Systemic versus cartilage-specific expression of a type II collagen-specific T-cell epitope determines the level of tolerance and susceptibility to arthritis.
Immunization of mice with rat type II collagen (CII), a cartilage-specific protein, leads to development of collagen-induced arthritis (CIA), a model for rheumatoid arthritis. To define the interaction between the immune system and cartilage, we produced two sets of transgenic mice. In the first we point mutated the mouse CII gene to express an earlier defined T-cell epitope, CII-(256-270), present in rat CII. In the second we mutated the mouse type I collagen gene to express the same T-cell epitope. The mice with mutated type I collagen showed no T-cell reactivity to rat CII and were resistant to CIA. Thus, the CII-(256-270) epitope is immunodominant and critical for development of CIA. In contrast, the mice with mutated CII had an intact B-cell response and had T cells which could produce gamma interferon, but not proliferate, in response to CII. They developed CIA, albeit with a reduced incidence. Thus, we conclude that T cells recognize CII derived from endogenous cartilage and are partially tolerized but may still be capable of mediating CIA.
Malmström
V
V
Department of Cell and Molecular Biology, Lund University, Sweden.
Michaëlsson
E
E
Burkhardt
H
H
Mattsson
R
R
Vuorio
E
E
Holmdahl
R
R
D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001224:Aspartic Acid; D002356:Cartilage / Q000276:immunology*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology*; D004198:Disease Susceptibility; D000939:Epitopes / Q000276:immunology*; D018698:Glutamic Acid; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009928:Organ Specificity; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
D000939:Epitopes; D001224:Aspartic Acid; D018698:Glutamic Acid; D007371:Interferon-gamma; D003094:Collagen