Genetic dissection of the effects of stimulatory and inhibitory IgG fc receptors on murine lupus

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