Genetic Dissection of the Effects of Stimulatory and Inhibitory IgG Fc Receptors on Murine Lupus

Abstract

Immune complex (IC)-mediated tissue inflammation is controlled by stimulatory and inhibitory IgG Fc receptors (FcγRs). Systemic lupus erythematosus is a prototype of IC-mediated autoimmune disease; thus, imbalance of these two types of FcγRs is probably involved in pathogenesis. However, how and to what extent each FcγR contributes to the disease remains unclear. In lupus-prone BXSB mice, while stimulatory FcγRs are intact, inhibitory FcγRIIB expression is impaired because of promoter region polymorphism. To dissect roles of stimulatory and inhibitory FcγRs, we established two gene-manipulated BXSB strains: one deficient in stimulatory FcγRs (BXSB.γ−/−) and the other carrying wild-type Fcgr2b (BXSB.IIBB6/B6). The disease features were markedly suppressed in both mutant strains. Despite intact renal function, however, BXSB.γ−/− had IC deposition in glomeruli associated with high-serum IgG anti-DNA Ab levels, in contrast to BXSB.IIBB6/B6, which showed intact renal pathology and anti-DNA levels. Lymphocytes in BXSB.γ−/− were activated, as in wild-type BXSB, but not in BXSB.IIBB6/B6. Our results strongly suggest that both types of FcγRs in BXSB mice are differently involved in the process of disease progression, in which, while stimulatory FcγRs play roles in effecter phase of IC-mediated tissue inflammation, the BXSB-type impaired FcγRIIB promotes spontaneous activation of self-reactive lymphocytes and associated production of large amounts of autoantibodies and ICs.