Deletion of Fcγ Receptor IIB Renders H-2b Mice Susceptible to Collagen-induced Arthritis

TLDR

Autoimmune diseases such as rheumatoid arthritis arise from dysregulated immune responses that hyperactivate effector cells, and inhibitory pathways—particularly the low‑affinity FcγRIIB receptor—are thought to restrain such activation and prevent autoimmunity. The study aimed to determine whether loss of FcγRIIB would enable the normally resistant H‑2b haplotype to develop collagen‑induced arthritis. To test this, FcγRIIB‑deficient H‑2b mice were immunized with bovine type II collagen and monitored for arthritis development. Deletion of FcγRIIB in H‑2b mice conferred susceptibility to collagen‑induced arthritis, with a 42.2 % incidence, arthritis scores comparable to the susceptible DBA/1 strain, elevated anti‑collagen IgG responses, and histopathology showing cartilage destruction and bone erosion similar to DBA/1 mice, demonstrating that FcγRIIB suppresses CIA induction.

Abstract

Autoimmune diseases, like rheumatoid arthritis, result from a dysregulation of the immune response culminating in hyperactivation of effector cells leading to immune-mediated injury. To maintain an appropriate immune response and prevent the emergence of autoimmune disease, activation signals must be regulated by inhibitory pathways. Biochemical and genetic studies indicate that the type IIB low-affinity receptor for immunoglobulin (Ig)G (FcγRIIB) inhibits cellular activation triggered through antibody or immune complexes and may be an important component in preventing the emergence of autoimmunity. To investigate the role of FcγRIIB in the development of type II collagen (CII)-induced arthritis (CIA), a model for rheumatoid arthritis in humans, we have examined its contribution in determining the susceptibility to CIA in the nonpermissive H-2b haplotype. H-2b mice immunized with bovine CII do not develop appreciable disease. In contrast, immunization of the FcγRIIB-deficient, H-2b mice with bovine CII induced CIA at an incidence of 42.2%. The maximal arthritis index of the FcγRIIB-deficient mice developing CIA (6.9 ± 3.6) was comparable to that of DBA/1 mice (8.6 ± 1.9), an H-2q strain susceptible for CIA induction. IgG1, IgG2a, and IgG2b antibody responses against CII were elevated in the FcγRIIB-deficient animals, especially in those mice showing arthritis, but less pronounced than DBA/1 mice. Histological examinations of the arthritic paws from FcγRIIB-deficient mice revealed that cartilage was destroyed and bone was focally eroded in association with marked lymphocyte and monocyte/macrophage infiltration, very similar to the pathologic findings observed in DBA/1 mice. These results indicate that a nonpermissive H-2b haplotype can be rendered permissive to CIA induction through deletion of FcγRIIB, suggesting that FcγRIIB plays a critical role in suppressing the induction of CIA.