Abstract
In this brief review, inspired partly by a symposium at the autumn meeting of the British Society for Immunology, 1992, varying hypotheses concerning the etiopathogenesis of rheumatoid arthritis (RA) are explored and tested against current evidence. Immunogenetic considerations, whilst of interest, have not aided our understanding of the development of this disease. The association with restricted HLA-DR beta chain hypervariable sequences does not hold true with all cases of RA (but may be related to disease severity) and studies of T cell receptor (TCR) beta chain usage fail to show consistent oligoclonality of infiltrating T cells in the synovial compartment. Etiologies based on triggering by bacteria are also considered: homologies between the 'shared epitope' sequences of HLA-DR1 and DR4 beta chains, Escherichia coli dnaJ and Proteus haemolysin do not indicate any feasible mechanisms for the development of RA, and cannot explain the many cases in which such DR sequences do not occur, though new data from man and animals enhance interest in the role of bowel flora. Finally, the striking parallels between slow bacterial infections and RA, in terms of immunogenetics, pathology, IgG glycosylation abnormalities and autoimmune manifestations, are put forward as circumstantial evidence that such bacterial infections may underly, or trigger, this serious disease.
Full text
PDF





Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Albani S., Tuckwell J. E., Esparza L., Carson D. A., Roudier J. The susceptibility sequence to rheumatoid arthritis is a cross-reactive B cell epitope shared by the Escherichia coli heat shock protein dnaJ and the histocompatibility leukocyte antigen DRB10401 molecule. J Clin Invest. 1992 Jan;89(1):327–331. doi: 10.1172/JCI115580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bahr G. M., Sattar M. A., Stanford J. L., Shaaban M. A., Al Shimali B., Siddiqui Z., Gabriel M., Al Saffar M., Shahin A., Chugh T. D. HLA-DR and tuberculin tests in rheumatoid arthritis and tuberculosis. Ann Rheum Dis. 1989 Jan;48(1):63–68. doi: 10.1136/ard.48.1.63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barnes D. J., Naraqi S., Temu P., Turtle J. R. Adrenal function in patients with active tuberculosis. Thorax. 1989 May;44(5):422–424. doi: 10.1136/thx.44.5.422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blauer K. L., Poth M., Rogers W. M., Bernton E. W. Dehydroepiandrosterone antagonizes the suppressive effects of dexamethasone on lymphocyte proliferation. Endocrinology. 1991 Dec;129(6):3174–3179. doi: 10.1210/endo-129-6-3174. [DOI] [PubMed] [Google Scholar]
- Bocart D., Lecossier D., De Lassence A., Valeyre D., Battesti J. P., Hance A. J. A search for mycobacterial DNA in granulomatous tissues from patients with sarcoidosis using the polymerase chain reaction. Am Rev Respir Dis. 1992 May;145(5):1142–1148. doi: 10.1164/ajrccm/145.5.1142. [DOI] [PubMed] [Google Scholar]
- Calogero A. E., Sternberg E. M., Bagdy G., Smith C., Bernardini R., Aksentijevich S., Wilder R. L., Gold P. W., Chrousos G. P. Neurotransmitter-induced hypothalamic-pituitary-adrenal axis responsiveness is defective in inflammatory disease-susceptible Lewis rats: in vivo and in vitro studies suggesting globally defective hypothalamic secretion of corticotropin-releasing hormone. Neuroendocrinology. 1992 May;55(5):600–608. doi: 10.1159/000126173. [DOI] [PubMed] [Google Scholar]
- Chikanza I. C., Petrou P., Kingsley G., Chrousos G., Panayi G. S. Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum. 1992 Nov;35(11):1281–1288. doi: 10.1002/art.1780351107. [DOI] [PubMed] [Google Scholar]
