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. 1998 Sep 1;102(5):938–946. doi: 10.1172/JCI3234

Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sjögren's syndrome.

D I Stott 1, F Hiepe 1, M Hummel 1, G Steinhauser 1, C Berek 1
PMCID: PMC508959  PMID: 9727062

Abstract

Structures resembling germinal centers are seen in the salivary glands of patients with Sjögren's syndrome, but it is not known whether the microenvironment of these cell clusters is sufficient for the induction of a germinal center response. Therefore, we cloned and sequenced rearranged Ig V genes expressed by B cells isolated from sections of labial salivary gland biopsies from two Sjögren's syndrome patients. Rearranged V genes from B cells within one cell cluster were polyclonal and most had few somatic mutations. Two adjacent clusters from another patient each contained one dominant B cell clone expressing hypermutated V genes. None of the rearranged V genes was found in both clusters, suggesting that cells are unable to migrate out into the surrounding tissue and seed new clusters. The ratios of replacement to silent mutations in the framework and complementarity determining regions suggest antigen selection of high-affinity mutants. These results show that an antigen-driven, germinal center-type B cell response is taking place within the salivary glands of Sjögren's syndrome patients. In view of the recent demonstration of a germinal center response within the rheumatoid synovial membrane and the existence of similar structures in the target tissues of other autoimmune diseases, we propose that germinal center- type responses can be induced in the nonlymphoid target tissues of a variety of autoimmune diseases.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bahler D. W., Miklos J. A., Swerdlow S. H. Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas. Blood. 1997 May 1;89(9):3335–3344. [PubMed] [Google Scholar]
  2. Børretzen M., Randen I., Zdárský E., Førre O., Natvig J. B., Thompson K. M. Control of autoantibody affinity by selection against amino acid replacements in the complementarity-determining regions. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12917–12921. doi: 10.1073/pnas.91.26.12917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Diamond B., Katz J. B., Paul E., Aranow C., Lustgarten D., Scharff M. D. The role of somatic mutation in the pathogenic anti-DNA response. Annu Rev Immunol. 1992;10:731–757. doi: 10.1146/annurev.iy.10.040192.003503. [DOI] [PubMed] [Google Scholar]
  4. Diss T. C., Peng H., Wotherspoon A. C., Pan L., Speight P. M., Isaacson P. G. Brief report: a single neoplastic clone in sequential biopsy specimens from a patient with primary gastric-mucosa-associated lymphoid-tissue lymphoma and Sjögren's syndrome. N Engl J Med. 1993 Jul 15;329(3):172–175. doi: 10.1056/NEJM199307153290305. [DOI] [PubMed] [Google Scholar]
  5. Dörner T., Brezinschek H. P., Brezinschek R. I., Foster S. J., Domiati-Saad R., Lipsky P. E. Analysis of the frequency and pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes. J Immunol. 1997 Mar 15;158(6):2779–2789. [PubMed] [Google Scholar]
  6. Fishleder A., Tubbs R., Hesse B., Levine H. Uniform detection of immunoglobulin-gene rearrangement in benign lymphoepithelial lesions. N Engl J Med. 1987 Apr 30;316(18):1118–1121. doi: 10.1056/NEJM198704303161803. [DOI] [PubMed] [Google Scholar]
  7. Forrester J. V., Stott D. I., Hercus K. M. Naturally occurring antibodies to bovine and human retinal S antigen: a comparison between uveitis patients and healthy volunteers. Br J Ophthalmol. 1989 Feb;73(2):155–159. doi: 10.1136/bjo.73.2.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Freni M. A., Artuso D., Gerken G., Spanti C., Marafioti T., Alessi N., Spadaro A., Ajello A., Ferraù O. Focal lymphocytic aggregates in chronic hepatitis C: occurrence, immunohistochemical characterization, and relation to markers of autoimmunity. Hepatology. 1995 Aug;22(2):389–394. [PubMed] [Google Scholar]
