Immunopathogenesis and Prevention of Uveitis with the Behçet’s Disease-Specific Peptide Linked to Cholera Toxin B

  • T. Lehner
  • M.R. Stanford
  • P.A. Phipps
  • J.B. Sun
  • B.G. Xiao
  • J. Holmgren
  • T. Shinnick
  • A. Hasan
  • Y. Mizushima
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 528)


Behçet’s disease (BD) is a multisystemic disease affecting mucocutaneous, ocular, central nervous system, joint and vascular tissues. The aetiology of BD has been associated with a variety of microorganisms, especially Herpes simplex virus and some strains of Streptococcus sanguis. A common microbial agent may be involved, such as heat shock protein (HSP) which has significant homology with human cellular HSP. The evidence in favour of HSP as an aetiological factor in BD is based on T cell proliferative responses and B cell antibodies to the defined HSP60 epitope p336-351 in patients with BD in Britain, Japan and Turkey. The proportion of γδ T cells is significantly increased in BD and HSP65 or HSP70 upregulates γδ T cells. The peptide determinant defined in patients with BD elicits uveitis in Lewis rats when administered by the oral mucosal or systemic route. It is noteworthy that the MICA gene is a cell stress response gene and shares nucleotide sequences with the human HSP70 promoter. The cytokine and chemokine networks stimulated by HSP induce polarisation towards the TH1 cytokines during active disease. The evidence from these studies has converged towards the concept that the multi-system immunopathology of BD is generated by an over-reaction to microbial stress proteins. We now demonstrate that p336-351 induced uveitis in rats can be prevented by oral tolerization with the peptide linked to recombinant cholera toxin B subunit. Preliminary evidence in an open clinical trial suggests that this novel tolerizing strategy may be effective in preventing relapse of uveitis in BD.


Heat Shock Protein Cholera Toxin Cell Epitope Mica Gene Open Clinical Trial 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Denman, A.M., Hylton, W., Pelton, B.K.. et al., 1986, In: Recent advances in Behçet’s Disease (T. Lehner, and C.G. Barnes, eds.), Royal Society of Medicine, London, pp. 23–29.Google Scholar
  2. 2.
    Lehner, T., 1986, In: Recent Advances in Behçet’s Disease (T. Lehner, and C.G. Barnes, eds.), Royal Society of Medicine, London, pp. 31–36.Google Scholar
  3. 3.
    Eglin, R.P., Lehner, T., and Subak-Sharpe, J.H., 1982, Lancet 2: 1356–1361.PubMedGoogle Scholar
  4. 4.
    Bonass, W.A., Bird-Steward, J.A., Chamberlain, M.A., et al., 1986, In: Recent Advances in Behçet’s Disease (T. Lehner, and C.G. Barnes, eds.), Royal Society of Medicine, London, pp. 37–41.Google Scholar
  5. 5.
    Studd, M., McCance, D.J., and Lehner, T., 1991, J. Med. Microbiol 34: 39.PubMedGoogle Scholar
  6. 6.
    Lee, S., Bang, D., Cho, Y.H., et al., 1996, Arch. Dermatol. Res. 288: 179–183.CrossRefPubMedGoogle Scholar
  7. 7.
    Hussain, L., Ward, R.G., Barnes, C.G., et al., 1986, In: Recent Advances in Behçet’s Disease (T. Lehner, and C.G. Barnes, eds.), Royal Society of Medicine, London, pp. 73–77.Google Scholar
  8. 8.
    Hamzaoui, K., Kahan, A., Ayed, K., et al., 1990, Clin. Exp. Immunol. 81: 390–395.PubMedGoogle Scholar
  9. 9.
    Sohn, S., Lee, E.S., Bang, D., et al., 1996, Eur. J. Dermatol. 8: 21–23.Google Scholar
  10. 10.
    Graykowski, E.A., Barile, M.F., Lee, W.B., et al., 1996, J. Am. Med. Assoc. 196: 637–644.Google Scholar
  11. 11.
    Donatsky, O., 1975, Scand. J. Dent, Res. 83: 111–119.Google Scholar
  12. 12.
    Wilton, J.M.A., and Lehner, T, 1968, J. Dent. Res. 47: 1001.Google Scholar
  13. 13.
    Kaneko, F., Takahashi, Y., Muramatsu, Y., et al., 1985, Br. J. Dermatol. 113: 303–312PubMedGoogle Scholar
  14. 14.
    Mizushima, Y., 1989, J. Rheumatol. 16: 506–511.Google Scholar
  15. 15.
    Isogai, E., Ohno, S., Takehashi, K., et al., 1990, Bifidobact. Microflora 9: 27–41.Google Scholar
  16. 16.
