Heat Shock Proteins in Rheumatoid Arthritis

  • W. van Eden
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 136)


In view of the fundamental role of stress proteins in the maintenance of protein homeostasis, it seems likely that malfunctions associated with members of stress protein families would have pathological effects. Such effects might be minimal under normal physiological conditions, but could be exacerbated at times when other disease stimuli trigger the requirement for local alterations in stress protein function in particular afflicted cells or tissues. During infection, it can be anticipated that the requirement of stress proteins for cell viability will be equally essential both for the pathogen and for the infected host. Just as stress proteins are essential in “normal” as well as stressed cells, it is clear that changes in stress protein expression will be associated with physiologically normal events accompanying infection as well as with any subsequent pathological events. In addition to the direct role of stress proteins in cell physiology, their potential medical influence is compounded by their ability to act as potent immunogens. Responses to microbial stress proteins are a prominent feature of the immune repertoire in patients and in experimental animals, and there has been wide discussion of the possibility that recognition of conserved, self-like, epitopes on such antigens could influence infectious and other diseases. Three broad hypotheses have been put forward concerning the relevance of immunological reactivity to stress proteins:


Rheumatoid Arthritis Heat Shock Protein Stress Protein Adjuvant Arthritis Reactive Arthritis 
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  1. Aho K, Leirisalo-Repo M, Repo H (1985) Reactive arthritis. Clin Rheum Dis 11:25 Anderton SM, Van der Zee R, Noordzij A, Van Eden W (1994) Differential hsp65 T cell epitope recognition following Adjuvant Arthritis inducing or protective immunisation protocols. J Immunol 152:3656–3664Google Scholar
  2. Anderton SM, Van der Zee R, Prakken B, Noordzij A, Van Eden W (1995) Activation of T cells recognizing self 60 kDa heat shock protein can protect against experimental arthritis. J Exp Med 181:943–952PubMedCrossRefGoogle Scholar
  3. Bahr GM, Rook GAW, Al-Saffar M, Van Embden JDA, Stanford JL, Behbehani K (1989) An analysis of antibody levels to mycobacteria in relation to HLA type: evidence for non-HLA-linked high levels of antibody to the 65kD heat shock protein of M. tuberculosis in rheumatoid arthritis. Clin Exp Immunol 74:211–215Google Scholar
  4. Beachy EN, Stollerman GH (1973) Mediation of cytotoxic effects of streptococcal M protein by non-type-specific antibody in human sera. J Clin Invest 52:2563CrossRefGoogle Scholar
  5. Ben-Nun A, Cohen IR (1982) Experimental autoimmune encephalomeyelitis(EAE) mediated by T cell lines: process of selection of lines and characterisation of the cells. J Immunol 129:303PubMedGoogle Scholar
  6. Billingham MEJ, Butler R, Colston MJ (1990) A mycobacterial 65-kD heat shock protein induces antigen-specific suppression of adjuvant arthritis, but is not itself arthritogenic. J Exp Med 171:339–344PubMedCrossRefGoogle Scholar
  7. Bloemendal A, Van der Zee R, Rutten VPMG, Van Kooten PJS, Farine JC., Van Eden W (1997) Experimental immunisation with anti-rheumatic bacterial extract OM-89 induces T cell responses to heat-shock protein 60 and 70; modulation of peripheral immunological tolerance as its possible mode of action in the treatment of rheumatoid arthritis. Clin Exp Immunol 110:72–78PubMedCrossRefGoogle Scholar
  8. Bonnin D, Albani S (1998) Mucosal modulation of immune responses to heat-shock proteins in autoimmune arthritis. Biotherapy 10:213–221PubMedCrossRefGoogle Scholar
  9. Boog CJP, de Graeff-Meeder ER, Lucassen MA, van der Zee R, Voorhorst-Ogink, van Kooten PJS, Geuze HJ, van Eden W (1992) Two monoclonal antibodies generated against human hsp60 show reactivity with synovial membranes of patients with juvenile chronic arthritis. J Exp Med 175:1805PubMedCrossRefGoogle Scholar
