BAFF receptor (BAFF-R/BR3/TNFRSF13C) is a recently identified molecule that specifically binds BLyS, a protein belonging to the tumor necrosis factor (TNF) family, and is involved in survival and maturation of B cells. Recent studies have demonstrated that mice defective in BAFF-R gene exhibit an altered profile of the B cell pool, a phenotype observed in BLyS knockout mice as well. These features suggest that mutations in this gene may result in humoral immunodeficiency. To test this hypothesis, we sequenced the BAFF-R gene in 48 patients with common variable immunodeficiency (CVID) along with 57 healthy controls. We have identified three novel variants present at the heterozygous state leading to amino acid substitutions, and have also confirmed the existence of a previously reported intronic variant. The hereby described novel variants were also present in healthy controls and in the healthy patients' parents. These variants do not affect the expression of BAFF-R neither at the mRNA nor at the protein level, suggesting that these variants represent novel polymorphic variants of the BAFF-R gene.
"Mutations in CD27  , PLCG2  , LRBA  , NFKB2  , PIK3CD   and NLRP12  cause CVID-like symptoms often combined with a more extensive clinical phenotype (Table S1). Variants in TNFRSF13B   , TNFRSF13C , FCGR2A  and HLA  have been described to predispose to CVID (Table S1). Together these variants only explain the genetic cause of CVID-like diseases in very few patients and all genes were identified in familial cases of CVID, while the vast majority of CVID patients are sporadic. "
"The P21R variant, located at the extracellular domain of BAFF-R (Fig. 1C), was recently reported to impair BAFF-R's multimerization contributing to common variable immunodeficiency (CVID) . The second variant, H159Y, located in the intracellular domain of BAFF-R (Fig. 1C), was initially identified in a patient with CVID, and in healthy controls . The same mutation was recently identified in non-Hodgkin lymphoma and was shown to be involved in Nf-kB signaling, altering TRAF recruitment to BAFF-R . "
"One sibling (the brother) had decreased IgG and IgM levels but normal IgA and the other (the sister), who was clinically normal, had a slightly diminished IgG and IgM levels in her serum. In other studies, heterozygous sequence variations in the BAFF-R gene (CVID4, MIM#613494) (Table 1) have been reported. "
[Show abstract][Hide abstract] ABSTRACT: Common variable immunodeficfiiency (CVID) is a primary immunodeficiency syndrome representing a heterogeneous set of disorders resulting mostly in antibody deficiency and recurrent infections. However, inflammatory and autoimmune disorders and some kinds of malignancies are frequently reported as a part of the syndrome. Although it is one of the most widespread primary immunodeficiency, only recently some genetic defects in CVID have been identified. Mutations have been detected in inducible T-cell costimulator (ICOS), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B-cell activating factor-receptor (BAFF-R), B-cell receptor complex (CD19, CD21 and CD81) and CD20. On the other hand, recent studies have shown a decrease in T-helper-17 cells frequency and their characteristic cytokines in CVID patients and this emphasis on the vital role of the T-cells in immunopathogenesis of the CVID. Furthermore, in the context of autoimmune diseases accompanying CVID, interleukin 9 has recently attracted a plenty of considerations. However, the list of defects is expanding as exact immunologic pathways and genetic disorders in CVID are not yet defined. In this review, we have a special focus on the immunopathogenesis of CVID, recent advances in understanding the underlying etiology and genetics for patients.
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