Cγ1 Deficiency Exacerbates Collagen-Induced Arthritis

Abstract

Objective: IgG antibodies protect by aggregating pathogens and activating complement and stimulatory Fcγ receptors (FcγR). Although IgG1 accounts for a large percentage of murine serum antibodies, it poorly activates complement, binds more avidly to inhibitory FcγRIIb than to stimulatory FcγRIII, and has a relatively low aggregating ability. We previously demonstrated that IgG1 protects against complement- and FcγR-independent renal disease by inhibiting immune complex obstruction of glomerular capillaries. The purpose of this study was to determine whether IgG1 also protects against the complement- and FcγR-dependent disorder, collagen-induced arthritis (CIA). Methods: CIA was induced by injecting mice with type II collagen (CII) (active model) or with IgG2a and IgG2b anti-CII monoclonal antibodies (ArthritoMab) (passive model). Arthritis severity was assessed, and CII-specific IgG was titered. Results: Cγ1-deficient C57BL/6 mice lack IgG1 (IgG1−/−); in these mice, arthritis developed at a higher frequency and was more severe compared with IgG1+/+ mice in the active model. Disease was FcγRIII- and C3-dependent in both the IgG+/+ and IgG−/− mouse strains and was not influenced by interleukin-4 receptor α in either strain. CII-specific IgG2a/c titers were considerably higher in IgG1−/− than in IgG1+/+ mice and correlated with CIA incidence and severity. IgG1+/+ mice that developed CIA had higher CII-specific IgG1 and IgG2a/c levels than did those without CIA. CII-inoculated BALB/c IgG1+/+ and IgG1−/− mice had much lower CII-specific IgG2a/c titers than did C57BL/6 mice and failed to develop CIA but developed passive CIA when given ArthritoMab. Conclusion: The absence of a functional Cγ1 gene indirectly promotes the development of CIA, likely through increased production of IgG2a/c, an isotype that strongly activates complement and stimulatory FcγR.