High susceptibility to collagen-induced arthritis in mice lacking IFN-gamma receptors.
Collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis, is induced in DBA/1 (H-2q) mice following immunization with type II collagen (CII) in CFA. Since we have previously shown that IFN-gamma exerts a biphasic effect during the evolution of CIA in DBA/1 mice, we analyzed the development of this disease in mice with a disruption of the IFN-gamma receptor gene (IFN-gammaR(0/0)). Mutant mice were interbred with the DBA/1 strain to yield IFN-gammaR(0/0) mice expressing the H-2q haplotype. In three consecutive experiments, IFN-gammaR(0/0) male mice were found to exhibit severe clinical and histologic arthritis with an average incidence of 88.5 vs 94.1% for the wild DBA/1 strain. Notably, onset of clinical symptoms occurred significantly earlier than in DBA/1 mice. Although of a lower magnitude than in males, CIA also developed early in IFN-gammaR(0/0) female mice and with higher clinical severity than in control DBA/1 females. Immunization of knockout mice with CII resulted in the generation of CII-specific T cells belonging to the Th1 phenotype that recognize the same immunodominant peptides as do DBA/1 mice. CIA in IFN-gammaR(0/0) mice was associated with a down-regulation of the CII-specific IgG response, and this impairment was essentially due to a strong reduction of Abs of the IgG2a isotype. Taken together, our findings provide evidence that IFN-gammaR deficiency in DBA/1 mice leads to the occurrence of severe CIA with an accelerated onset compared with that in wild-type mice, indicating that the proinflammatory action of IFN-gamma has been bypassed in the IFN-gammaR(0/0) mice.
Manoury-Schwartz
B
B
National Institute of Health and Medical Research (INSERM), Unit 283, René Descartes University, Paris, France.
Chiocchia
G
G
Bessis
N
N
Abehsira-Amar
O
O
Batteux
F
F
Muller
S
S
Huang
S
S
Boissier
M C
MC
Fournier
C
C
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000276:immunology*; D003094:Collagen; D004198:Disease Susceptibility; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D000096743:Interferon gamma Receptor
D003094:Collagen; D007074:Immunoglobulin G; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor