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Proc Natl Acad Sci U S A. Apr 30, 1996; 93(9): 4480–4485.
PMCID: PMC39564

Systemic versus cartilage-specific expression of a type II collagen-specific T-cell epitope determines the level of tolerance and susceptibility to arthritis.

Abstract

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.

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  • Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978 Apr 20;298(16):869–871. [PubMed]
  • Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987 Nov;30(11):1205–1213. [PubMed]
  • Holmdahl R, Malmström V, Vuorio E. Autoimmune recognition of cartilage collagens. Ann Med. 1993 Jun;25(3):251–264. [PubMed]
  • Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Rosa-Pimentel E, Sommarin Y, Wendel M, Oldberg A, Heinegård D. Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage. J Biol Chem. 1992 Mar 25;267(9):6132–6136. [PubMed]
  • Trentham DE, Townes AS, Kang AH. Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med. 1977 Sep 1;146(3):857–868. [PMC free article] [PubMed]
  • Glant TT, Mikecz K, Arzoumanian A, Poole AR. Proteoglycan-induced arthritis in BALB/c mice. Clinical features and histopathology. Arthritis Rheum. 1987 Feb;30(2):201–212. [PubMed]
  • Cremer MA, Ye XJ, Terato K, Owens SW, Seyer JM, Kang AH. Type XI collagen-induced arthritis in the Lewis rat. Characterization of cellular and humoral immune responses to native types XI, V, and II collagen and constituent alpha-chains. J Immunol. 1994 Jul 15;153(2):824–832. [PubMed]
  • Wooley PH, Luthra HS, Stuart JM, David CS. Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. J Exp Med. 1981 Sep 1;154(3):688–700. [PMC free article] [PubMed]
  • Cathcart ES, Hayes KC, Gonnerman WA, Lazzari AA, Franzblau C. Experimental arthritis in a nonhuman primate. I. Induction by bovine type II collagen. Lab Invest. 1986 Jan;54(1):26–31. [PubMed]
  • Holmdahl R, Andersson M, Goldschmidt TJ, Gustafsson K, Jansson L, Mo JA. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol Rev. 1990 Dec;118:193–232. [PubMed]
  • Brunsberg U, Gustafsson K, Jansson L, Michaëlsson E, Ahrlund-Richter L, Pettersson S, Mattsson R, Holmdahl R. Expression of a transgenic class II Ab gene confers susceptibility to collagen-induced arthritis. Eur J Immunol. 1994 Jul;24(7):1698–1702. [PubMed]
  • Michaëlsson E, Andersson M, Engström A, Holmdahl R. Identification of an immunodominant type-II collagen peptide recognized by T cells in H-2q mice: self tolerance at the level of determinant selection. Eur J Immunol. 1992 Jul;22(7):1819–1825. [PubMed]
  • Michaëlsson E, Malmström V, Reis S, Engström A, Burkhardt H, Holmdahl R. T cell recognition of carbohydrates on type II collagen. J Exp Med. 1994 Aug 1;180(2):745–749. [PMC free article] [PubMed]
  • Kappler JW, Staerz U, White J, Marrack PC. Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature. 1988 Mar 3;332(6159):35–40. [PubMed]
  • Webb S, Morris C, Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990 Dec 21;63(6):1249–1256. [PubMed]
  • Rammensee HG, Kroschewski R, Frangoulis B. Clonal anergy induced in mature V beta 6+ T lymphocytes on immunizing Mls-1b mice with Mls-1a expressing cells. Nature. 1989 Jun 15;339(6225):541–544. [PubMed]
  • Zinkernagel RM, Pircher HP, Ohashi P, Oehen S, Odermatt B, Mak T, Arnheiter H, Bürki K, Hengartner H. T and B cell tolerance and responses to viral antigens in transgenic mice: implications for the pathogenesis of autoimmune versus immunopathological disease. Immunol Rev. 1991 Aug;122:133–171. [PubMed]
  • Savagner P, Miyashita T, Yamada Y. Two silencers regulate the tissue-specific expression of the collagen II gene. J Biol Chem. 1990 Apr 25;265(12):6669–6674. [PubMed]
  • Horton W, Miyashita T, Kohno K, Hassell JR, Yamada Y. Identification of a phenotype-specific enhancer in the first intron of the rat collagen II gene. Proc Natl Acad Sci U S A. 1987 Dec;84(24):8864–8868. [PMC free article] [PubMed]
  • Metsäranta M, Toman D, de Crombrugghe B, Vuorio E. Mouse type II collagen gene. Complete nucleotide sequence, exon structure, and alternative splicing. J Biol Chem. 1991 Sep 5;266(25):16862–16869. [PubMed]
  • Garofalo S, Vuorio E, Metsaranta M, Rosati R, Toman D, Vaughan J, Lozano G, Mayne R, Ellard J, Horton W, et al. Reduced amounts of cartilage collagen fibrils and growth plate anomalies in transgenic mice harboring a glycine-to-cysteine mutation in the mouse type II procollagen alpha 1-chain gene. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9648–9652. [PMC free article] [PubMed]
  • Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R, Berns A. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 1991 Aug 11;19(15):4293–4293. [PMC free article] [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Smith BD, Martin GR, Miller EJ, Dorfman A, Swarm R. Nature of the collagen synthesized by a transplanted chondrosarcoma. Arch Biochem Biophys. 1975 Jan;166(1):181–186. [PubMed]
  • Miller EJ, Rhodes RK. Preparation and characterization of the different types of collagen. Methods Enzymol. 1982;82(Pt A):33–64. [PubMed]
  • Andersson M, Holmdahl R. Analysis of type II collagen-reactive T cells in the mouse. I. Different regulation of autoreactive vs. non-autoreactive anti-type II collagen T cells in the DBA/1 mouse. Eur J Immunol. 1990 May;20(5):1061–1066. [PubMed]
  • Holmdahl R, Klareskog L, Andersson M, Hansen C. High antibody response to autologous type II collagen is restricted to H-2q. Immunogenetics. 1986;24(2):84–89. [PubMed]
  • Vingsbo C, Larsson P, Andersson M, Holmdahl R. Association of pepsin with type II collagen (CII) breaks control of CII autoimmunity and triggers development of arthritis in rats. Scand J Immunol. 1993 Mar;37(3):337–342. [PubMed]
  • Metsäranta M, Garofalo S, Decker G, Rintala M, de Crombrugghe B, Vuorio E. Chondrodysplasia in transgenic mice harboring a 15-amino acid deletion in the triple helical domain of pro alpha 1(II) collagen chain. J Cell Biol. 1992 Jul;118(1):203–212. [PMC free article] [PubMed]
  • Vandenberg P, Khillan JS, Prockop DJ, Helminen H, Kontusaari S, Ala-Kokko L. Expression of a partially deleted gene of human type II procollagen (COL2A1) in transgenic mice produces a chondrodysplasia. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7640–7644. [PMC free article] [PubMed]
  • Stacey A, Bateman J, Choi T, Mascara T, Cole W, Jaenisch R. Perinatal lethal osteogenesis imperfecta in transgenic mice bearing an engineered mutant pro-alpha 1(I) collagen gene. Nature. 1988 Mar 10;332(6160):131–136. [PubMed]
  • Garofalo S, Metsäranta M, Ellard J, Smith C, Horton W, Vuorio E, de Crombrugghe B. Assembly of cartilage collagen fibrils is disrupted by overexpression of normal type II collagen in transgenic mice. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3825–3829. [PMC free article] [PubMed]
  • Andersson M, Cremer MA, Terato K, Burkhardt H, Holmdahl R. Analysis of type II collagen reactive T cells in the mouse. II. Different localization of immunodominant T cell epitopes on heterologous and autologous type II collagen. Scand J Immunol. 1991 May;33(5):505–510. [PubMed]
  • Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. [PubMed]
  • Holmdahl R, Jansson L, Andersson M, Jonsson R. Genetic, hormonal and behavioural influence on spontaneously developing arthritis in normal mice. Clin Exp Immunol. 1992 Jun;88(3):467–472. [PMC free article] [PubMed]
  • Stuart JM, Dixon FJ. Serum transfer of collagen-induced arthritis in mice. J Exp Med. 1983 Aug 1;158(2):378–392. [PMC free article] [PubMed]
  • Michaëlsson E, Holmdahl M, Engström A, Burkhardt H, Scheynius A, Holmdahl R. Macrophages, but not dendritic cells, present collagen to T cells. Eur J Immunol. 1995 Aug;25(8):2234–2241. [PubMed]
  • Rowley M, Tait B, Mackay IR, Cunningham T, Phillips B. Collagen antibodies in rheumatoid arthritis. Significance of antibodies to denatured collagen and their association with HLA-DR4. Arthritis Rheum. 1986 Feb;29(2):174–184. [PubMed]
  • Rowley MJ, Tait B, Doran T, Emery P, Mackay IR. Associations between HLA and antibodies to collagen in rheumatoid arthritis. Ann Rheum Dis. 1990 Aug;49(8):578–581. [PMC free article] [PubMed]
  • Rönnelid J, Lysholm J, Engström-Laurent A, Klareskog L, Heyman B. Local anti-type II collagen antibody production in rheumatoid arthritis synovial fluid. Evidence for an HLA-DR4-restricted IgG response. Arthritis Rheum. 1994 Jul;37(7):1023–1029. [PubMed]
  • Londei M, Savill CM, Verhoef A, Brennan F, Leech ZA, Duance V, Maini RN, Feldmann M. Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis. Proc Natl Acad Sci U S A. 1989 Jan;86(2):636–640. [PMC free article] [PubMed]
  • Yan T, Burkhardt H, Ritter T, Bröker B, Mann KH, Bertling WM, von der Mark K, Emmrich F. Specificity and T cell receptor beta chain usage of a human collagen type II-reactive T cell clone derived from a healthy individual. Eur J Immunol. 1992 Jan;22(1):51–56. [PubMed]
  • Fugger L, Rothbard JB, Sonderstrup-McDevitt G. Specificity of an HLA-DRB1*0401-restricted T cell response to type II collagen. Eur J Immunol. 1996 Apr;26(4):928–933. [PubMed]

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