  10. Chang Y-H, Pearson CM, Abe C (1980) Adjuvant polyarthritis IV. Induction by a synthetic adjuvant: immunologic, histopathogic and other studies. Arthritis Rheum 23:62PubMedCrossRefGoogle Scholar
  11. Cohen IR (1986) Regulation of autoimmune disease: physiological and therapeutic. Immunol Rev 94:5PubMedCrossRefGoogle Scholar
  12. Cohen IR, Young DB (1991) The immune system’s view of invading microorganisms, autoimmunity and the immunological homunculus. Immunol Today 12:105PubMedCrossRefGoogle Scholar
  13. Cromartie WJ, Craddock JG, Schwab JH, Anderle SK, Yang C (1977) Arthritis in rats after systemic injection of streptococcal cells or cell walls. J Exp Med 146:1585PubMedCrossRefGoogle Scholar
  14. De Graeff-Meeder ER, Van Eden W, Rijkers GT, Prakken ABJ, Kuis W, Voorhorst-Ogink MM, Van der Zee R, Schuurman HJ, Helders PJM, Zegers BJM (1995) Juvenile chronic arthritis: T cell reactivity to human hsp60 in patients with a favourable course of arthritis. J Clin Invest 95:934–940PubMedCrossRefGoogle Scholar
  15. Hill JL, Yu DTY (1987) Development of an experimental animal model for reactive arthritis induced by Yersinia enterocolitica infection. Infect Immun 55:721PubMedGoogle Scholar
  16. Holoshitz J, Naparstek Y, Ben-Nun A, Cohen IR (1983) Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science 219:56–58PubMedCrossRefGoogle Scholar
  17. Holoshitz J, Matitiau A, Cohen IR (1984) Arthritis induced in rats by clones of T lymphocytes responsive to mycobacteria but not to collagen type II. J Clin Invest 73:211–215PubMedCrossRefGoogle Scholar
  18. Hughes RA, Allard SA, Maini RN (1989)Arthritis associated wtih adjuvant mycobacterial treatment for carcinoma of the bladder. Ann Rheum Dis 48:432PubMedCrossRefGoogle Scholar
  19. Ito J, Krco C., Yu D, Luthra HS, David CS (1991) Preadministration of a 65kD heat-shock protein GroEL, inhibits collagen induced arthritis in mice (abstract). J Cell Biochem 15A:284Google Scholar
  20. Keat A (1986) Is spondylitis caused by Klebsiella?. Immunol Today 7:144CrossRefGoogle Scholar
  21. Kohashi O, Kohashi Y, Takahashi T, Ozawa A, Shigematsu N (1986) Suppressive effect of E. coli on adjuvant induced arthritis in germ-free rats. Arthritis Rheum 29:547–555PubMedCrossRefGoogle Scholar
  22. Lamm DL, Stogdill VD, Stogdill B, Crispen RG (1986) Complications of bacille Calmette-Guerin immunotherapy in patients with bladder cancer. J Urol 135: 274Google Scholar
  23. Ochsenkuhn T, Weber MW, Caselmann WH (1990) Arthritis after M. bovis immunotherapy for bladder cancer (letter). Ann Intern Med 112:882PubMedGoogle Scholar
  24. Oldstone MBA (1988) Prevention of type I diabetes in nonobese diabetic mice by virus infection. Science 239:500PubMedCrossRefGoogle Scholar
  25. Pearson CM (1956) Development of arthritis, periarthritis and periostitis in rats given adjuvant. Proc Soc Exp Biol Med 91:95–101PubMedGoogle Scholar
  26. Prakken ABJ, Van Eden W, Rijkers GT, Kuis W, Toebes EA, de Graeff-Meeder ER, Van der Zee R, Zegers BJM (1996) Autoreactivity to human hsp60 predicts disease remission in oligoarticular juvenile chronic arthritis. Arthritis Rheum 39:1826–1832PubMedCrossRefGoogle Scholar
  27. Prakken ABJ, Van der Zee R, Anderton SM, van Kooten PJS, Kuis W, Van Eden W (1997) Peptide induced nasal tolerance for a mycobacterial hsp60 T cell epitope in rats suppresses both adjuvant arthritis and non-microbially induced experimental arthritis. Proc Natl Acad Sci USA 94:3284–3289PubMedCrossRefGoogle Scholar
  28. Ragno S, Winrow VR et al (1996) A synthetic 10 kD heat-shock protein (hsplO) from Mycobacterium tuberculosis modulates adjuvant arthritis. Clin Exp Immunol 103:384–390PubMedCrossRefGoogle Scholar
  29. Severijnen AJ, Hazenberg MP, Van de Merwe JP (1988) Induction of chronic arthritis in rats by cell-wall fragments of anaerobic coccoid rods isolated from the faecal flora of patients with Crohn’s disease. Digestion 39:118PubMedCrossRefGoogle Scholar