- Daynes R. A., Araneo B. A., Dowell T. A., Huang K., Dudley D. Regulation of murine lymphokine production in vivo. III. The lymphoid tissue microenvironment exerts regulatory influences over T helper cell function. J Exp Med. 1990 Apr 1;171(4):979–996. doi: 10.1084/jem.171.4.979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- De Graeff-Meeder E. R., van der Zee R., Rijkers G. T., Schuurman H. J., Kuis W., Bijlsma J. W., Zegers B. J., 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. doi: 10.1016/0140-6736(91)93057-g. [DOI] [PubMed] [Google Scholar]
- De Vries R. R. An immunogenetic view of delayed type hypersensitivity. Tubercle. 1991 Sep;72(3):161–167. doi: 10.1016/0041-3879(91)90001-9. [DOI] [PubMed] [Google Scholar]
- Derijk R., Berkenbosch F. The immune-hypothalamo-pituitary-adrenal axis and autoimmunity. Int J Neurosci. 1991 Jul;59(1-3):91–100. doi: 10.3109/00207459108985452. [DOI] [PubMed] [Google Scholar]
- Duby A. D., Sinclair A. K., Osborne-Lawrence S. L., Zeldes W., Kan L., Fox D. A. Clonal heterogeneity of synovial fluid T lymphocytes from patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6206–6210. doi: 10.1073/pnas.86.16.6206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dudani A. K., Gupta R. S. Immunological characterization of a human homolog of the 65-kilodalton mycobacterial antigen. Infect Immun. 1989 Sep;57(9):2786–2793. doi: 10.1128/iai.57.9.2786-2793.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ebringer A., Khalafpour S., Wilson C. Rheumatoid arthritis and Proteus: a possible aetiological association. Rheumatol Int. 1989;9(3-5):223–228. doi: 10.1007/BF00271885. [DOI] [PubMed] [Google Scholar]
- Elkayam O., Zinger H., Zisman E., Segal R., Yaron M., Brautbar C., Mozes E. Regulatory T cell activity specific to human type II and III collagens in rheumatoid arthritis. J Rheumatol. 1991 Apr;18(4):516–521. [PubMed] [Google Scholar]
- Ellis M. E., Tayoub F. Adrenal function in tuberculosis. Br J Dis Chest. 1986 Jan;80(1):7–12. doi: 10.1016/0007-0971(86)90003-3. [DOI] [PubMed] [Google Scholar]
- Goulding N. J., Guyre P. M. Regulation of inflammation by lipocortin 1. Immunol Today. 1992 Aug;13(8):295–297. doi: 10.1016/0167-5699(92)90040-E. [DOI] [PubMed] [Google Scholar]
- Gregersen P. K., Silver J., Winchester R. J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987 Nov;30(11):1205–1213. doi: 10.1002/art.1780301102. [DOI] [PubMed] [Google Scholar]
- Gudmundsson S., Rönnelid J., Karlsson-Parra A., Lysholm J., Gudbjörnsson B., Widenfalk B., Janson C. H., Klareskog L. T-cell receptor V-gene usage in synovial fluid and synovial tissue from RA patients. Scand J Immunol. 1992 Nov;36(5):681–688. doi: 10.1111/j.1365-3083.1992.tb03128.x. [DOI] [PubMed] [Google Scholar]
- Hazenberg M. P., Klasen I. S., Kool J., Ruseler-van Embden J. G., Severijnen A. J. Are intestinal bacteria involved in the etiology of rheumatoid arthritis? Review article. APMIS. 1992 Jan;100(1):1–9. doi: 10.1111/j.1699-0463.1992.tb00833.x. [DOI] [PubMed] [Google Scholar]
- Hermann E., Lohse A. W., Van der Zee R., Van Eden W., Mayet W. J., Probst P., Poralla T., Meyer zum Büschenfelde K. H., Fleischer B. Synovial fluid-derived Yersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells. Eur J Immunol. 1991 Sep;21(9):2139–2143. doi: 10.1002/eji.1830210923. [DOI] [PubMed] [Google Scholar]
- Jindal S., Dudani A. K., Singh B., Harley C. B., Gupta R. S. 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. doi: 10.1128/mcb.9.5.2279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koga T., Wand-Württenberger A., DeBruyn J., Munk M. E., Schoel B., Kaufmann S. H. T cells against a bacterial heat shock protein recognize stressed macrophages. Science. 1989 Sep 8;245(4922):1112–1115. doi: 10.1126/science.2788923. [DOI] [PubMed] [Google Scholar]
- Kohashi O., Kohashi Y., Takahashi T., Ozawa A., Shigematsu N. Reverse effect of gram-positive bacteria vs. gram-negative bacteria on adjuvant-induced arthritis in germfree rats. Microbiol Immunol. 1985;29(6):487–497. doi: 10.1111/j.1348-0421.1985.tb00851.x. [DOI] [PubMed] [Google Scholar]
