Genetic dissection of the effect of Fcgr2b polymorphism on systemic lupus erythematosus (49.30)

Abstract

Abstract Telomeric chromosome 1 contains a cluster of potent polymorphic autoimmune-susceptibility genes including Fcgr2b. SLE-prone strains, including BXSB, share deletion polymorphism in Fcgr2b promoter region. Here we established congenic BXSB.IIBB6 that carry normal C57BL/6-type Fcgr2b. While BXSB females do not develop severe disease, BXSB males develop much severe disease because of Y chromosome-linked autoimmune acceleration (Yaa) mutation. Compared with BXSB females, (NZW x BXSB) F1 females develop severe SLE even in absence of Yaa because of the contribution of susceptibility alleles from the NZW strain. The present study addressed the question of whether wild-type Fcgr2b could prevent SLE in mice prone to develop SLE. As compared to BXSB males and (NZW x BXSB) F1 females, all SLE features were markedly suppressed in BXSB.IIBB6 males and (NZW x BXSB.IIBB6) F1 females, respectively. Importantly, activation and proliferation of not only B cells, but also T cells and monocytes/macrophages, were all inhibited in the latter two strains. Thus, the wild-type Fcgr2b appears to have a strong suppressive effect on the susceptibility of both Yaa-dependent and Yaa-independent murine lupus through the mechanisms that inhibit the activation of a wide variety of immune cells. Conversely, due to the loss of such inhibitory effects, autoimmune-type Fcgr2b probably plays a crucial role in SLE susceptibility.