  30. Steere AC., Malawista SE, Suydman DR, Shope RE, Andiman WA, Ross MR, Steele FM (1977) Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum 20:7–17PubMedCrossRefGoogle Scholar
  31. Thole JER, Dauwerse HG, Das PK, Groothuis DG, Schouls LM, Van Embden JDA (1985)Cloning of the Mycobacterium bovis BCG DNA and expression of antigens in Escherichia coli. Infect Immun 50:800–806PubMedGoogle Scholar
  32. Thole JER, Hindersson P, De Bruyn J, Cremers F, Van der Zee J, De Cock H, Tommassen J, Van Eden W, Van Embden JDA (1988) Antigenic relatedness of a strongly immunogenic 65kD mycobacterial protein antigen with a similarly sized ubiquitous bacterial common antigen. Microb Pathog 4:71–83PubMedCrossRefGoogle Scholar
  33. Thompson SJ, Rook GA, Brearley RJ, Van der Zee R, Elson CJ (1990) Autoimmune reactions to heat-shock proteins in pristane induced arthritis. Eur J Immunol 20:2479PubMedCrossRefGoogle Scholar
  34. Todd JA (1990) Genetic control of autoimmunity in type I diabetes. Immunol Today 11:122PubMedCrossRefGoogle Scholar
  35. Torisu M, Miyahara T, Shinohara N, Ohsato K, Sonozaki H (1978) A new side effect of BCG immunotherapy: BCG-induced arthritis in man. Cancer Immunol Immunother 5:77–83CrossRefGoogle Scholar
  36. Utsinger PD (1980) Bypass disease: a bacterial antigen-antibody systemic immune complex disease. Arthritis Rheum 23:758Google Scholar
  37. Van den Broek MF, Van de Putte LBA, Van den Berg WB (1988) Crohn’s disease associated with arthritis: a possible role for crossrectivity between gut bacteria and cartilage in the pathogenesis of arthritis. Arthritis Rheum 31:1077PubMedCrossRefGoogle Scholar
  38. Van den Broek MF, Hogervorst EMJ, Van der Bruggen MCJ, Van Eden W, Van der Zee R, Van den Berg WB (1989) Protection against streptococcal cell wall induced arthritis by pretreatment with 65kD mycobacterial heat-shock protein. J Exp Med 170:449–466PubMedCrossRefGoogle Scholar
  39. Van Eden W, Holoshitz J, Nevo Z, Frenkel A, Klajman A, Cohen IR (1985) Arthritis induced by a T lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc Natl Acad Sci USA 82:5064–5067CrossRefGoogle Scholar
  40. Van Eden W, Holoshitz J, Cohen IR (1987) Antigenic mimicry between mycobacteria and cartilage proteoglycans: the model of adjuvant arthritis. In: Cruse TM (ed) Concepts immunopathol 4. Karger, Basel, pp 144–170Google Scholar
  41. Van Eden W, Thole JER, Van der Zee R, Noordzij A, van Embden JDA, Hensen EJ, Cohen IR (1988) Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis, Nature 331:171–173PubMedCrossRefGoogle Scholar
  42. Van Eden W, Young DB (1996) Stress proteins in medicine. Dekker, New YorkGoogle Scholar
  43. Van Eden W, van der Zee R, Paul AGA, Prakken BJ, Wendling U, Anderton SM, Wanben MHM (1998) Do heat-shock proteins control the balance of T cell regulation in inflammatory diseases? Immunol Today 19:303–307PubMedCrossRefGoogle Scholar
  44. van Roon J, van Eden W, van Roy J, Lafeber F, Bijlsma JWJ (1997) Stimulation of suppressive T cell responses by human but not bacterial 60 kDa heat-shock protein in synovial fluid of patients with rheumatoid arthritis. J Clin Invest 100:459–463PubMedCrossRefGoogle Scholar
  45. Vischer TL, Van Eden W (1994) Oral desensibilization in rheumatoid arthritis (RA). Ann Rheum Dis 53:708–710PubMedCrossRefGoogle Scholar
  46. Whitehouse DJ, Whitehouse MW, Pearson CM (1969) Passive transfer of adjuvant induced arthritis and allergic encephalomyelitis in rats using thoracic duct lymphocytes. Nature 224:1322PubMedCrossRefGoogle Scholar
  47. Wilbrink B, Holewijn M, Bijlsma JWJ, van Roy JLAM, den Otter W, van Eden W (1993) Suppression of human cartilage proteoglycan synthesis by rheumatoid synovial fluid mononuclear cells activated with mycobacterial 60kD heat-shock protein. Arthritis Rheum 36:514PubMedCrossRefGoogle Scholar
  48. Young DB, Ivanyi J, Cox JH, Lamb JR (1987) The 65 kDa antigen of mycobacteria-a common bacterial protein?. Immunol Today 8:215–219CrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1999

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  • W. van Eden

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