  9. Friedman D. F., Cho E. A., Goldman J., Carmack C. E., Besa E. C., Hardy R. R., Silberstein L. E. The role of clonal selection in the pathogenesis of an autoreactive human B cell lymphoma. J Exp Med. 1991 Sep 1;174(3):525–537. doi: 10.1084/jem.174.3.525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Griffiths G. M., Berek C., Kaartinen M., Milstein C. Somatic mutation and the maturation of immune response to 2-phenyl oxazolone. Nature. 1984 Nov 15;312(5991):271–275. doi: 10.1038/312271a0. [DOI] [PubMed] [Google Scholar]
  11. Haneji N., Nakamura T., Takio K., Yanagi K., Higashiyama H., Saito I., Noji S., Sugino H., Hayashi Y. Identification of alpha-fodrin as a candidate autoantigen in primary Sjögren's syndrome. Science. 1997 Apr 25;276(5312):604–607. doi: 10.1126/science.276.5312.604. [DOI] [PubMed] [Google Scholar]
  12. Horsfall A. C., Rose L. M., Maini R. N. Autoantibody synthesis in salivary glands of Sjögren's syndrome patients. J Autoimmun. 1989 Aug;2(4):559–568. doi: 10.1016/0896-8411(89)90189-3. [DOI] [PubMed] [Google Scholar]
  13. Horsfall A. C., Venables P. J., Allard S. A., Maini R. N. Co-existent anti-La antibodies and rheumatoid factors bear distinct idiotypic markers. Scand J Rheumatol Suppl. 1988;75:84–88. doi: 10.3109/03009748809096745. [DOI] [PubMed] [Google Scholar]
  14. Horsfall A. C., Venables P. J., Taylor P. V., Maini R. N. Ro and La antigens and maternal anti-La idiotype on the surface of myocardial fibres in congenital heart block. J Autoimmun. 1991 Feb;4(1):165–176. doi: 10.1016/0896-8411(91)90015-5. [DOI] [PubMed] [Google Scholar]
  15. Jacob J., Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J Exp Med. 1992 Sep 1;176(3):679–687. doi: 10.1084/jem.176.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jordan R. C., Speight P. M. Lymphoma in Sjögren's syndrome. From histopathology to molecular pathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Mar;81(3):308–320. doi: 10.1016/s1079-2104(96)80331-3. [DOI] [PubMed] [Google Scholar]
  17. Jordan R., Diss T. C., Lench N. J., Isaacson P. G., Speight P. M. Immunoglobulin gene rearrangements in lymphoplasmacytic infiltrates of labial salivary glands in Sjögren's syndrome. A possible predictor of lymphoma development. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995 Jun;79(6):723–729. doi: 10.1016/s1079-2104(05)80307-5. [DOI] [PubMed] [Google Scholar]
  18. Kaartinen M., Griffiths G. M., Markham A. F., Milstein C. mRNA sequences define an unusually restricted IgG response to 2-phenyloxazolone and its early diversification. 1983 Jul 28-Aug 3Nature. 304(5924):320–324. doi: 10.1038/304320a0. [DOI] [PubMed] [Google Scholar]
  19. Kassan S. S., Thomas T. L., Moutsopoulos H. M., Hoover R., Kimberly R. P., Budman D. R., Costa J., Decker J. L., Chused T. M. Increased risk of lymphoma in sicca syndrome. Ann Intern Med. 1978 Dec;89(6):888–892. doi: 10.7326/0003-4819-89-6-888. [DOI] [PubMed] [Google Scholar]
  20. Kipps T. J., Tomhave E., Chen P. P., Fox R. I. Molecular characterization of a major autoantibody-associated cross-reactive idiotype in Sjogren's syndrome. J Immunol. 1989 Jun 15;142(12):4261–4268. [PubMed] [Google Scholar]
  21. Knecht H., Saremaslani P., Hedinger C. Immunohistological findings in Hashimoto's thyroiditis, focal lymphocytic thyroiditis and thyroiditis de Quervain. Comparative study. Virchows Arch A Pathol Anat Histol. 1981;393(2):215–231. doi: 10.1007/BF00431078. [DOI] [PubMed] [Google Scholar]
  22. Küppers R., Zhao M., Hansmann M. L., Rajewsky K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 1993 Dec 15;12(13):4955–4967. doi: 10.1002/j.1460-2075.1993.tb06189.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Liversidge J., Dick A., Cheng Y. F., Scott G. B., Forrester J. V. Retinal antigen specific lymphocytes, TCR-gamma delta T cells and CD5+ B cells cultured from the vitreous in acute sympathetic ophthalmitis. Autoimmunity. 1993;15(4):257–266. doi: 10.3109/08916939309115747. [DOI] [PubMed] [Google Scholar]
  24. MacLennan I. C. Germinal centers. Annu Rev Immunol. 1994;12:117–139. doi: 10.1146/annurev.iy.12.040194.001001. [DOI] [PubMed] [Google Scholar]
