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J Exp Med. 1995 Mar 1; 181(3): 943–952.
PMCID: PMC2191900

Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis


Lewis rats are susceptible to several forms of experimental arthritis- induced using heat-killed Mycobacterium tuberculosis (adjuvant arthritis, or AA), streptococcal cell walls, collagen type II, and the lipoidal amine CP20961. Prior immunization with the mycobacterial 65-kD heat shock protein (hsp65) was reported to protect against AA, and other athritis models not using M. tuberculosis, via a T cell-mediated mechanism. Hsp65 shares 48% amino acid identity with mammalian hsp60, which is expressed at elevated levels in inflamed synovia. Several studies have reported cross-reactive T cell recognition of mycobacterial hsp65 and self hsp60 in arthritic and normal individuals. We previously described nine major histocompatibility complex class II- restricted epitopes in mycobacterial hsp65 recognized by Lewis rat T cells. Of these only one, covering the 256-270 sequence, primed for cross-reactive T cell responses to the corresponding region of rat hsp60. Here we have tested each hsp65 epitope for protective activity by immunizing rats with synthetic peptides. A peptide containing the 256-270 epitope, which induced cross-reactive T cells, was the only one able to confer protection against AA. Similarly, administration of a T cell line specific for this epitope protected against AA. Preimmunization with the 256-270 epitope induced T cells that responded to heat-shocked syngeneic antigen-presenting cells, and also protected against CP20961-induced arthritis, indicating that activation of T cells, recognizing an epitope in self hsp60 can protect against arthritis induced without mycobacteria. Therefore, in contrast to the accepted concept that cross-reactive T cell recognition of foreign and self antigens might induce aggressive autoimmune disease, we propose that cross-reactivity between bacterial and self hsp60 might also be used to maintain a protective self-reactive T cell population. This discovery might have important implications for understanding T cell- mediated regulation of inflammation.