- Lacour M., Rudolphi U., Schlesier M., Peter H. H. Type II collagen-specific T cells in healthy donors. Eur J Immunol. 1991 Apr;21(4):1092–1092. doi: 10.1002/eji.1830210409. [DOI] [PubMed] [Google Scholar]
- Lehmann P. V., Forsthuber T., Miller A., Sercarz E. E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992 Jul 9;358(6382):155–157. doi: 10.1038/358155a0. [DOI] [PubMed] [Google Scholar]
- Li S. G., Quayle A. J., Shen Y., Kjeldsen-Kragh J., Oftung F., Gupta R. S., Natvig J. B., Førre O. T. Mycobacteria and human heat shock protein-specific cytotoxic T lymphocytes in rheumatoid synovial inflammation. Arthritis Rheum. 1992 Mar;35(3):270–281. doi: 10.1002/art.1780350305. [DOI] [PubMed] [Google Scholar]
- Life P. F., Viner N. J., Bacon P. A., Gaston J. S. Synovial fluid antigen-presenting cells unmask peripheral blood T cell responses to bacterial antigens in inflammatory arthritis. Clin Exp Immunol. 1990 Feb;79(2):189–194. doi: 10.1111/j.1365-2249.1990.tb05177.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Londei M., Savill C. M., Verhoef A., Brennan F., Leech Z. A., Duance V., Maini R. N., 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. doi: 10.1073/pnas.86.2.636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lydyard P. M., Tsoulfa G., Sharif M., Bröker B., Smith M., Rook G. A. Immunity to heat shock proteins in rheumatoid arthritis. Clin Exp Rheumatol. 1990 Jul-Aug;8 (Suppl 5):69–74. [PubMed] [Google Scholar]
- Moreland L. W., Koopman W. J. Infection as a cause of arthritis. Curr Opin Rheumatol. 1991 Aug;3(4):639–649. doi: 10.1097/00002281-199108000-00015. [DOI] [PubMed] [Google Scholar]
- Ottenhoff T. H., Torres P., de las Aguas J. T., Fernandez R., van Eden W., de Vries R. R., Stanford J. L. Evidence for an HLA-DR4-associated immune-response gene for Mycobacterium tuberculosis. A clue to the pathogenesis of rheumatoid arthritis? Lancet. 1986 Aug 9;2(8502):310–313. doi: 10.1016/s0140-6736(86)90004-8. [DOI] [PubMed] [Google Scholar]
- Paliard X., West S. G., Lafferty J. A., Clements J. R., Kappler J. W., Marrack P., Kotzin B. L. Evidence for the effects of a superantigen in rheumatoid arthritis. Science. 1991 Jul 19;253(5017):325–329. doi: 10.1126/science.1857971. [DOI] [PubMed] [Google Scholar]
- Panayi G. S., Lanchbury J. S., Kingsley G. H. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum. 1992 Jul;35(7):729–735. doi: 10.1002/art.1780350702. [DOI] [PubMed] [Google Scholar]
- Pelton B. K., Harvey A. R., Denman A. M. The rheumatoid synovial membrane participates in systemic anti-viral immune responses. Clin Exp Immunol. 1985 Dec;62(3):657–661. [PMC free article] [PubMed] [Google Scholar]
- Poussier P., Edouard P., Lee C., Binnie M., Julius M. Thymus-independent development and negative selection of T cells expressing T cell receptor alpha/beta in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes. J Exp Med. 1992 Jul 1;176(1):187–199. doi: 10.1084/jem.176.1.187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Quayle A. J., Wilson K. B., Li S. G., Kjeldsen-Kragh J., Oftung F., Shinnick T., Sioud M., Førre O., Capra J. D., Natvig J. B. 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. doi: 10.1002/eji.1830220529. [DOI] [PubMed] [Google Scholar]
- Rademacher T. W., Parekh R. B., Dwek R. A., Isenberg D., Rook G., Axford J. S., Roitt I. The role of IgG glycoforms in the pathogenesis of rheumatoid arthritis. Springer Semin Immunopathol. 1988;10(2-3):231–249. doi: 10.1007/BF01857227. [DOI] [PubMed] [Google Scholar]
- Richardson B. C. T cell receptor usage in rheumatic disease. Clin Exp Rheumatol. 1992 May-Jun;10(3):271–283. [PubMed] [Google Scholar]
- Rook G. A., Stanford J. L. Slow bacterial infections or autoimmunity? Immunol Today. 1992 May;13(5):160–164. doi: 10.1016/0167-5699(92)90119-R. [DOI] [PubMed] [Google Scholar]
