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

Abstract

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.

Comment on “The Inhibiting Fc Receptor for IgG, FcγRIIB, Is a Modifier of Autoimmune Susceptibility”

“…Given that increased nuclear levels of p202 protein in B6.Nba2 congenic female mice are associated with the production of ANAs (3,4) 2/2 mice express increased levels of p202 protein ( Fig. 1) at the age of ∼8 wk, the observations by Boross et al (5) support an interesting possibility that epistatic interactions between Fcgr2b and Ifi200 family genes contribute to an increased production of type I IFN and ANAs. Therefore, further work is needed to characterize these epistatic interactions to understand their role in the development of lupus disease.…”

The HLA-DRB1*15

“…We chose FcgRs because alterations in this system are associated with glomerular disease in rodents and humans. 23,25,46,47 This additional susceptibility enhanced injury in HLA-DRB1*15:01-expressing mice after a3 136-146 immunization, without promoting initial T cell autoimmune responses or injury in HLA-DRB1*01:01 Tg mice. By 42 days after a3 136-146 immunization, FcgRIIb-deficient HLA-DRB1*01:01 Tg mice did develop serum anti-a3(IV) NC1 antibodies (suggesting also some T cell autoreactivity), but these were not deposited in the kidney.…”

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

“…Nephritis experiments were conducted at 10 wk posttransplant. Confirmation of chimerism was obtained using PCR on DNA extracted from 0.1 ml blood obtained at the terminal bleed, as previously described (4).…”

“…On B cells, cross-linking of FcgRIIb and the BCR activates a distinct pathway that inhibits cell proliferation, maturation, and the production of cytokines (1); however, cross-linking of FcgRIIb in the absence of the BCR initiates a bim-dependent apoptosis pathway (2). Reduced expression of FcgRIIb is associated with enhanced activation and proliferation of B cells and plasma cells (3), as well as increased Ab production to T-dependent Ags (3,4) and increased macrophage activation by immune complexes (4)(5)(6).…”