    Lehner, T., Lavery, E., Smith, R., et al., 1991, Infect. Immun. 59: 1434–1441.PubMedGoogle Scholar
  17. 17.
    Hirohata, S., Oka, H., and Mizushima, Y., 1992, Cell Immunol. 140: 410–419.CrossRefPubMedGoogle Scholar
  18. 18.
    Mochizuki, M., Suzuki, N., Takeno, M., et al., 1994, Eur. J. Immunol. 24: 1536–1543.PubMedGoogle Scholar
  19. 19.
    Shimizu, T., Katsuta, Y., and Oshima, Y., 1965, Ann. Rheum. Dis. 24: 494.PubMedGoogle Scholar
  20. 20.
    Lehner, T., 1967, Br. Med. J. 1: 465–467.PubMedGoogle Scholar
  21. 21.
    Thole, J.E.R., Hindersson, R.P., de Bruyn, J., et al., 1988, Microb. Pathol. 4: 71–83.Google Scholar
  22. 22.
    Pervin, K., Childerstone, A., Shinnick, T., et al., 1993, J. Immunol. 151: 1–10.Google Scholar
  23. 23.
    Hasan, A., Fortune, F., Wilson, A., et al., 1996, Lancet 347: 789–794.CrossRefPubMedGoogle Scholar
  24. 24.
    Direskeneli, H., Hasan, A., Shinnick, T., et al., 1996, Scand. J. Immunol. 43:464–471.CrossRefPubMedGoogle Scholar
  25. 25.
    Kaneko, S., Suzuki, N., Yamashita, N., et al., 1997, Clin. Exp. Immunol. 108: 204–212.CrossRefPubMedGoogle Scholar
  26. 26.
    Direskeneli, H., Eksloglu-Demiralp, E., Yavuz, T., et al., 2000, J. Rheumatol. 27: 708–713.PubMedGoogle Scholar
  27. 27.
    Ergun, T., Ince, U., Demiralp, E., et al., 2000, In Behçet’s Disease (D. Bang, E.-S. Lee, and S. Lee, eds.), Design Mecca Publishing, Seoul, p. 715.Google Scholar
  28. 28.
    Tasci, B., Direskeneli, H., Serdaroglu, P., et al., 1998, Clin. Exp. Immunol. 113: 100–104.CrossRefPubMedGoogle Scholar
  29. 29.
    Hasan, A., Childerstone, A., Pervin, K. et al., 1998, Clin. Exp. Immunol. 99: 392–397.Google Scholar
  30. 30.
    Hasan, A., Wilson, A., Shinnick, T., et al., 2002, Clin. Exp. Immunol. 128: 318–325.CrossRefPubMedGoogle Scholar
  31. 31.
    Stanford, M.R., Kasp, E., Whiston, R., et al., 1994, Clin. Exp. Immunl. 97: 226–231.Google Scholar
  32. 32.
    Uchio, E., Stanford, M., Hasan, A., et al., 1998, Exp. Eye Res. 16: 174–180.Google Scholar
  33. 33.
    Hu, W., Hasan, A., Wilson, A., et al., 1998, Eur. J. Immunol. 28: 2444–2455.PubMedGoogle Scholar
  34. 34.
    Sakane, T., Suzuki, N. and Taneko, M., 2000, In Behçet’s Disease (D. Bang, E.-S. Lee, and S. Lee, eds.), Design Mecca Publishing, Seoul, p. 673.Google Scholar
  35. 35.
    Lehner, T., Bergmeier, L.A., Wang, Y., et al.. 2000, Eur. J. Immunol. 30: 594–603.PubMedGoogle Scholar
  36. 36.
    Murphey, P.M., 1994, Annu. Rev. Immunol. 12: 593–633.Google Scholar
  37. 37.
    Meurer, R, Van Riper, G., Feeney, W., et al., 1993, J. Exp. Med. 178: 1913–1921.CrossRefPubMedGoogle Scholar
  38. 38.
    Kim, J.J., Nottingham, L.K., Sin, J.I., et al., 1998, J. Clin. Invest. 102: 1112–1124.PubMedGoogle Scholar
  39. 39.
    Schall, T.J., Bacon, K., Camp, R.D., et al., 1993, J. Exp, Med. 177: 1821–1826.CrossRefGoogle Scholar
  40. 40.
    Dieu, M.C., Vanbervliet, B., Vicari, A., et al, 1998, J. Exp. Med. 188: 378–386.CrossRefGoogle Scholar
  41. 41.
    Lussow, A.R., Barrios, C., van Embden, J., et al., 1991, Eur. J. Immunol. 21: 2297–2302.PubMedGoogle Scholar
  42. 42.
