Cγ1 Deficiency Exacerbates Collagen-Induced Arthritis.

Abstract

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). 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. 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. 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.