  25. MacSween R. N., Goudie R. B., Anderson J. R., Armstrong E., Murray M. A., Mason D. K., Jasani M. K., Boyle J. A., Buchanan W. W., Williamson J. Occurrence of antibody to salivary duct epithelium in Sjogren's disease, rheumatoid arthritis, and other arthritides. A clinical and laboratory study. Ann Rheum Dis. 1967 Sep;26(5):402–411. doi: 10.1136/ard.26.5.402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Manser T., Wysocki L. J., Margolies M. N., Gefter M. L. Evolution of antibody variable region structure during the immune response. Immunol Rev. 1987 Apr;96:141–162. doi: 10.1111/j.1600-065x.1987.tb00513.x. [DOI] [PubMed] [Google Scholar]
  27. Marks J. D., Tristem M., Karpas A., Winter G. Oligonucleotide primers for polymerase chain reaction amplification of human immunoglobulin variable genes and design of family-specific oligonucleotide probes. Eur J Immunol. 1991 Apr;21(4):985–991. doi: 10.1002/eji.1830210419. [DOI] [PubMed] [Google Scholar]
  28. Mosnier J. F., Degott C., Marcellin P., Hénin D., Erlinger S., Benhamou J. P. The intraportal lymphoid nodule and its environment in chronic active hepatitis C: an immunohistochemical study. Hepatology. 1993 Mar;17(3):366–371. [PubMed] [Google Scholar]
  29. Price E. J., Venables P. J. The etiopathogenesis of Sjögren's syndrome. Semin Arthritis Rheum. 1995 Oct;25(2):117–133. doi: 10.1016/s0049-0172(95)80025-5. [DOI] [PubMed] [Google Scholar]
  30. Randen I., Mellbye O. J., Førre O., Natvig J. B. The identification of germinal centres and follicular dendritic cell networks in rheumatoid synovial tissue. Scand J Immunol. 1995 May;41(5):481–486. doi: 10.1111/j.1365-3083.1995.tb03596.x. [DOI] [PubMed] [Google Scholar]
  31. Reichlin M., Brucato A., Frank M. B., Maddison P. J., McCubbin V. R., Wolfson-Reichlin M., Lee L. A. Concentration of autoantibodies to native 60-kd Ro/SS-A and denatured 52-kd Ro/SS-A in eluates from the heart of a child who died with congenital complete heart block. Arthritis Rheum. 1994 Nov;37(11):1698–1703. doi: 10.1002/art.1780371120. [DOI] [PubMed] [Google Scholar]
  32. Reth M., Hämmerling G. J., Rajewsky K. Analysis of the repertoire of anti-NP antibodies in C57BL/6 mice by cell fusion. I. Characterization of antibody families in the primary and hyperimmune response. Eur J Immunol. 1978 Jun;8(6):393–400. doi: 10.1002/eji.1830080605. [DOI] [PubMed] [Google Scholar]
  33. Schröder A. E., Greiner A., Seyfert C., Berek C. Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):221–225. doi: 10.1073/pnas.93.1.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stott D. I., McLearie J., Neilson L. Analysis of the clonal origins of autoantibodies against thyroglobulin and DNA in autoimmune thyroiditis and systemic lupus erythematosus. Clin Exp Immunol. 1986 Sep;65(3):520–533. [PMC free article] [PubMed] [Google Scholar]
  35. Stott D. I. Spectrotypes of anti-DNA antibodies show that anti-DNA-secreting B-cell clones of SLE patients are restricted in number, stable and long lived. Autoimmunity. 1992;12(4):249–258. doi: 10.3109/08916939209148467. [DOI] [PubMed] [Google Scholar]
  36. Tomlinson I. M., Walter G., Marks J. D., Llewelyn M. B., Winter G. The repertoire of human germline VH sequences reveals about fifty groups of VH segments with different hypervariable loops. J Mol Biol. 1992 Oct 5;227(3):776–798. doi: 10.1016/0022-2836(92)90223-7. [DOI] [PubMed] [Google Scholar]
  37. Wallace W. A., Howie S. E., Krajewski A. S., Lamb D. The immunological architecture of B-lymphocyte aggregates in cryptogenic fibrosing alveolitis. J Pathol. 1996 Mar;178(3):323–329. doi: 10.1002/(SICI)1096-9896(199603)178:3<323::AID-PATH467>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  38. Wysocki L., Manser T., Gefter M. L. Somatic evolution of variable region structures during an immune response. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1847–1851. doi: 10.1073/pnas.83.6.1847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Young C. L., Adamson T. C., 3rd, Vaughan J. H., Fox R. I. Immunohistologic characterization of synovial membrane lymphocytes in rheumatoid arthritis. Arthritis Rheum. 1984 Jan;27(1):32–39. doi: 10.1002/art.1780270106. [DOI] [PubMed] [Google Scholar]
  40. 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. doi: 10.1002/eji.1830241020. [DOI] [PubMed] [Google Scholar]

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