| First Author | Boross P | Year | 2011 |
| Journal | J Immunol | Volume | 187 |
| Issue | 3 | Pages | 1304-13 |
| PubMed ID | 21724994 | Mgi Jnum | J:179175 |
| Mgi Id | MGI:5301232 | Doi | 10.4049/jimmunol.1101194 |
| Citation | Boross P, et al. (2011) The inhibiting Fc receptor for IgG, FcgammaRIIB, is a modifier of autoimmune susceptibility. J Immunol 187(3):1304-13 |
| abstractText | FcgammaRIIB-deficient mice generated in 129 background (FcgammaRIIB(129)(-/-)) if back-crossed into C57BL/6 background exhibit a hyperactive phenotype and develop lethal lupus. Both in mice and humans, the Fcgammar2b 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 FcgammaRIIB deficiency to the development of lupus in FcgammaRIIB(129)(-/-) mice. Moreover, in humans genetic linkage studies revealed contradictory results regarding the association of "loss of function" mutations in the Fcgammar2b gene and susceptibility to systemic lupus erythematosis. In this study, we demonstrate that FcgammaRIIB(-/-) mice generated by gene targeting in B6-derived ES cells (FcgammaRIIB(B6)(-/-)), lacking the 129-derived flanking Sle16 region, exhibit a hyperactive phenotype but fail to develop lupus indicating that in FcgammaRIIB(129)(-/-) mice, not FcgammaRIIB deficiency but epistatic interactions between the C57BL/6 genome and the 129-derived Fcgammar2b 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 FcgammaRIIB, culminating in lethal lupus. In the presence of the Yaa lupus-susceptibility locus, FcgammaRIIB(B6)(-/-) mice do develop lethal lupus, confirming that FcgammaRIIB deficiency only amplifies spontaneous autoimmunity determined by other loci. |
