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. 1992 Jan 15;89(2):549–553. doi: 10.1073/pnas.89.2.549

Perforin and granzyme A expression identifying cytolytic lymphocytes in rheumatoid arthritis.

G M Griffiths 1, S Alpert 1, E Lambert 1, J McGuire 1, I L Weissman 1
PMCID: PMC48276  PMID: 1731326

Abstract

Lymphocytes from the synovial fluid of patients with rheumatoid arthritis were examined for the expression of granzyme A and perforin. Previous studies have demonstrated that the expression of these proteins, which are implicated as mediators of cytotoxicity, can be used to identify putative cytolytic lymphocytes in vivo. Twenty-two synovial fluid samples were analyzed by in situ hybridization and immunohistochemistry. In six patients receiving low doses of immunosuppressant, a population of granzyme A- and perforin-expressing lymphocytes could be identified. In contrast, lymphocytes from patients who were receiving high doses of immunosuppressant did not contain any granzyme A- or perforin-expressing lymphocytes. Synovial fluid lymphocytes from patients with osteoarthritis did not express either marker. The expression of these markers demonstrates the presence of potentially functional cytolytic lymphocytes, expressing proteins required to mediate killing, in the synovial fluid of patients with rheumatoid arthritis. This suggests that cytolytic lymphocytes may be involved in the pathogenesis of rheumatoid arthritis.