- Rook G., Thompson S., Buckley M., Elson C., Brealey R., Lambert C., White T., Rademacher T. The role of oil and agalactosyl IgG in the induction of arthritis in rodent models. Eur J Immunol. 1991 Apr;21(4):1027–1032. doi: 10.1002/eji.1830210425. [DOI] [PubMed] [Google Scholar]
- Rudensky AYu, Preston-Hurlburt P., Hong S. C., Barlow A., Janeway C. A., Jr Sequence analysis of peptides bound to MHC class II molecules. Nature. 1991 Oct 17;353(6345):622–627. doi: 10.1038/353622a0. [DOI] [PubMed] [Google Scholar]
- Sarma G. R., Immanuel C., Ramachandran G., Krishnamurthy P. V., Kumaraswami V., Prabhakar R. Adrenocortical function in patients with pulmonary tuberculosis. Tubercle. 1990 Dec;71(4):277–282. doi: 10.1016/0041-3879(90)90041-6. [DOI] [PubMed] [Google Scholar]
- Shoenfeld Y., Isenberg D. A. Mycobacteria and autoimmunity. Immunol Today. 1988 Jun;9(6):178–182. doi: 10.1016/0167-5699(88)91294-7. [DOI] [PubMed] [Google Scholar]
- Siegele D. A., Kolter R. Life after log. J Bacteriol. 1992 Jan;174(2):345–348. doi: 10.1128/jb.174.2.345-348.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Silman A. J. Is rheumatoid arthritis an infectious disease? BMJ. 1991 Jul 27;303(6796):200–201. doi: 10.1136/bmj.303.6796.200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Silman A. J. The genetic epidemiology of rheumatoid arthritis. Clin Exp Rheumatol. 1992 May-Jun;10(3):309–312. [PubMed] [Google Scholar]
- Smilek D. E., Wraith D. C., Hodgkinson S., Dwivedy S., Steinman L., McDevitt H. O. A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9633–9637. doi: 10.1073/pnas.88.21.9633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sottini A., Imberti L., Gorla R., Cattaneo R., Primi D. Restricted expression of T cell receptor V beta but not V alpha genes in rheumatoid arthritis. Eur J Immunol. 1991 Feb;21(2):461–466. doi: 10.1002/eji.1830210231. [DOI] [PubMed] [Google Scholar]
- Stanford J. L. Much's granules revisited. Tubercle. 1987 Dec;68(4):241–242. doi: 10.1016/0041-3879(87)90063-8. [DOI] [PubMed] [Google Scholar]
- Steinhoff U., Schoel B., Kaufmann S. H. Lysis of interferon-gamma activated Schwann cell by cross-reactive CD8+ alpha/beta T cells with specificity for the mycobacterial 65 kd heat shock protein. Int Immunol. 1990;2(3):279–284. doi: 10.1093/intimm/2.3.279. [DOI] [PubMed] [Google Scholar]
- Sumar N., Colaço C. B., Bodman K. B., Parekh R., Williams P., Dwek R., Rademacher T., Isenberg D. A., Soltys A., Hay F. C. Abnormalities in the glycosylation of IgG in spouses of patients with rheumatoid arthritis. A family study. J Autoimmun. 1991 Dec;4(6):907–914. doi: 10.1016/0896-8411(91)90053-f. [DOI] [PubMed] [Google Scholar]
- Suzuki T., Suzuki N., Daynes R. A., Engleman E. G. Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells. Clin Immunol Immunopathol. 1991 Nov;61(2 Pt 1):202–211. doi: 10.1016/s0090-1229(05)80024-8. [DOI] [PubMed] [Google Scholar]
- Thompson S. J., Rook G. A., Brealey R. J., Van der Zee R., Elson C. J. Autoimmune reactions to heat-shock proteins in pristane-induced arthritis. Eur J Immunol. 1990 Nov;20(11):2479–2484. doi: 10.1002/eji.1830201118. [DOI] [PubMed] [Google Scholar]
- Uematsu Y., Wege H., Straus A., Ott M., Bannwarth W., Lanchbury J., Panayi G., Steinmetz M. The T-cell-receptor repertoire in the synovial fluid of a patient with rheumatoid arthritis is polyclonal. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8534–8538. doi: 10.1073/pnas.88.19.8534. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van den Broek M. F., van Bruggen M. C., Koopman J. P., Hazenberg M. P., van den Berg W. B. Gut flora induces and maintains resistance against streptococcal cell wall-induced arthritis in F344 rats. Clin Exp Immunol. 1992 May;88(2):313–317. doi: 10.1111/j.1365-2249.1992.tb03079.x. [DOI] [PMC free article] [PubMed] [Google Scholar]