Abstract
Background
Reactive arthritis (ReA) can develop as a consequence of a bacterial infection with organisms such as Chlamydia trachomata, Shigella flexneri, or Yersinia enterocolitica. Although the mechanism underlying the induction of a chronic synovitis is unknown, the expression of HLA-B27 seems to play a crucial role in the etiology of the disease. Bacterial antigens induce a humoral immune response, but little is known about the impact of B cells on the inflammatory processes developing in the synovial membrane.
Materials and Methods
Cryostat sections were prepared from the synovial tissue (ST) of patients with ReA and stained with antibodies specific for T, B, and follicular dendritic cells. Lymphoid infiltrates were directly isolated by microdisection and DNA was prepared from them. The rearranged V genes were amplified by polymerase chain reaction (PCR), cloned, and sequenced.
Results
Histological staining showed that germinal, center-like structures develop in the ST of patients with ReA. B cells with a heterogenous repertoire were isolated from these lymphoid infiltrates. The majority of V regions carried somatic mutations indicating that sequences are derived from memory B cells. Genealogical trees demonstrate clonal expansion and diversification of the B cell repertoire in the ST.
Conclusions
The finding of local V-region diversification suggests that in the ST of patients with ReA, an antigen-driven, T cell-dependent differentiation of B cells occurs. This local B cell response may contribute to the progress of the disease. Whether B cells are specific for the bacteria inducing the synovitis or for self-determinants present in the ST remains to be determined.
Similar content being viewed by others
References
Sieper J, Kingsley G. (1996) Recent advances in the pathogenesis of reactive arthritis. Immunol. Today 17: 160–163.
Siskind GW, Benacerraf B. (1969) Cell selection by antigen in the immune response. Adv. Immunol. 10: 1–50.
Berek C, Berger A, Apel M. (1991) Maturation of the immune response in germinal centers. Cell 67: 1121–1129.
Jacob J, Kelsoe G, Rajewsky K, Weiss U. (1991) Intraclonal generation of antibody mutants in germinal centres. Nature 354: 389–392.
Liu YJ, Johnson GD, Gordon J, MacLennan IC. (1992) Germinal centres in T-cell-dependent antibody responses. Immunol. Today 13: 17–21.
Weigert M. (1994) The influence of somatic mutation on the immune response. Prog. Immunol. 6: 138–142.
Shokat KM, Goodnow CC. (1995) Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 375: 334–338.
Pulendran B, Kannourakis G, Nouri S, Smith KGC, Nossal GJV. (1995) Soluble antigen can cause enhanced apoptosis of germinal-centre B cells. Nature 375: 331–334.
Ray SK, Putterman C, Diamond B. (1996) Pathogenic autoantibodies are routinely 271 generated during the response to foreign antigen: A paradigm for autoimmune disease. Proc. Natl. Acad. Sci. U.S.A. 93: 2019–2024.
Avrameas S. (1991) Natural autoantibodies: From “horror autotoxicus” to “gnothi seauton.” Immunol. Today 12: 154–159.
Welch MJ, Fong S, Vaughan J, Carson D. (1983) Increased frequency of rheumatic factor precursor B lymphocytes after immunization of normal adults with tetanus toxoid. Cin. Exp. Immunol. 51: 299–304.
Børretzen M, Randen I, Zdarsky E, Førre Ø, Natvig JB. (1994) Control of autoantibody affinity by selection against amino acid replacements in the complementary-determining regions. Proc. Natl. Acad. Sci. U.S.A. 91: 12917–12921.
Radic MZ, Weigert M. (1994) Genetic and structural evidence for antigen selection of anti-DNA antibodies. Annu. Rev. Immunol. 12: 487–520.
Randen I, Brown D, Thompson KM, Hughes-Jones N, Psacual V, Victor K, Capra JD, Førre Ø, Natvig J. (1992) Clonally related IgM rheumatoid factors undergo affinity maturation in rheumatoid synovial tissue. J. Immunol. 148: 3296–3301.
Portolano S, McLachlan SM, Rapoport B. (1993) High affinity, thyroid specific human autoantibodies displayed on the surface of filamentous phage use V genes similiar to other autoantibodies. J. Immunol. 151: 2839–2851.
Richter W, Jury KM, Loeffler D, Manfras BJ, Eiermann TH, Boehm BO. (1995) Immunoglobulin variable gene analysis of human autoantibodies reveals antigen-driven immune response to glutamate decarboxylase in type 1 diabetes mellitus. Eur. J. Immunol. 25: 1703–1712.
Cardona A, Pritsch O, Dumas G, Bach J-F, Dighiero G. (1995) Evidence for an antigen-driven selection process in human autoantibodies against acetylcholine receptor. Mol. Immunol. 32: 1215–1223.
