The inhibiting Fc receptor for IgG, FcγRIIB, is a modifier of autoimmune susceptibility

Peter Boross, Victoria L. Arandhara, Javier Martin-Ramirez, Marie Laure Santiago-Raber, Francesco Carlucci, Roelof Flierman, Jos Van Der Kaa, Cor Breukel, Jill W C Claassens, Marcel Camps, Erik Lubberts, Daniela Salvatori, Maria Pia Rastaldi, Ferry Ossendorp, Mohamed R. Daha, H. Terence Cook, Shozo Izui, Marina Botto, J. Sjef Verbeek

Research output: Contribution to journalArticlepeer-review


FcγRIIB-deficient mice generated in 129 background (FcγRIIB129-/-) if back-crossed into C57BL/6 background exhibit a hyperactive phenotype and develop lethal lupus. Both in mice and humans, the Fcγr2b gene is located within a genomic interval on chromosome 1 associated with lupus susceptibility. In mice, the 129-derived haplotype of this interval, named Sle16, causes loss of self-tolerance in the context of the B6 genome, hampering the analysis of the specific contribution of FcγRIIB deficiency to the development of lupus in FcγRIIB129-/- mice. Moreover, in humans genetic linkage studies revealed contradictory results regarding the association of "loss of function" mutations in the Fcγr2b gene and susceptibility to systemic lupus erythematosis. In this study, we demonstrate that FcγRIIB-/- mice generated by gene targeting in B6-derived ES cells (FcγRIIBB6-/-), lacking the 129-derived flanking Sle16 region, exhibit a hyperactive phenotype but fail to develop lupus indicating that in FcγRIIB129-/- mice, not FcγRIIB deficiency but epistatic interactions between the C57BL/6 genome and the 129-derived Fcγr2b flanking region cause loss of tolerance. The contribution to the development of autoimmune disease by the resulting autoreactive B cells is amplified by the absence of FcγRIIB, culminating in lethal lupus. In the presence of the Yaa lupus-susceptibility locus, FcγRIIBB6-/- mice do develop lethal lupus, confirming that FcγRIIB deficiency only amplifies spontaneous autoimmunity determined by other loci.

Original languageEnglish
Pages (from-to)1304-1313
Number of pages10
JournalJournal of Immunology
Issue number3
Publication statusPublished - Aug 1 2011

ASJC Scopus subject areas

  • Immunology


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