A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency

摘要

Binding of the B-cell activating factor (BAFF) to its receptor (BAFFR) is essential for B-cell development and survival.1 A homozygous deletion in the BAFFR-encoding TNFRSF13C gene causes common variable immunodeficiency (CVID),2 one of the most frequent primary antibody deficiencies in humans characterized by the strong reduction in immunoglobulin serum liters.3 Five single-nucleotide polymorphisms resulting in BAFFR missense mutations have been found. Interestingly, in patients with CVID, the single-nucleotide polymorphism Pro21>Arg (P21R) (c.62C>G; rs77874543) has been described but its effects on BAFFR function and disease association are unknown.On comparing BAFFR expression by and BAFF binding to B cells, we observed that B lymphocytes expressing the BAFFR P21R mutation bound less BAFF than did cells expressing only major (wild-type [WT]) alleles (Fig 1, A) although BAFFR expression levels were very similar (Fig 1, B). Binding studies with B cells from healthy donors (see Fig El in this article's Online Repository at www.jacionline.org) and from patients with CVID (see Fig E2 in this article's Online Repository at www.jacionline.org) revealed reduced BAFF binding by cells expressing homozygous or heterozygous P21R BAFFR under ligand saturation, showing that the heterozygous P21R allele dominantly interferes with BAFF binding.