Reduced susceptibility to collagen-induced arthritis in mice deficient in IFN-gamma receptor.

Collagen-induced arthritis (CIA) is an arthritic model that was developed after immunization with type II collagen (CII). Apparently, contradictory results have been reported regarding the role of IFN-gamma in the development of CIA. Therefore, we employed IFN-gamma R-deficient mice to study the role of IFN-gamma. To introduce the CIA susceptibility gene (H-2q), IFN-gamma R-deficient (H-2b/b/IFN-gamma R-/-) mice were mated with DBA/1 (H-2q/q/IFN-gamma R+/+) mice; next, the F1 mice were interbred to yield F2 offspring bearing different combinations of H-2 (H-2q/q, H-2q/b, and H-2b/b) and IFN-gamma R (IFN-gamma R+/+, IFN-gamma R+/-, and IFN-gamma R-/-) genes. Although the H-2q allele appeared to confer susceptibility to CIA, mice that were homozygous for the IFN-gamma R mutation showed a substantially decreased incidence and severity of CIA. The CII-specific IgG levels of serum samples, which are known to be involved in the development of CIA, were remarkably reduced in IFN-gamma R-/- mice. Furthermore, the anti-CII IgG2a levels controlled by IFN-gamma R were significantly reduced in IFN-gamma R-/- F2 mice compared with those seen in IFN-gamma R+/+ and IFN-gamma R+/- mice, although the levels of all IgG subclass Abs examined were lower in IFN-gamma R-/- mice than in IFN-gamma R+/+ mice. No clear evidence of the imbalance of Th1/Th2 cytokines was observed in CII-immunized, IFN-gamma R-deficient mice. Taken together, these results suggest that IFN-gamma exacerbates CIA by affecting, at least, levels of CII-specific IgG Ab rather than the imbalance of Th1/Th2 cells.