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Selected References

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  • PEARSON CM. Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol Med. 1956 Jan;91(1):95–101. [PubMed]
  • Cromartie WJ, Craddock JG, Schwab JH, Anderle SK, Yang CH. Arthritis in rats after systemic injection of streptococcal cells or cell walls. J Exp Med. 1977 Dec 1;146(6):1585–1602. [PMC free article] [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]
  • Chang YH, Pearson CM, Abe C. Adjuvant polyarthritis. IV. Induction by a synthetic adjuvant: immunologic, histopathologic, and other studies. Arthritis Rheum. 1980 Jan;23(1):62–71. [PubMed]
  • van Eden W, Thole JE, van der Zee R, Noordzij A, van Embden JD, Hensen EJ, Cohen IR. Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature. 1988 Jan 14;331(6152):171–173. [PubMed]
  • Billingham ME, Carney S, Butler R, Colston MJ. A mycobacterial 65-kD heat shock protein induces antigen-specific suppression of adjuvant arthritis, but is not itself arthritogenic. J Exp Med. 1990 Jan 1;171(1):339–344. [PMC free article] [PubMed]
  • Hogervorst EJ, Wagenaar JP, Boog CJ, van der Zee R, van Embden JD, van Eden W. Adjuvant arthritis and immunity to the mycobacterial 65 kDa heat shock protein. Int Immunol. 1992 Jul;4(7):719–727. [PubMed]
  • van den Broek MF, Hogervorst EJ, Van Bruggen MC, Van Eden W, van der Zee R, van den Berg WB. Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein. J Exp Med. 1989 Aug 1;170(2):449–466. [PMC free article] [PubMed]
  • Thompson SJ, Rook GA, Brealey RJ, Van der Zee R, Elson CJ. Autoimmune reactions to heat-shock proteins in pristane-induced arthritis. Eur J Immunol. 1990 Nov;20(11):2479–2484. [PubMed]
  • Jindal S, Dudani AK, Singh B, Harley CB, Gupta RS. Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen. Mol Cell Biol. 1989 May;9(5):2279–2283. [PMC free article] [PubMed]
  • Karlsson-Parra A, Söderström K, Ferm M, Ivanyi J, Kiessling R, Klareskog L. Presence of human 65 kD heat shock protein (hsp) in inflamed joints and subcutaneous nodules of RA patients. Scand J Immunol. 1990 Jun;31(6):283–288. [PubMed]
  • Boog CJ, de Graeff-Meeder ER, Lucassen MA, van der Zee R, Voorhorst-Ogink MM, van Kooten PJ, Geuze HJ, van Eden W. Two monoclonal antibodies generated against human hsp60 show reactivity with synovial membranes of patients with juvenile chronic arthritis. J Exp Med. 1992 Jun 1;175(6):1805–1810. [PMC free article] [PubMed]
  • Kleinau S, Söderström K, Kiessling R, Klareskog L. A monoclonal antibody to the mycobacterial 65 kDa heat shock protein (ML 30) binds to cells in normal and arthritic joints of rats. Scand J Immunol. 1991 Feb;33(2):195–202. [PubMed]
  • Munk ME, Schoel B, Modrow S, Karr RW, Young RA, Kaufmann SH. T lymphocytes from healthy individuals with specificity to self-epitopes shared by the mycobacterial and human 65-kilodalton heat shock protein. J Immunol. 1989 Nov 1;143(9):2844–2849. [PubMed]
  • Lamb JR, Bal V, Mendez-Samperio P, Mehlert A, So A, Rothbard J, Jindal S, Young RA, Young DB. Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol. 1989;1(2):191–196. [PubMed]
  • Anderton SM, van der Zee R, Goodacre JA. Inflammation activates self hsp60-specific T cells. Eur J Immunol. 1993 Jan;23(1):33–38. [PubMed]
  • Quayle AJ, Wilson KB, Li SG, Kjeldsen-Kragh J, Oftung F, Shinnick T, Sioud M, Førre O, Capra JD, Natvig JB. Peptide recognition, T cell receptor usage and HLA restriction elements of human heat-shock protein (hsp) 60 and mycobacterial 65-kDa hsp-reactive T cell clones from rheumatoid synovial fluid. Eur J Immunol. 1992 May;22(5):1315–1322. [PubMed]
  • Anderton SM, van der Zee R, Noordzij A, van Eden W. Differential mycobacterial 65-kDa heat shock protein T cell epitope recognition after adjuvant arthritis-inducing or protective immunization protocols. J Immunol. 1994 Apr 1;152(7):3656–3664. [PubMed]
  • Yang XD, Gasser J, Feige U. Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat-shock protein. Clin Exp Immunol. 1990 Aug;81(2):189–194. [PMC free article] [PubMed]
  • Yang XD, Gasser J, Feige U. Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat shock protein: specificity and mechanism. Clin Exp Immunol. 1992 Jan;87(1):99–104. [PMC free article] [PubMed]
  • Paul WE, Seder RA. Lymphocyte responses and cytokines. Cell. 1994 Jan 28;76(2):241–251. [PubMed]
  • Miller A, al-Sabbagh A, Santos LM, Das MP, Weiner HL. Epitopes of myelin basic protein that trigger TGF-beta release after oral tolerization are distinct from encephalitogenic epitopes and mediate epitope-driven bystander suppression. J Immunol. 1993 Dec 15;151(12):7307–7315. [PubMed]
  • Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A, Moudgil K. Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol. 1993;11:729–766. [PubMed]
  • Oldstone MB. Molecular mimicry and autoimmune disease. Cell. 1987 Sep 11;50(6):819–820. [PubMed]
  • Kohashi O, Kuwata J, Umehara K, Uemura F, Takahashi T, Ozawa A. Susceptibility to adjuvant-induced arthritis among germfree, specific-pathogen-free, and conventional rats. Infect Immun. 1979 Dec;26(3):791–794. [PMC free article] [PubMed]
  • Kohashi O, Kohashi Y, Takahashi T, Ozawa A, Shigematsu N. Suppressive effect of Escherichia coli on adjuvant-induced arthritis in germ-free rats. Arthritis Rheum. 1986 Apr;29(4):547–553. [PubMed]
  • Shehadeh N, Calcinaro F, Bradley BJ, Bruchim I, Bruchlim I, Vardi P, Lafferty KJ. Effect of adjuvant therapy on development of diabetes in mouse and man. Lancet. 1994 Mar 19;343(8899):706–707. [PubMed]
  • Elias D, Reshef T, Birk OS, van der Zee R, Walker MD, Cohen IR. Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3088–3091. [PMC free article] [PubMed]
  • De Graeff-Meeder ER, van der Zee R, Rijkers GT, Schuurman HJ, Kuis W, Bijlsma JW, Zegers BJ, van Eden W. Recognition of human 60 kD heat shock protein by mononuclear cells from patients with juvenile chronic arthritis. Lancet. 1991 Jun 8;337(8754):1368–1372. [PubMed]

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