Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. 1992 Jan 15; 89(2): 549–553.

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


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.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978 Apr 20;298(16):869–871. [PubMed]
  • Harris ED., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. [PubMed]
  • Ziff M. Rheumatoid arthritis--its present and future. J Rheumatol. 1990 Feb;17(2):127–133. [PubMed]
  • Kingsley G, Pitzalis C, Panayi GS. Immunogenetic and cellular immune mechanisms in rheumatoid arthritis: relevance to new therapeutic strategies. Br J Rheumatol. 1990 Feb;29(1):58–64. [PubMed]
  • Winchester RJ, Agnello V, Kunkel HG. 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]
  • 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. [PubMed]
  • Cush JJ, Lipsky PE. Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum. 1988 Oct;31(10):1230–1238. [PubMed]
  • Firestein GS, Alvaro-Gracia JM, Maki R, Alvaro-Garcia JM. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol. 1990 May 1;144(9):3347–3353. [PubMed]
  • Nykänen P, Bergroth V, Raunio P, Nordström D, Konttinen YT. Phenotypic characterization of 3H-thymidine incorporating cells in rheumatoid arthritis synovial membrane. Rheumatol Int. 1986;6(6):269–271. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Fox RI, Fong S, Sabharwal N, Carstens SA, Kung PC, Vaughan JH. Synovial fluid lymphocytes differ from peripheral blood lymphocytes in patients with rheumatoid arthritis. J Immunol. 1982 Jan;128(1):351–354. [PubMed]
  • Lasky HP, Bauer K, Pope RM. Increased helper inducer and decreased suppressor inducer phenotypes in the rheumatoid joint. Arthritis Rheum. 1988 Jan;31(1):52–59. [PubMed]
  • Kingsley G, Pitzalis C, Kyriazis N, Panayi GS. 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. [PubMed]
  • Gershenfeld HK, Hershberger RJ, Shows TB, Weissman IL. 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. [PMC free article] [PubMed]
  • Hershberger RJ, Mueller C, Gershenfeld HK, Weissman IL. A serine protease-encoding gene that marks activated cytotoxic T cells in vivo and in vitro. Curr Top Microbiol Immunol. 1989;140:81–92. [PubMed]
  • Jenne DE, Tschopp J. Granzymes: a family of serine proteases in granules of cytolytic T lymphocytes. Curr Top Microbiol Immunol. 1989;140:33–47. [PubMed]
  • Bleackley RC, Lobe CG, 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. [PubMed]
  • Liu CC, Rafii S, Granelli-Piperno A, Trapani JA, Young JD. 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. [PMC free article] [PubMed]
  • Hayes MP, Berrebi GA, Henkart PA. 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. [PMC free article] [PubMed]
  • Podack ER, Olsen KJ, Lowrey DM, Lichtenheld M. Structure and function of perforin. Curr Top Microbiol Immunol. 1989;140:11–17. [PubMed]
  • Mueller C, Gershenfeld HK, Lobe CG, Okada CY, Bleackley RC, Weissman IL. 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. [PMC free article] [PubMed]
  • Müller C, Kägi D, Aebischer T, Odermatt B, Held W, Podack ER, Zinkernagel RM, 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. [PubMed]
  • Wood GS, Mueller C, Warnke RA, Weissman IL. 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]
  • Griffiths GM, Namikawa R, Mueller C, Liu CC, Young JD, Billingham M, Weissman I. Granzyme A and perforin as markers for rejection in cardiac transplantation. Eur J Immunol. 1991 Mar;21(3):687–693. [PubMed]
  • Jalkanen S, Steere AC, Fox RI, Butcher EC. A distinct endothelial cell recognition system that controls lymphocyte traffic into inflamed synovium. Science. 1986 Aug 1;233(4763):556–558. [PubMed]
  • Alvaro-Gracia JM, Zvaifler NJ, Firestein GS. 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. [PMC free article] [PubMed]
  • Amento EP, Bhan AK, McCullagh KG, Krane SM. 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. [PMC free article] [PubMed]
  • Burmester GR, Jahn B, Rohwer P, Zacher J, Winchester RJ, Kalden JR. Differential expression of Ia antigens by rheumatoid synovial lining cells. J Clin Invest. 1987 Sep;80(3):595–604. [PMC free article] [PubMed]
  • Holoshitz J, Koning F, Coligan JE, 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. [PubMed]
  • Gaston JS, Life PF, Bailey LC, Bacon PA. 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]
  • Stamenkovic I, Stegagno M, Wright KA, Krane SM, Amento EP, Colvin RB, Duquesnoy RJ, Kurnick JT. Clonal dominance among T-lymphocyte infiltrates in arthritis. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1179–1183. [PMC free article] [PubMed]
  • Duby AD, Sinclair AK, Osborne-Lawrence SL, Zeldes W, Kan L, Fox DA. 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. [PMC free article] [PubMed]
  • Brennan FM, Allard S, Londei M, Savill C, Boylston A, Carrel S, Maini RN, Feldmann M. Heterogeneity of T cell receptor idiotypes in rheumatoid arthritis. Clin Exp Immunol. 1988 Sep;73(3):417–423. [PMC free article] [PubMed]
  • Savill CM, Delves PJ, Kioussis D, Walker P, Lydyard PM, Colaco B, Shipley M, Roitt IM. 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. [PubMed]
  • Keystone EC, Minden M, Klock R, Poplonski L, Zalcberg J, Takadera T, Mak TW. 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. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...