The Inhibiting Fc Receptor for IgG, Fc gamma RIIB, Is a Modifier of Autoimmune Susceptibility

P Boross, VL Arandhara, J Martin-Ramirez, ML Santiago-Raber, F Carlucci, R Flierman, J van der Kaa, C Breukel, JWC Claassens, M Camps, Erik Lubberts, D Salvatori, MP Rastaldi, F Ossendorp, MR Daha, HT Cook, S Izui, M Botto, JS Verbeek

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Abstract

Fc gamma RIIB-deficient mice generated in 129 background (Fc gamma RIIB(129)(-/-)) if back-crossed into C57BL/6 background exhibit a hyperactive phenotype and develop lethal lupus. Both in mice and humans, the Fc gamma r2b 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 Fc gamma RIIB deficiency to the development of lupus in Fc gamma RIIB(129)(-/-) mice. Moreover, in humans genetic linkage studies revealed contradictory results regarding the association of "loss of function" mutations in the Fc gamma r2b gene and susceptibility to systemic lupus erythematosis. In this study, we demonstrate that Fc gamma RIIB(-/-) mice generated by gene targeting in B6-derived ES cells (Fc gamma RIIB(B6)(-/-)), lacking the 129-derived flanking Sle16 region, exhibit a hyperactive phenotype but fail to develop lupus indicating that in Fc gamma RIIB(129)(-/-) mice, not Fc gamma RIIB deficiency but epistatic interactions between the C57BL/6 genome and the 129-derived Fc gamma r2b 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 Fc gamma RIIB, culminating in lethal lupus. In the presence of the Yaa lupus-susceptibility locus, Fc gamma RIIB(B6)(-/-) mice do develop lethal lupus, confirming that FcgRIIB deficiency only amplifies spontaneous autoimmunity determined by other loci. The Journal of Immunology, 2011, 187: 1304-1313.
Original languageUndefined/Unknown
Pages (from-to)1304-1313
Number of pages10
JournalJournal of Immunology
Volume187
Issue number3
DOIs
Publication statusPublished - 2011

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