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. 1990 Mar 1;171(3):831–841. doi: 10.1084/jem.171.3.831

Recognition of a mycobacteria-specific epitope in the 65-kD heat-shock protein by synovial fluid-derived T cell clones

PMCID: PMC2187794  PMID: 1689764

Abstract

Adjuvant arthritis in rats is induced by a T cell clone specific for amino acids 180-188 of the mycobacterial 65-kD heat-shock protein, and synovial T cell responses to this same Ag have been noted in human arthritis. We have isolated 65-kD Ag-specific T cell clones from synovial fluid mononuclear cells of a patient with acute arthritis, which, unlike the corresponding PBMC, showed a marked proliferative response to the 65-kD Ag. Using synthetic peptides corresponding to the whole sequence of the 65-kD Ag, all the clones were shown to recognize an epitope present in the first NH2-terminal peptide (amino acids 1- 15), with no response to the adjacent peptide (amino acids 6-22) or to any other peptide. The complete dominance of this epitope in the response to the 65-kD Ag was shown by documenting responses to the peptide in PBMC obtained after recovery from the arthritis. This epitope, like that recognized by the rat arthritogenic T cell clone, is in a portion of the 65-kD sequence that is not conserved between bacteria and eukaryotes, so that in this case, joint inflammation could not be attributed to bacteria-induced T cell clones cross-reacting with the self 65-kD Ag.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aho K., Leirisalo-Repo M., Repo H. Reactive arthritis. Clin Rheum Dis. 1985 Apr;11(1):25–40. [PubMed] [Google Scholar]
  2. Bahr G. M., Rook G. A., al-Saffar M., Van Embden J., Stanford J. L., Behbehani K. Antibody levels to mycobacteria in relation to HLA type: evidence for non-HLA-linked high levels of antibody to the 65 kD heat shock protein of M. bovis in rheumatoid arthritis. Clin Exp Immunol. 1988 Nov;74(2):211–215. [PMC free article] [PubMed] [Google Scholar]
  3. Cohen I. R., Holoshitz J., van Eden W., Frenkel A. T lymphocyte clones illuminate pathogenesis and affect therapy of experimental arthritis. Arthritis Rheum. 1985 Aug;28(8):841–845. doi: 10.1002/art.1780280802. [DOI] [PubMed] [Google Scholar]
  4. Emery P., Gentry K. C., Mackay I. R., Muirden K. D., Rowley M. Deficiency of the suppressor inducer subset of T lymphocytes in rheumatoid arthritis. Arthritis Rheum. 1987 Aug;30(8):849–856. doi: 10.1002/art.1780300802. [DOI] [PubMed] [Google Scholar]
  5. Gaston J. S., Life P. F., Bailey L. C., Bacon P. A. In vitro responses to a 65-kilodalton mycobacterial protein by synovial T cells from inflammatory arthritis patients. J Immunol. 1989 Oct 15;143(8):2494–2500. [PubMed] [Google Scholar]
  6. Gaston J. S., Life P. F., Granfors K., Merilahti-Palo R., Bailey L., Consalvey S., Toivanen A., Bacon P. A. Synovial T lymphocyte recognition of organisms that trigger reactive arthritis. Clin Exp Immunol. 1989 Jun;76(3):348–353. [PMC free article] [PubMed] [Google Scholar]
  7. Heber-Katz E., Acha-Orbea H. The V-region disease hypothesis: evidence from autoimmune encephalomyelitis. Immunol Today. 1989 May;10(5):164–169. doi: 10.1016/0167-5699(89)90174-6. [DOI] [PubMed] [Google Scholar]
  8. Holoshitz J., Klajman A., Drucker I., Lapidot Z., Yaretzky A., Frenkel A., van Eden W., Cohen I. R. T lymphocytes of rheumatoid arthritis patients show augmented reactivity to a fraction of mycobacteria cross-reactive with cartilage. Lancet. 1986 Aug 9;2(8502):305–309. doi: 10.1016/s0140-6736(86)90003-6. [DOI] [PubMed] [Google Scholar]
  9. Holoshitz J., Koning F., Coligan J. E., De Bruyn J., Strober S. Isolation of CD4- CD8- mycobacteria-reactive T lymphocyte clones from rheumatoid arthritis synovial fluid. Nature. 1989 May 18;339(6221):226–229. doi: 10.1038/339226a0. [DOI] [PubMed] [Google Scholar]
  10. Houghten R. A. General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5131–5135. doi: 10.1073/pnas.82.15.5131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lamb F. I., Kingston A. E., Estrada I., Colston M. J. Heterologous expression of the 65-kilodalton antigen of Mycobacterium leprae and murine T-cell responses to the gene product. Infect Immun. 1988 May;56(5):1237–1241. doi: 10.1128/iai.56.5.1237-1241.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lamb J. R., Bal V., Mendez-Samperio P., Mehlert A., So A., Rothbard J., Jindal S., Young R. A., Young D. B. Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol. 1989;1(2):191–196. doi: 10.1093/intimm/1.2.191. [DOI] [PubMed] [Google Scholar]