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Selected References

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

  1. Alvaro-Gracia J. M., Zvaifler N. J., Firestein G. S. Cytokines in chronic inflammatory arthritis. IV. Granulocyte/macrophage colony-stimulating factor-mediated induction of class II MHC antigen on human monocytes: a possible role in rheumatoid arthritis. J Exp Med. 1989 Sep 1;170(3):865–875. doi: 10.1084/jem.170.3.865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amento E. P., Bhan A. K., McCullagh K. G., Krane S. M. Influences of gamma interferon on synovial fibroblast-like cells. Ia induction and inhibition of collagen synthesis. J Clin Invest. 1985 Aug;76(2):837–848. doi: 10.1172/JCI112041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bleackley R. C., Lobe C. G., Duggan B., Ehrman N., Fregeau C., Meier M., Letellier M., Havele C., Shaw J., Paetkau V. The isolation and characterization of a family of serine protease genes expressed in activated cytotoxic T lymphocytes. Immunol Rev. 1988 Mar;103:5–19. doi: 10.1111/j.1600-065x.1988.tb00746.x. [DOI] [PubMed] [Google Scholar]
  4. Brennan F. M., Allard S., Londei M., Savill C., Boylston A., Carrel S., Maini R. N., Feldmann M. Heterogeneity of T cell receptor idiotypes in rheumatoid arthritis. Clin Exp Immunol. 1988 Sep;73(3):417–423. [PMC free article] [PubMed] [Google Scholar]
  5. Burmester G. R., Jahn B., Rohwer P., Zacher J., Winchester R. J., Kalden J. R. Differential expression of Ia antigens by rheumatoid synovial lining cells. J Clin Invest. 1987 Sep;80(3):595–604. doi: 10.1172/JCI113111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cush J. J., Lipsky P. E. Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum. 1988 Oct;31(10):1230–1238. doi: 10.1002/art.1780311003. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Firestein G. S., Alvaro-Gracia J. M., Maki R., Alvaro-Garcia J. M. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol. 1990 May 1;144(9):3347–3353. [PubMed] [Google Scholar]
  9. Fox R. I., Fong S., Sabharwal N., Carstens S. A., Kung P. C., Vaughan J. H. Synovial fluid lymphocytes differ from peripheral blood lymphocytes in patients with rheumatoid arthritis. J Immunol. 1982 Jan;128(1):351–354. [PubMed] [Google Scholar]
  10. Gaston J. S., Life P. F., Bailey L. C., Bacon P. A. In vitro responses to a 65-kilodalton mycobacterial protein by synovial T cells from inflammatory arthritis patients. J Immunol. 1989 Oct 15;143(8):2494–2500. [PubMed] [Google Scholar]
  11. Gershenfeld H. K., Hershberger R. J., Shows T. B., Weissman I. L. Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1184–1188. doi: 10.1073/pnas.85.4.1184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Griffiths G. M., Namikawa R., Mueller C., Liu C. C., Young J. D., Billingham M., Weissman I. Granzyme A and perforin as markers for rejection in cardiac transplantation. Eur J Immunol. 1991 Mar;21(3):687–693. doi: 10.1002/eji.1830210322. [DOI] [PubMed] [Google Scholar]
  13. Harris E. D., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. doi: 10.1056/NEJM199005033221805. [DOI] [PubMed] [Google Scholar]
  14. Hayes M. P., Berrebi G. A., Henkart P. A. Induction of target cell DNA release by the cytotoxic T lymphocyte granule protease granzyme A. J Exp Med. 1989 Sep 1;170(3):933–946. doi: 10.1084/jem.170.3.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hershberger R. J., Mueller C., Gershenfeld H. K., Weissman I. L. A serine protease-encoding gene that marks activated cytotoxic T cells in vivo and in vitro. Curr Top Microbiol Immunol. 1989;140:81–92. doi: 10.1007/978-3-642-73911-8_7. [DOI] [PubMed] [Google Scholar]
  16. Holoshitz J., Koning F., Coligan J. E., De Bruyn J., Strober S. Isolation of CD4- CD8- mycobacteria-reactive T lymphocyte clones from rheumatoid arthritis synovial fluid. Nature. 1989 May 18;339(6221):226–229. doi: 10.1038/339226a0. [DOI] [PubMed] [Google Scholar]
  17. Jalkanen S., Steere A. C., Fox R. I., Butcher E. C. A distinct endothelial cell recognition system that controls lymphocyte traffic into inflamed synovium. Science. 1986 Aug 1;233(4763):556–558. doi: 10.1126/science.3726548. [DOI] [PubMed] [Google Scholar]
  18. Jenne D. E., Tschopp J. Granzymes: a family of serine proteases in granules of cytolytic T lymphocytes. Curr Top Microbiol Immunol. 1989;140:33–47. doi: 10.1007/978-3-642-73911-8_4. [DOI] [PubMed] [Google Scholar]
  19. Keystone E. C., Minden M., Klock R., Poplonski L., Zalcberg J., Takadera T., Mak T. W. Structure of T cell antigen receptor beta chain in synovial fluid cells from patients with rheumatoid arthritis. Arthritis Rheum. 1988 Dec;31(12):1555–1557. doi: 10.1002/art.1780311213. [DOI] [PubMed] [Google Scholar]
