IgG Fc receptor polymorphisms and association with autoimmune disease

The aim of this study was to investigate whether a genetic polymorphism of Fc gamma RIII exists in mice, which could explain the different susceptibility to pathogenic IgG anti-collagen type II (CII) antibodies in mice carrying the collagen-induced arthritis (CIA)susceptible H-2(q) haplotype. The gene for Fc gamma RIII was sequenced in 11 common mouse strains, and the results revealed three different haplotypes of mouse Fc gamma RIII: Fc gamma RIII:V, Fc gamma RIII:H and Fc gamma RIII:T. To study the consequences of this polymorphism, we generated mice carrying the Fc gamma RIII:H haplotype from the CIA-susceptible, H-2(q)-positive DBA/1 mouse or the Fc gamma RIII:V haplotype from the CIA-resistant, H-2(q)-positive SWR mouse. After CII immunization or transfer of IgG anti-CII antibodies, Fc gamma RIII:H-expressing mice, but not Fc gamma RIII:V-expressing mice, developed progressively severe arthritis. We also investigated if C5, in addition to Fc gamma RIII polymorphism, could affect the susceptibility to the pathogenic IgG anti-CII antibodies in H-2(q)-positive mice. Here we show that SWR mice, naturally deficient in C5, can develop CIA when supplemented with C5 and that anti-C5 antibody treatment of Fc gamma RIII:H-expressing mice inhibits arthritis development. These data demonstrate for the first time a genetic polymorphism of Fc gamma RIII in mice that may, together with C5, regulate induction of autoimmune disease.