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Ann Rheum Dis. 1996 June; 55(6): 363–369.
PMCID: PMC1010187

Role of enteric bacteria in the pathogenesis of rheumatoid arthritis: evidence for antibodies to enterobacterial common antigens in rheumatoid sera and synovial fluids.


OBJECTIVE: To study antibodies to Escherichia coli O:14, which expresses large amounts of enterobacterial common antigen (ECA), and their corresponding antigen molecules in serum and synovial fluid samples from patients with rheumatoid arthritis (RA). METHODS: Enzyme linked immunosorbent assay (ELISA) was used to measure antibodies to heat killed E coli O:14 in serum and synovial fluid samples from patients with RA and control subjects including healthy donors and patients with osteoarthritis. ELISA was also used to perform absorption analyses of antibodies to E coli O:14 with several enteric bacteria and their lipopolysaccharide (LPS). In addition, antigenic molecules reacting with E coli O:14 antibodies from patients with RA were examined using immunoblot analysis and N-terminal amino acid analysis. RESULTS: Compared with control subjects, patients with RA showed significantly increased titres of antibodies against heat killed E coli O:14 in 33 of 83 serum samples (39.8%) and 38 of 58 joint fluid samples (65.5%). Absorption analyses with enteric bacteria and their LPS resulted in the reduction of antibody titres to heat killed E coli O:14 in serum and synovial fluid samples from the RA patients. In addition, immunoblot analysis of the samples from RA patients revealed not only a ladder-like banding pattern equivalent to ECA associated with LPS, but also two clear bands of bacterial outer membrane proteins of 35 kDa (Omp A) and 38 kDa (Omp C), having amino acid sequence homology with those of other Enterobacteriaceae. CONCLUSION: These results suggest that some patients with RA are sensitised to antigens common to Enterobacteriaceae, and this may prove relevant to the future development of immunotherapy for RA. Furthermore, this sensitisation to antigens found commonly in Enterobacteriaceae may have a key role in the pathogenesis of human RA similar to that described previously in our animal model.