  13. Lamb J. R., O'Hehir R. E., Young D. B. The use of nitrocellulose immunoblots for the analysis of antigen recognition by T lymphocytes. J Immunol Methods. 1988 May 25;110(1):1–10. doi: 10.1016/0022-1759(88)90076-2. [DOI] [PubMed] [Google Scholar]
  14. Mehra V., Sweetser D., Young R. A. Efficient mapping of protein antigenic determinants. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7013–7017. doi: 10.1073/pnas.83.18.7013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Polla B. S. A role for heat shock proteins in inflammation? Immunol Today. 1988 May;9(5):134–137. doi: 10.1016/0167-5699(88)91199-1. [DOI] [PubMed] [Google Scholar]
  16. Res P. C., Schaar C. G., Breedveld F. C., van Eden W., van Embden J. D., Cohen I. R., de Vries R. R. Synovial fluid T cell reactivity against 65 kD heat shock protein of mycobacteria in early chronic arthritis. Lancet. 1988 Aug 27;2(8609):478–480. doi: 10.1016/s0140-6736(88)90123-7. [DOI] [PubMed] [Google Scholar]
  17. Svejgaard A., Platz P., Ryder L. P. HLA and disease 1982--a survey. Immunol Rev. 1983;70:193–218. doi: 10.1111/j.1600-065x.1983.tb00715.x. [DOI] [PubMed] [Google Scholar]
  18. Synovial fluid T cells and 65 kD heat-shock protein. Lancet. 1988 Oct 8;2(8615):856–857. [PubMed] [Google Scholar]
  19. Thole J. E., Hindersson P., de Bruyn J., Cremers F., van der Zee J., de Cock H., Tommassen J., van Eden W., van Embden J. D. Antigenic relatedness of a strongly immunogenic 65 kDA mycobacterial protein antigen with a similarly sized ubiquitous bacterial common antigen. Microb Pathog. 1988 Jan;4(1):71–83. doi: 10.1016/0882-4010(88)90049-6. [DOI] [PubMed] [Google Scholar]
  20. Tsoulfa G., Rook G. A., Van-Embden J. D., Young D. B., Mehlert A., Isenberg D. A., Hay F. C., Lydyard P. M. Raised serum IgG and IgA antibodies to mycobacterial antigens in rheumatoid arthritis. Ann Rheum Dis. 1989 Feb;48(2):118–123. doi: 10.1136/ard.48.2.118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Van Schooten W. C., Elferink D. G., Van Embden J., Anderson D. C., De Vries R. R. DR3-restricted T cells from different HLA-DR3-positive individuals recognize the same peptide (amino acids 2-12) of the mycobacterial 65-kDa heat-shock protein. Eur J Immunol. 1989 Nov;19(11):2075–2079. doi: 10.1002/eji.1830191116. [DOI] [PubMed] [Google Scholar]
  22. Van der Zee R., Van Eden W., Meloen R. H., Noordzij A., Van Embden J. D. Efficient mapping and characterization of a T cell epitope by the simultaneous synthesis of multiple peptides. Eur J Immunol. 1989 Jan;19(1):43–47. doi: 10.1002/eji.1830190108. [DOI] [PubMed] [Google Scholar]
  23. Wang A., Lu S. D., Mark D. F. Site-specific mutagenesis of the human interleukin-2 gene: structure-function analysis of the cysteine residues. Science. 1984 Jun 29;224(4656):1431–1433. doi: 10.1126/science.6427925. [DOI] [PubMed] [Google Scholar]
  24. Young D., Lathigra R., Hendrix R., Sweetser D., Young R. A. Stress proteins are immune targets in leprosy and tuberculosis. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4267–4270. doi: 10.1073/pnas.85.12.4267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. de Vries R. R., Ottenhoff T. H., van Schooten W. C. Human leukocyte antigens (HLA) and mycobacterial disease. Springer Semin Immunopathol. 1988;10(4):305–318. doi: 10.1007/BF02053843. [DOI] [PubMed] [Google Scholar]
  26. van Eden W., Holoshitz J., Nevo Z., Frenkel A., Klajman A., Cohen I. R. Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5117–5120. doi: 10.1073/pnas.82.15.5117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. van Eden W., Thole J. E., van der Zee R., Noordzij A., van Embden J. D., Hensen E. J., Cohen I. R. Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature. 1988 Jan 14;331(6152):171–173. doi: 10.1038/331171a0. [DOI] [PubMed] [Google Scholar]
  28. van Eden W., de Vries R. R., D'Amaro J., Schreuder I., Leiker D. L., van Rood J. J. HLA-DR-associated genetic control of the type of leprosy in a population from surinam. Hum Immunol. 1982 Jul;4(4):343–350. doi: 10.1016/0198-8859(82)90007-6. [DOI] [PubMed] [Google Scholar]
  29. van Eden W., de Vries R. R., Stanford J. L., Rook G. A. HLA-DR3 associated genetic control of response to multiple skin tests with new tuberculins. Clin Exp Immunol. 1983 May;52(2):287–292. [PMC free article] [PubMed] [Google Scholar]
  30. van den Broek M. F., Hogervorst E. J., Van Bruggen M. C., Van Eden W., van der Zee R., van den Berg W. B. 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. doi: 10.1084/jem.170.2.449. [DOI] [PMC free article] [PubMed] [Google Scholar]

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