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Proc Natl Acad Sci U S A. Jan 9, 1996; 93(1): 221–225.
PMCID: PMC40210

Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis.

Abstract

In patients with rheumatoid arthritis the synovial membrane of the affected joint is infiltrated with lymphoid cells which may be arranged in structures resembling germinal centers. We have directly isolated such infiltrates to determine whether B-cell clones within them are selected and expanded in a process analogous to that which normally takes place in the germinal centers in secondary lymphoid organs. The data suggest that an antigen-driven process leads to the accumulation of B cells in the synovial membrane. The finding of identical sequences in consecutive sections suggests that under conditions of chronic stimulation, memory B cells may enter a stage of differentiation in which they proliferate without further accumulation of somatic mutations. Further we see intraclonal diversity which underlines the germinal center-like character of these infiltrates and demonstrates that a microenvironment is built up in this nonlymphoid tissue which supports antigen-dependent differentiation of B cells. This is the first demonstration, to our knowledge, of a germinal center-like reaction outside lymphoid tissue.

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Selected References

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  • Berek C, Berger A, Apel M. Maturation of the immune response in germinal centers. Cell. 1991 Dec 20;67(6):1121–1129. [PubMed]
  • Jacob J, Kelsoe G, Rajewsky K, Weiss U. Intraclonal generation of antibody mutants in germinal centres. Nature. 1991 Dec 5;354(6352):389–392. [PubMed]
  • Liu YJ, Johnson GD, Gordon J, MacLennan IC. Germinal centres in T-cell-dependent antibody responses. Immunol Today. 1992 Jan;13(1):17–21. [PubMed]
  • Berek C, Ziegner M. The maturation of the immune response. Immunol Today. 1993 Aug;14(8):400–404. [PubMed]
  • Shlomchik MJ, Marshak-Rothstein A, Wolfowicz CB, Rothstein TL, Weigert MG. The role of clonal selection and somatic mutation in autoimmunity. Nature. 328(6133):805–811. [PubMed]
  • van Es JH, Gmelig Meyling FH, van de Akker WR, Aanstoot H, Derksen RH, Logtenberg T. Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus. J Exp Med. 1991 Feb 1;173(2):461–470. [PMC free article] [PubMed]
  • Randen I, Brown D, Thompson KM, Hughes-Jones N, Pascual V, Victor K, Capra JD, Førre O, Natvig JB. Clonally related IgM rheumatoid factors undergo affinity maturation in the rheumatoid synovial tissue. J Immunol. 1992 May 15;148(10):3296–3301. [PubMed]
  • Mariette X, Brouet JC, Danon F, Tsapis A, Lassoued K. Nucleotide sequence analysis of the VL and VH domains of five human IgM directed to lamin B. Evidence for an antigen-driven process in the generation of human autoantibodies to lamin B. Arthritis Rheum. 1993 Sep;36(9):1315–1324. [PubMed]
  • Young CL, Adamson TC, 3rd, Vaughan JH, Fox RI. Immunohistologic characterization of synovial membrane lymphocytes in rheumatoid arthritis. Arthritis Rheum. 1984 Jan;27(1):32–39. [PubMed]
  • Randen I, Mellbye OJ, Førre O, Natvig JB. The identification of germinal centres and follicular dendritic cell networks in rheumatoid synovial tissue. Scand J Immunol. 1995 May;41(5):481–486. [PubMed]
  • Guigou V, Emilie D, Berrih-Aknin S, Fumoux F, Fougereau M, Schiff C. Individual germinal centres of myasthenia gravis human thymuses contain polyclonal activated B cells that express all the Vh and Vk families. Clin Exp Immunol. 1991 Feb;83(2):262–266. [PMC free article] [PubMed]
  • Zvaifler NJ. The immunopathology of joint inflammation in rheumatoid arthritis. Adv Immunol. 1973;16(0):265–336. [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]
  • Ziegner M, Steinhauser G, Berek C. Development of antibody diversity in single germinal centers: selective expansion of high-affinity variants. Eur J Immunol. 1994 Oct;24(10):2393–2400. [PubMed]
  • Marks JD, Hoogenboom HR, Bonnert TP, McCafferty J, Griffiths AD, Winter G. By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J Mol Biol. 1991 Dec 5;222(3):581–597. [PubMed]
  • Matsuda F, Shin EK, Nagaoka H, Matsumura R, Haino M, Fukita Y, Taka-ishi S, Imai T, Riley JH, Anand R, et al. Structure and physical map of 64 variable segments in the 3'0.8-megabase region of the human immunoglobulin heavy-chain locus. Nat Genet. 1993 Jan;3(1):88–94. [PubMed]
  • Klein U, Küppers R, Rajewsky K. Variable region gene analysis of B cell subsets derived from a 4-year-old child: somatically mutated memory B cells accumulate in the peripheral blood already at young age. J Exp Med. 1994 Oct 1;180(4):1383–1393. [PMC free article] [PubMed]
  • McKean D, Huppi K, Bell M, Staudt L, Gerhard W, Weigert M. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc Natl Acad Sci U S A. 1984 May;81(10):3180–3184. [PMC free article] [PubMed]
  • Berek C, Milstein C. Mutation drift and repertoire shift in the maturation of the immune response. Immunol Rev. 1987 Apr;96:23–41. [PubMed]
  • Reynaud CA, Garcia C, Hein WR, Weill JC. Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process. Cell. 1995 Jan 13;80(1):115–125. [PubMed]
  • Chang B, Casali P. The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement. Immunol Today. 1994 Aug;15(8):367–373. [PubMed]
  • Betz AG, Neuberger MS, Milstein C. Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol Today. 1993 Aug;14(8):405–411. [PubMed]

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