addition, heterozygous coding variants (C104R, A1S1E, S194X, R202H and ins204A) were identified in several individuals with CVID. Furthermore, Castigli et al. showed a strict correlation between the presence of heterozygous coding variants (C104R, A181E and R202H) and CVID and selective IgA deficiency (IgAD) in members of their multicase families, suggesting a causal relationship. In our study, one of the siblings of a CVID proband, who is heterozygous for the A181E variant, suffered from IgAD. However, her mother, who is also heterozygous for the A181E variant, had normal immunoglobulin levels, suggesting incomplete penetrance.