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  • Harris ED., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. [PubMed]
  • Firestein GS. Mechanisms of tissue destruction and cellular activation in rheumatoid arthritis. Curr Opin Rheumatol. 1992 Jun;4(3):348–354. [PubMed]
  • Gregersen PK. T-cell receptor-major histocompatibility complex genetic interactions in rheumatoid arthritis. Rheum Dis Clin North Am. 1992 Nov;18(4):793–807. [PubMed]
  • Sewell KL, Trentham DE. Pathogenesis of rheumatoid arthritis. Lancet. 1993 Jan 30;341(8840):283–286. [PubMed]
  • Tarkowski A, Klareskog L, Carlsten H, Herberts P, Koopman WJ. Secretion of antibodies to types I and II collagen by synovial tissue cells in patients with rheumatoid arthritis. Arthritis Rheum. 1989 Sep;32(9):1087–1092. [PubMed]
  • Wordsworth P. Rheumatoid arthritis. Curr Opin Immunol. 1992 Dec;4(6):766–769. [PubMed]
  • Aoki S, Ikuta K, Aoyama G. Induction of chronic polyarthritis in rabbits. Nature. 1972 May 19;237(5351):168–169. [PubMed]
  • Aoki S, Ikuta K, Nonogaki T, Ito Y. Induction of chronic polyarthritis in rabbits by hyperimmunization with Escherichia coli. I. Pathologic and serologic features in two breeds of rabbits. Arthritis Rheum. 1985 May;28(5):522–528. [PubMed]
  • Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. [PubMed]
  • Beck E, Bremer E. Nucleotide sequence of the gene ompA coding the outer membrane protein II of Escherichia coli K-12. Nucleic Acids Res. 1980 Jul 11;8(13):3011–3027. [PMC free article] [PubMed]
  • Braun G, Cole ST. The nucleotide sequence coding for major outer membrane protein OmpA of Shigella dysenteriae. Nucleic Acids Res. 1982 Apr 10;10(7):2367–2378. [PMC free article] [PubMed]
  • Freudl R, Cole ST. Cloning and molecular characterization of the ompA gene from Salmonella typhimurium. Eur J Biochem. 1983 Aug 15;134(3):497–502. [PubMed]
  • Braun G, Cole ST. Molecular characterization of the gene coding for major outer membrane protein OmpA from Enterobacter aerogenes. Eur J Biochem. 1983 Dec 15;137(3):495–500. [PubMed]
  • Mizuno T, Chou MY, Inouye M. A comparative study on the genes for three porins of the Escherichia coli outer membrane. DNA sequence of the osmoregulated ompC gene. J Biol Chem. 1983 Jun 10;258(11):6932–6940. [PubMed]
  • Venegas A, Gómez I, Zaror I, Yudelevich A. The nucleotide sequence of the Salmonella typhi ompC porin gene. Nucleic Acids Res. 1988 Aug 11;16(15):7721–7721. [PMC free article] [PubMed]
  • Aoki S, Merkel M, McCabe WR. Immunofluorescent demonstration of the common enterobacterial antigen. Proc Soc Exp Biol Med. 1966 Jan;121(1):230–234. [PubMed]
  • Hammarström S, Carlsson HE, Perlmann P, Svensson S. Immunochemistry of the common antigen of Enterobacteriaceae (Kunin). Relation to lipopolysaccharide core structure. J Exp Med. 1971 Sep 1;134(3 Pt 1):565–576. [PMC free article] [PubMed]
  • Kuhn HM, Basu S, Mayer H. Comparison of enterobacterial common antigen from different species by serological techniques. Eur J Biochem. 1987 Jan 2;162(1):69–74. [PubMed]
  • Palva ET, Mäkelä PH. Lipopolysaccharide heterogeneity in Salmonella typhimurium analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Eur J Biochem. 1980;107(1):137–143. [PubMed]
  • Chen R, Schmidmayr W, Krämer C, Chen-Schmeisser U, Henning U. Primary structure of major outer membrane protein II (ompA protein) of Escherichia coli K-12. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4592–4596. [PubMed]
  • Albani S, Tuckwell JE, Esparza L, Carson DA, 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. [PMC free article] [PubMed]
  • Neidhardt FC, VanBogelen RA, Vaughn V. The genetics and regulation of heat-shock proteins. Annu Rev Genet. 1984;18:295–329. [PubMed]
  • Tsoulfa G, Rook GA, Van-Embden JD, Young DB, Mehlert A, Isenberg DA, Hay FC, Lydyard PM. Raised serum IgG and IgA antibodies to mycobacterial antigens in rheumatoid arthritis. Ann Rheum Dis. 1989 Feb;48(2):118–123. [PMC free article] [PubMed]
  • Lai NS, Lan JL, Yu CL, Lin RH. Antibody to Mycobacterium tuberculosis 65 kDa heat shock protein in patients with rheumatoid arthritis--a survey of antigen-specific antibody isotypes and subclasses in an endemic area of previous tuberculosis infection. Ann Rheum Dis. 1995 Mar;54(3):225–228. [PMC free article] [PubMed]
  • Evans DJ, Norton P, Ivanyi J. Distribution in tissue sections of the human groEL stress-protein homologue. APMIS. 1990 May;98(5):437–441. [PubMed]
  • Bennett JC. The infectious etiology of rheumatoid arthritis. New considerations. Arthritis Rheum. 1978 Jun;21(5):531–538. [PubMed]
  • Midtvedt T. Intestinal bacteria and rheumatic disease. Scand J Rheumatol Suppl. 1987;64:49–54. [PubMed]
  • Hazenberg MP, Klasen IS, Kool J, Ruseler-van Embden JG, Severijnen AJ. Are intestinal bacteria involved in the etiology of rheumatoid arthritis? Review article. APMIS. 1992 Jan;100(1):1–9. [PubMed]
  • Olhagen B, Månsson I. Intestinal Clostridium perfringens in rheumatoid arthritis and other collagen diseases. Acta Med Scand. 1968 Nov;184(5):395–402. [PubMed]
  • Gripenberg M. Common serological features in rheumatoid arthritis and yersinia arthritis. Demonstration of rheumatoid factors and antibodies against ssDNA and Yersinia enterocolitica Lipopolysaccharide by ELISA. Scand J Rheumatol. 1981;10(2):85–91. [PubMed]
  • Ebringer A, Ptaszynska T, Corbett M, Wilson C, Macafee Y, Avakian H, Baron P, James DC. Antibodies to proteus in rheumatoid arthritis. Lancet. 1985 Aug 10;2(8450):305–307. [PubMed]
  • Månsson I, Norberg R, Olhagen B, Björklund NE. Arthritis in pigs induced by dietary factors. Microbiologic, clinical and histologic studies. Clin Exp Immunol. 1971 Nov;9(5):677–693. [PubMed]
  • Ebringer A, Cox NL, Abuljadayel I, Ghuloom M, Khalafpour S, Ptaszynska T, Shodjai-Moradi F, Wilson C. Klebsiella antibodies in ankylosing spondylitis and Proteus antibodies in rheumatoid arthritis. Br J Rheumatol. 1988;27 (Suppl 2):72–85. [PubMed]
  • Ebringer A, Cunningham P, Ahmadi K, Wrigglesworth J, Hosseini R, Wilson C. Sequence similarity between HLA-DR1 and DR4 subtypes associated with rheumatoid arthritis and proteus/serratia membrane haemolysins. Ann Rheum Dis. 1992 Nov;51(11):1245–1246. [PMC free article] [PubMed]
  • Wilson C, Ebringer A, Ahmadi K, Wrigglesworth J, Tiwana H, Fielder M, Binder A, Ettelaie C, Cunningham P, Joannou C, et al. Shared amino acid sequences between major histocompatibility complex class II glycoproteins, type XI collagen and Proteus mirabilis in rheumatoid arthritis. Ann Rheum Dis. 1995 Mar;54(3):216–220. [PMC free article] [PubMed]
  • Aoki S, Imamura S, Aoki M, McCabe WR. "Abacterial" and bacterial pyelonephritis. Immunofluorescent localization of bacterial antigen. N Engl J Med. 1969 Dec 18;281(25):1375–1382. [PubMed]
  • Noyori K, Okamoto R, Takagi T, Hyodo A, Suzuki K, Koshino T. Experimental induction of arthritis in rats immunized with Escherichia coli 0:14 lipopolysaccharide. J Rheumatol. 1994 Mar;21(3):484–488. [PubMed]

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