Deletion of Fc gamma receptor IIB renders H-2(b) mice susceptible to collagen-induced arthritis

Autoimmune diseases, like rheumatoid arthritis, result from a dysregulation of the immune response culminating in hyperactivation of effector cells le ading to immune-mediated injury. To maintain an appropriate immune response and prevent the emergence of autoimmune disease, activation signals must b e regulated by inhibitory pathways. Biochemical and genetic studies indicat e that the type IIB low-affinity receptor for immunoglobulin (Ig)G (Fc gamm a RIIB) inhibits cellular activation triggered through antibody or immune c omplexes and may be an important component in preventing the emergence of a utoimmunity. To investigate the role of Fc gamma RIIB in the development of type II collagen (CII)-induced arthritis (CIA), a model for rheumatoid art hritis in humans, we have examined its contribution in determining the susc eptibility to CIA in the nonpermissive H-2(b) haplotype. H-2(b) mice immuni zed with bovine CII do not develop appreciable disease. In contrast, immuni zation of the Fc gamma RIIB-deficient, H-2(b) mice with bovine CII induced CIA at an incidence of 42.2%. The maximal arthritis index of the Fc gamma R IIB-deficient mice developing CIA (6.9 +/- 3.6) was comparable to that of D BA/1 mice (8.6 +/- 1.9), an H-2(q) strain susceptible for CIA induction. Ig G1, IgG2a, and IgG2b antibody responses against CII were elevated in the Fc gamma RIIB-deficient animals, especially in those mice showing arthritis, but less pronounced than DBA/1 mice. Histological examinations of the arthr itic paws from Fc gamma RIIB-deficient mice revealed that cartilage was des troyed and bone was focally eroded ill association with marked lymphocyte a nd monocyte/macrophage infiltration, very similar to the pathologic finding s observed in DBA/1 mice. These results indicate that a nonpermissive H-2b haplotype can be rendered permissive to CIA induction through deletion of F c gamma RIIB, suggesting that Fc gamma RIIB plays a critical role in suppre ssing the induction of CIA.