Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Agematsu K, Futatani T, Hokibara S, Kobayashi N, Takamoto M, Tsukada S, Suzuki H, Koyasu S, Miyawaki T, Sugane K, Komiyama A, Ochs HD: Absence of memory B cells in patient with common variable immunodeficiency. Clin Immunol 103:34–42, 2002
Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, Eibel H, Fischer B, Schäffer A, Mages HW, Kroczek RA, Peter HH: Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4:261–268, 2003
Gross JA, Dillon SR, Mudri S, Johnston J, Littau A, Roque R, Rixon M, Schou O, Foley KP, Haugen H, McMillens S, Waggie K, Schrechhise RV, Shoemaker K, Vu T, Moore M, Grossman A, Clegg CH: TACI-Ig neutralized molecules critical for B cell development and autoimmune disease. Impaired B cell maturation in mice lacking BLyS. Immunity 15:289–302, 2001
Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles D, Frew E, and Scott ML: An essential role for BAFF in the normal development of B cells trough a BCMA-independent pathway. Science 293:2111–2114, 2001
Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, Browning JL: Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 190(11):1697–1710, 1999
Bodmer JL, Shneider P, Tschopp J: The molecular architecture of the TNF superfamily. TIBS 27:18–26, 2002
Thompson JS, Bixler SA, Quian F, Vora K, Scott ML, Cachero TG, Heisson C, Schneider P, Sizing ID, Mullen C, Strauch K, Zafari M, Benjamin CD, Tschopp J, Browning JL, Ambrose C: BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science 293:2108–2111, 2001
Yan M, Brady JR, Chan B, Lee WP, Hsu B, Harless S, Cancro M, Grewal IS, Dixit VM: Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Curr Biol 11:1547–1552, 2001
Sasaki S, Casola S, Kutok JL, Rajewsky K, Schmidt-Supprian M: TNF family member B cell- activating factor (BAFF) receptor-depending and -independing roles for BAFF in B cell physiology. J Immunol 173:2245–2252, 2004
Gorelik L, Cutler AH, Thill G, Miklasz D, Shea DE, Ambrose C, Bixler SA, Su L, Scott ML, Kalled SL: Cutting Edge: BAFF regulated CD21/35 and CD23 expression independent of its B cell survival function. J Immunol 172:762–766, 2004
Shulga-Morskaya S, Dobles M, Walsh ME, Ng LG, MacKay F, Rao SP, Kalled SL, Scott ML: B cell-activating factor belonging to the TNF family acts through separate receptors to support B cell survival and T cell-independent antibody formation. J Immunol 173:2331–2341, 2004
Ng LG, Sutherland AP, Newton R, Qian F, Cachero TG, Scott ML, Thompson JS, Wheway J, Chtanova T, Groom J, Sutton IJ, Xin C, Tangye SG, Kalled SL, Mackay F, Mackay CR: B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol 173:807–817, 2004
Castigli C, Wilson SA, Scott S, Dedeoglu F, Xu S, Lam KP, Bram RJ, Jabara H, Geha RS: TACI and BAFF-R mediate isotype switching in B cells. J Exp Med 201:35–39, 2005
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Losi, C.G., Silini, A., Fiorini, C. et al. Mutational Analysis of Human BAFF Receptor TNFRSF13C (BAFF-R) in Patients with Common Variable Immunodeficiency. J Clin Immunol 25, 496–502 (2005). https://doi.org/10.1007/s10875-005-5637-2
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10875-005-5637-2