Monoallelic BAFFR P21R/H159Y Mutations and Familiar Primary Antibody Deficiencies.

Abstract

To the Editor Primary antibody deficiency syndromes (PADs) comprise an heterogeneous group of disorders characterized by low immunoglobulin serum levels. PADs encompass a wide range of disorders with Selective IgA deficiency (SIgAD) and Common Variable Immunodeficiency (CVID) being the more frequent ones. The incidence of SIgAD varies notably depending on ethnicity, while CVID presents an estimated incidence of 1:10.000–1:25.000; both may affect pediatric and adult patients. Regarding CVID, the genetic landscape is continuously becoming broader, involving genes encoding for, among others, TACI, BAFFR, CD19, CD20, CD21, CD81 and LRBA [1]. Mutations in TACI, the most frequently mutated gene in CVID, may be present in almost 8–10 % of affected patients [1]. TACI genetic variants have also been associated with SIgAD. TACI together with BAFFR and BCMA, are members of the Tumor Necrosis Factor Receptor (TNFR) superfamily. They are only expressed on B cells, as known so far, and their ligation to BAFF (all three) or APRIL (only TACI and BCMA) affects B cell homeostasis. Mutations in TACI associated with CVID abrogate the receptor’s expression on B cells as well as its capacity to bind APRIL. Homozygous deletions in the BAFFR gene on the other hand are very rare. Only two adult onset patients affected with complete BAFFR deficiency and hypogammaglobulinemia have been reported so far [2]. Mutations in BAFFR not resulting in lack of BAFFR expression have also been reported in CVID patients [3]. The P21R mutation in BAFFR was recently reported to alter the multimerization of BAFFR on B cell surface, contributing to common variable immunodeficiency [4]. So far, mutations in BAFFR have not been associated with SIgAD. We report on three family members (father and two daughters) affected with Common Variable Immunodeficiency (patient 1), selective IgA deficiency (Patient 2) and Hypo-IgM (father) that carry the monoallelic P21R/H159Y mutations in TNFRSF13C associated with reduced BAFFR expression on B cells suggesting that the P21R/H159Y monoallelic mutations may contribute to primary antibody deficiency with variable immunological presentation. The immunological data of the reported patients are summarized in Fig. 1a. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individuals (or their parents in case of pediatric patients) participating in this study. In brief, patient 1 presented a history of recurrent respiratory infections starting at the age of 2 years. Her clinical history was complicated by an episode of meningitis and mastoiditis at the age of 5 years. During this admission, immunological work-up showed hypogammaglobulinemia, normal peripheral B cell percentages, absent humoral response to vaccinations leading to the diagnosis of CVID. Patient 2, the sister of patient 1, presented occasional gastrointestinal and respiratory infections and was evaluated due to positive family history for CVID. IgA serum levels were below the threshold of * Vassilios Lougaris vlougaris@yahoo.co.uk