  20. Kingsley G., Pitzalis C., Kyriazis N., Panayi G. S. Abnormal helper-inducer/suppressor-inducer T-cell subset distribution and T-cell activation status are common to all types of chronic synovitis. Scand J Immunol. 1988 Aug;28(2):225–232. doi: 10.1111/j.1365-3083.1988.tb02435.x. [DOI] [PubMed] [Google Scholar]
  21. Kingsley G., Pitzalis C., Panayi G. S. Immunogenetic and cellular immune mechanisms in rheumatoid arthritis: relevance to new therapeutic strategies. Br J Rheumatol. 1990 Feb;29(1):58–64. doi: 10.1093/rheumatology/29.1.58. [DOI] [PubMed] [Google Scholar]
  22. Klareskog L., Johnell O. Induced expression of class II transplantation antigens in the cartilage-pannus junction in RA: chronic synovitis as a model system for aberrant T-lymphocyte activation. Br J Rheumatol. 1988;27 (Suppl 2):141–149. doi: 10.1093/rheumatology/xxvii.suppl_2.141. [DOI] [PubMed] [Google Scholar]
  23. Kurosaka M., Ziff M. Immunoelectron microscopic study of the distribution of T cell subsets in rheumatoid synovium. J Exp Med. 1983 Oct 1;158(4):1191–1210. doi: 10.1084/jem.158.4.1191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lasky H. P., Bauer K., Pope R. M. Increased helper inducer and decreased suppressor inducer phenotypes in the rheumatoid joint. Arthritis Rheum. 1988 Jan;31(1):52–59. doi: 10.1002/art.1780310108. [DOI] [PubMed] [Google Scholar]
  25. Liu C. C., Rafii S., Granelli-Piperno A., Trapani J. A., Young J. D. Perforin and serine esterase gene expression in stimulated human T cells. Kinetics, mitogen requirements, and effects of cyclosporin A. J Exp Med. 1989 Dec 1;170(6):2105–2118. doi: 10.1084/jem.170.6.2105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mueller C., Gershenfeld H. K., Lobe C. G., Okada C. Y., Bleackley R. C., Weissman I. L. A high proportion of T lymphocytes that infiltrate H-2-incompatible heart allografts in vivo express genes encoding cytotoxic cell-specific serine proteases, but do not express the MEL-14-defined lymph node homing receptor. J Exp Med. 1988 Mar 1;167(3):1124–1136. doi: 10.1084/jem.167.3.1124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Müller C., Kägi D., Aebischer T., Odermatt B., Held W., Podack E. R., Zinkernagel R. M., Hengartner H. Detection of perforin and granzyme A mRNA in infiltrating cells during infection of mice with lymphocytic choriomeningitis virus. Eur J Immunol. 1989 Jul;19(7):1253–1259. doi: 10.1002/eji.1830190716. [DOI] [PubMed] [Google Scholar]
  28. Nykänen P., Bergroth V., Raunio P., Nordström D., Konttinen Y. T. Phenotypic characterization of 3H-thymidine incorporating cells in rheumatoid arthritis synovial membrane. Rheumatol Int. 1986;6(6):269–271. doi: 10.1007/BF00541318. [DOI] [PubMed] [Google Scholar]
  29. Podack E. R., Olsen K. J., Lowrey D. M., Lichtenheld M. Structure and function of perforin. Curr Top Microbiol Immunol. 1989;140:11–17. doi: 10.1007/978-3-642-73911-8_2. [DOI] [PubMed] [Google Scholar]
  30. Savill C. M., Delves P. J., Kioussis D., Walker P., Lydyard P. M., Colaco B., Shipley M., Roitt I. M. A minority of patients with rheumatoid arthritis show a dominant rearrangement of T-cell receptor beta chain genes in synovial lymphocytes. Scand J Immunol. 1987 Jun;25(6):629–635. doi: 10.1111/j.1365-3083.1987.tb01089.x. [DOI] [PubMed] [Google Scholar]
  31. Stamenkovic I., Stegagno M., Wright K. A., Krane S. M., Amento E. P., Colvin R. B., Duquesnoy R. J., Kurnick J. T. Clonal dominance among T-lymphocyte infiltrates in arthritis. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1179–1183. doi: 10.1073/pnas.85.4.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978 Apr 20;298(16):869–871. doi: 10.1056/NEJM197804202981602. [DOI] [PubMed] [Google Scholar]
  33. Winchester R. J., Agnello V., Kunkel H. G. Gamma globulin complexes in synovial fluids of patients with rheumatoid arthritis. Partial characterization and relationship to lowered complement levels. Clin Exp Immunol. 1970 May;6(5):689–706. [PMC free article] [PubMed] [Google Scholar]
  34. Wood G. S., Mueller C., Warnke R. A., Weissman I. L. In situ localization of HuHF serine protease mRNA and cytotoxic cell-associated antigens in human dermatoses. A novel method for the detection of cytotoxic cells in human tissues. Am J Pathol. 1988 Nov;133(2):218–225. [PMC free article] [PubMed] [Google Scholar]
  35. Ziff M. Rheumatoid arthritis--its present and future. J Rheumatol. 1990 Feb;17(2):127–133. [PubMed] [Google Scholar]

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