A role for complement in antibody-mediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis.
Collagen-induced arthritis (CIA) represents an animal model of autoimmune polyarthritis with significant similarities to human rheumatoid arthritis that can be induced upon immunization with native type II collagen. As in rheumatoid arthritis, both cellular and humoral immune mechanisms contribute to disease pathogenesis. Genotypic studies have identified at least six genetic loci contributing to arthritis susceptibility, including the class II MHC. We have examined the mechanism of Ab-mediated inflammation in CIA joints, specifically the role of complement activation, by deriving a line of mice from the highly CIA-susceptible DBA/1LacJ strain that are congenic for deficiency of the C5 complement component. We show that such C5-deficient DBA/1LacJ animals mount normal cellular and humoral immune responses to native type II collagen, with the activation of collagen-specific TNF-alpha-producing T cells in the periphery and substantial intra-articular deposition of complement-fixing IgG Abs. Nevertheless, these C5-deficient mice are highly resistant to the induction of CIA. These data provide evidence for an important role of complement in Ab-triggered inflammation and in the pathogenesis of autoimmune arthritis.
Wang
Y
Y
Alexion Pharmaceuticals, Inc., New Haven, CT 06511; and Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. WANGY@alxn.com
Kristan
J
J
Hao
L
L
Lenkoski
C S
CS
Shen
Y
Y
Matis
L A
LA
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D001323:Autoantibodies / Q000096:biosynthesis / Q000502:physiology*; D002417:Cattle; D003094:Collagen / Q000276:immunology*; D003182:Complement C5 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D001323:Autoantibodies; D003182:Complement C5; D016207:Cytokines; D007074:Immunoglobulin G; D003094:Collagen