Development of Inflammation in Proteoglycan-Induced Arthritis Is Dependent on FcγR Regulation of the Cytokine/Chemokine Environment

Abstract

FcγRs are specialized cell surface receptors that coordinately regulate immune responses. Although FcγR expression is a prerequisite for the development of several immune complex-mediated diseases, the mechanism responsible for FcγR-dependent regulation in autoimmunity remains unclear. Therefore, we assessed FcγR-dependent regulation of inflammation in proteoglycan-induced arthritis (PGIA) using FcγR−/− mice. FcγRIIb−/− mice developed arthritis at an earlier time point and with a greater severity than wild-type (WT) mice. In γ-chain−/− (FcγRI−/− and FcγRIII−/−) mice, no clinical or histological evidence of inflammation was observed. Exacerbation of arthritis in FcγRIIb−/− mice correlated with enhanced PG-specific Ab production, but did not significantly affect PG-specific T cell priming. In γ-chain−/− mice, the absence of arthritis did not correlate with serum Ab responses, as PG-specific Ab production was normal. Although PG-specific T cell proliferation was diminished, spleen cells from γ-chain−/− mice successfully adoptively transferred arthritis into SCID mice. Our studies indicated that the mechanism responsible for FcγR regulation of PGIA development was at the level of inflammatory cytokine and β-chemokine expression within the joint. FcγRIIb regulated the development of PGIA by controlling the initiation of cytokine and chemokine expression within the joint before the onset of arthritis, whereas the expression of FcγRI and or FcγRIII controlled cytokine and chemokine expression late in the development of PGIA during the onset of disease. These results suggest that FcγRs are critical for the development of inflammation during PGIA, possibly by maintaining or enhancing inflammatory cytokine and β-chemokine production.