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

07.01.2014

Pieper K, Rizzi M, Speletas M, Smulski CR, Sic H, Kraus H, Salzer U, Fiala GJ, Schamel WW, Lougaris V, Plebani A, Hammarstrom L, Recher M, Germenis AE, Grimbacher B, Warnatz K, Rolink AG, Schneider P, Notarangelo LD, Eibel H.

J Allergy Clin Immunol. 2014;133(4):1222-5

J Allergy Clin Immunol.         online article

The individual genetic background shapes the immune system and the susceptibility to infections. The B cell-activating factor receptor (BAFF-R), is essential for B cell survival. In this BIOSS publication, we report that a frequent SNP in the BAFFR coding region changing the proline residue 21 into arginine (P21R) disturbs ligand independent multimerization of BAFF-R. The impaired multimerization reduces the BAFF binding capacity of B cells and decreases BAFF-dependent survival of B cells. Screening different disease cohorts, we found that P21R predisposes to common variable immunodeficiency (CVID) but protects against chronic lymphocytic leukemia (CLL). Thus, BAFF-R multimerization is a critical parameter in directing B cell responses. In the context of the rapidly growing insight into human genetic diversity our data highlight the importance of individual genetic variations in in determining disease susceptibility.