title: A transient post-translationally modified form of cartilage type II collagen is ignored by self-reactive T cells.
abstract: Lysine residues in type II collagen (CII) are normally hydroxylated and subsequently glycosylated in the chondrocyte. The immunodominant T cell epitope of CII involves such post-translationally modified lysine at position 264 that has been shown to be critical in the pathogenesis of murine collagen-induced arthritis and also in human rheumatoid arthritis. In this study we identified a line of transgenic mice expressing a TCR specific for hydroxylated rat CII epitope. They were crossed with transgenic mice expressing the rat CII epitope, either specifically in cartilage (MMC mice) or systemically (TSC mice), to analyze T cell tolerance to a post-translationally modified form of self-CII. The mechanism of T cell tolerance to the hydroxylated CII epitope in TSC mice was found to involve intrathymic deletion and induction of peripheral tolerance. In contrast, we did not observe T cell tolerance in the MMC mice. Analysis of CII prepared from rat or human joint cartilage revealed that most of the lysine 264 is glycosylated rather than remaining hydroxylated. Therefore, we conclude that the transient post-translationally modified form of cartilage CII does not induce T cell tolerance. This lack of T cell tolerance could increase the risk of developing autoimmune arthritis.
authors.affiliation: Medical Inflammation Research, Department of Cell and Molecular Biology, Lund University, Lund, Sweden.
authors.forename: Hisakata
authors.initials: H
authors.lastname: Yamada
authors.forename: Balik
authors.initials: B
authors.lastname: Dzhambazov
authors.forename: Robert
authors.initials: R
authors.lastname: Bockermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Blom
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology; D002358:Cartilage, Articular / Q000276:immunology / Q000378:metabolism*; D002417:Cattle; D002999:Clone Cells; D024043:Collagen Type II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006825:Hybridomas; D006900:Hydroxylation; D007108:Immune Tolerance / Q000235:genetics; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational / Q000235:genetics; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D017384:Sequence Deletion; D016176:T-Lymphocyte Subsets / Q000378:metabolism*; D019076:Transgenes
chemical_list: D024043:Collagen Type II; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D008239:Lysine