Young CL, Adamson TC, Vaughan JH, Fox RI. (1984) Immunohistologic characterisation of synovial membrane lymphocytes in rheumatoid arthritis. Arthritis Rheum. 27: 32–39.
Bigazzi PE. (1993) Hashimoto’s disease. In: Bona C, Siminovitch KA, Zanetti M, Theophilopoulos AN (eds). The Molecular Pathology of Autoimmune Diseases. Harwood Academic Publishers, Chur, Switzerland, pp. 493–510.
Randen I, Mellbye J, Førre Ø, Natvig JB. (1995) The identification of germinal centres and follicular dendritic cell networks in rheumatoid synovial tissue. Scand. J. Immunol. 41: 481–486.
Guigou V, Emilie D, Berrih-Aknin S, Fumoux F, Fougerau M, Schiff C. (1991) Individual germinal centres of myasthenia gravis human thymuses contain polyclonal activated B cells that express all the VH and Vκ families. Clin. Exp. Immunol. 83: 262–266.
Gause A, Gundlach K, Zdichavsky M, Jacobs G, Koch B, Hopf T, Pfreundschuh M. (1995) The B lymphocyte in rheumatoid arthritis: Analysis of rearranged Vκ genes from B cells infiltrating the synovial membrane. Eur. J. Immunol. 25: 2775–2782.
Schröder AE, Greiner A, Seyfert C, Berek C. (1996) Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc. Natl. Acad. Sci. U.S.A. 93: 221–225.
Nanagara R, Li F, Beutler A, Hudson A, Schumacher HR. (1995) Alteration of Chlamydia tracjomatis biologic behavior in synovial membranes. Arthritis Rheum. 38: 1410–1417.
Taylor-Robinson D, Gilroy CB, Thomas BJ, Keat AC. (1992) Detection of Chlamydia trachomatis DNA in joints of reactive arthritis patients by polymerase chain reaction. Lancet 340: 81–82.
Rahman MU, Cheema MA, Schumacher HR, Hudson AP. (1992) Molecular evidence for the presence of Chlamydia in the synovium of patients with Reiterts syndrome. Arthritis Rheum. 35: 521–529.
Hammer M, Nettlnbreker E, Hopf S, Schmitz E, Pörschke K, Zeidler H. (1992) Chlamydial rRNA in the joints of patients with Chlamydia-induced arthritis and undifferentiated arthritis. Clin. Exp. Rheumatol. 10: 63–66.
Klein U, Küppers R, Rajewsky K. (1993) Human IgM + IgD + B cells, the major B cell subset in the peripheral blood, express Vκ genes with little or no somatic mutation throughout life. Eur. J. Immunol. 23: 3272–3277.
Bas S, Giffais R, Kvien TK, Glennås A, Melby K, Vischer TL. (1995) Amplification of plasmid and chromosome Chlamydia DNA in the synovial fluid of patients with reactive 272 arthritis and undifferentiated seronegative oligoarthrities. Arthritis Rheum. 38: 1005–1013.
Nossal GJV, Abbot A, Mitchell J, Lummus Z. (1968) Antigens in immunity XV. Ultra-structural features of antigen capture in primary and secondary lymphoid follicles. J. Exp. Med. 127: 277–290.
Kasaian MT, Ikematsu H, Balow JE, Casali P. (1994) Structure of VH and VL segments of monoreactive and polyreactive IgA autoantibodies to DNA in patients with systemic lupus erythematosus. J. Immunol. 152: 3137–3151.
Berinstein N, Levy S, Levy R. (1988) Activation of an excluded immunoglobulin allele in a human B lymphoma cell line. Science 244: 337–339.
Tsunetsugu-Yokota Y, Minekawa T, Shigemoto K, Shirasawa T, Takemori T. (1992) Characterisation of a new subgroup of human Ig V-lambda cDNA clone and its expression. Mol. Immunol. 29: 723–728.
Kabat EA, Wu TT, Perry HM, Gottesman KS, Foeller C (ed). (1991) Sequences of Proteins of Immunological Interest. Bethesda, MD, NIH, U.S. Department of Health and Human Services.
Acknowledgements
We thank R.S. Jack, B. Müller, and S.A. Camacho for critical reading of the manuscript and helpful discussion, and L. Neure for technical assistance. This work was supported by the Senate for Research and Education of the City of Berlin.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by A.N. Mitchison.
Rights and permissions
About this article
Cite this article
Schröder, A.E., Sieper, J. & Berek, C. Antigen-Dependent B Cell Differentiation in the Synovial Tissue of a Patient with Reactive Arthritis. Mol Med 3, 260–272 (1997). https://doi.org/10.1007/BF03401679
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03401679