    Perraut, R., Lussow, A.R., Gavoille, S., et al., 1993, Clin. Exp. Immunol. 93: 382–386.PubMedGoogle Scholar
  43. 43.
    Barrios, C., Lussow, J.W., van Embden, J, et al., 1992, Eur. J. Immunol. 22: 1365–1372.PubMedGoogle Scholar
  44. 44.
    Pilon, M., and Schekman, R., 1999, Cell 97: 679–682.CrossRefPubMedGoogle Scholar
  45. 45.
    Fujihara, S.M., and Nadler, S.G., 1999, The EMBO J. 18: 411–419.Google Scholar
  46. 46.
    Wang, Y., Kelly, C., Kartunen, J, et al., 2001, Immunity 15: 971–983.CrossRefPubMedGoogle Scholar
  47. 47.
    Becker, T., Hartl E-U., and Wieland F., J. Cell Biol. 158: 1277–1285.Google Scholar
  48. 48.
    Ridge, J.P., Di Rose, F., and Matzinger, P., 1998, Nature 393: 474–478.CrossRefPubMedGoogle Scholar
  49. 49.
    Bennett, S.R.M, Carbone, F.R., Karamalis, F, et al., 1998, Nature 393: 478–480.PubMedGoogle Scholar
  50. 50.
    Wang, Y., Kelly, C.G, Singh, M., et al., 2002, J. Immunol. 169: 2422–2429.PubMedGoogle Scholar
  51. 51.
    Haregewoin, A, Soman, G., Hom, R.C, et al., 1989, Nature 340: 309–312.CrossRefPubMedGoogle Scholar
  52. 52.
    Born, W., Hall, L, Dallas, A., et al., 1990, Science 249:67.PubMedGoogle Scholar
  53. 53.
    Kaur, I., Voss, S.D., Gupta, R.S., et al., 1993, J. Immunol. 150: 2046–2055.PubMedGoogle Scholar
  54. 54.
    Fortune, F., Walker. J., and Lehner, T., 1990, Clin. Exp. Immunol. 82: 326–332.PubMedGoogle Scholar
  55. 55.
    Suzuki, Y., Hoshi, K., Matsuda, T., et al., 1992, J. Rheumatol. 19: 588–592.PubMedGoogle Scholar
  56. 56.
    Hamzaoui, K., Hamzaoui, A., Hentati, F., et al., 1994, J. Rheumatol. 21: 2301–2306.PubMedGoogle Scholar
  57. 57.
    Yamashita, N., Kaneoka, H., Kaneko, S., et al., 1997, Clin. Exp. Immunol. 107: 241–247.CrossRefPubMedGoogle Scholar
  58. 58.
    Steinle, A., Groh, V., and Spies, T., 1998, Proc. Natl. Acad. Sci. USA 95: 12510–12515.CrossRefPubMedGoogle Scholar
  59. 59.
    Ferrick, D.A., Schrenzel, M.D., Mulvania, T., et al., 1995, Nature 373: 255–257.CrossRefPubMedGoogle Scholar
  60. 60.
    Munk, E., Gatrill, A.J., and Kaufmann, S.H.E., 1990, J. Immunol. 145: 2434–2439.PubMedGoogle Scholar
  61. 61.
    Boismenu, R., and Havran, R., 1994, Science 266: 1253–1255.PubMedGoogle Scholar
  62. 62.
    Groh, V., Bahram, S., Bauer, S., et al., 1996, Proc. Natl. Acad. Sci. USA 93: 12445–12450.CrossRefPubMedGoogle Scholar
  63. 63.
    Kol, A., Lightman, A.H., Finberg, R.W., et al., 2000, J. Immunol. 164: 13–17.PubMedGoogle Scholar
  64. 64.
    Phipps, P.A., Stanford, M.R., Sun J.-B., et al., 2003, Eur. J. Immunol. 33 (submitted).Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • T. Lehner
    • 2
  • M.R. Stanford
    • 2
  • P.A. Phipps
    • 2
  • J.B. Sun
    • 3
  • B.G. Xiao
    • 4
  • J. Holmgren
    • 3
  • T. Shinnick
    • 1
  • A. Hasan
    • 2
  • Y. Mizushima
    • 5
  1. 1.CDCAtlantaUSA
  2. 2.Guy’s, King’s and St Thomas’ Hospital Medical SchoolKings CollegeLondonEngland
  3. 3.Gothenburg University Vaccine Research Institute (GUVAX)Goteborg UniversityGoteborgSweden
  4. 4.Karolinska InstituteStockholmSweden
  5. 5.Institute of Medical SciencesKawasakiJapan

Personalised recommendations