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J Clin Invest. 1996 Jun 15; 97(12): 2905–2910.
PMCID: PMC507387

Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.

Abstract

Polymyositis (PM) and dermatomyositis (DM) are the prototypical inflammatory diseases of skeletal muscle. In PM, CD8+ T cells invade and destroy muscle fibers, whereas humoral effector mechanisms prevail in DM. We studied the expression of the cytotoxic mediator perforin in inflammatory cells in PM and DM muscle by semiquantitative PCR, immunohistochemistry and confocal laser microscopy. Similar levels of perforin mRNA were expressed in PM and DM, and abundant perforin-expressing CD3+CD8+ and CD3+ CD4+ T cells were observed in both diseases. However, there was a striking difference in the intracellular localization of perforin. In DM, perforin was distributed randomly in the cytoplasm of the inflammatory T cells. In contrast, 43% of the CD8+ T cells that contacted a muscle fiber in PM showed perforin located vectorially towards the target muscle fiber. The results suggest (a) that the random distribution of perforin in the cytoplasm of muscle-infiltrating T cells observed in DM reflects nonspecific activation, and (b) that the vectorial orientation observed only in PM reflects the specific recognition via the T cell receptor of an antigen on the muscle fiber surface, pointing to a perforin- and secretion-dependent mechanism of muscle fiber injury.

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Selected References

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  • Tschopp J, Nabholz M. Perforin-mediated target cell lysis by cytolytic T lymphocytes. Annu Rev Immunol. 1990;8:279–302. [PubMed]
  • Podack ER, Hengartner H, Lichtenheld MG. A central role of perforin in cytolysis? Annu Rev Immunol. 1991;9:129–157. [PubMed]
  • Henkart PA. Lymphocyte-mediated cytotoxicity: two pathways and multiple effector molecules. Immunity. 1994 Aug;1(5):343–346. [PubMed]
  • Berke G. The binding and lysis of target cells by cytotoxic lymphocytes: molecular and cellular aspects. Annu Rev Immunol. 1994;12:735–773. [PubMed]
  • Liu CC, Walsh CM, Young JD. Perforin: structure and function. Immunol Today. 1995 Apr;16(4):194–201. [PubMed]
  • Henkart PA, Williams MS, Nakajima H. Degranulating cytotoxic lymphocytes inflict multiple damage pathways on target cells. Curr Top Microbiol Immunol. 1995;198:75–93. [PubMed]
  • Hohlfeld R, Engel AG. The immunobiology of muscle. Immunol Today. 1994 Jun;15(6):269–274. [PubMed]
  • Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med. 1991 Nov 21;325(21):1487–1498. [PubMed]
  • Bender A, Ernst N, Iglesias A, Dornmair K, Wekerle H, Hohlfeld R. T cell receptor repertoire in polymyositis: clonal expansion of autoaggressive CD8+ T cells. J Exp Med. 1995 May 1;181(5):1863–1868. [PMC free article] [PubMed]
  • Emslie-Smith AM, Engel AG. Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol. 1990 Apr;27(4):343–356. [PubMed]
  • Goebels N, Michaelis D, Wekerle H, Hohlfeld R. Human myoblasts as antigen-presenting cells. J Immunol. 1992 Jul 15;149(2):661–667. [PubMed]
  • Dupuis M, Schaerer E, Krause KH, Tschopp J. The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. J Exp Med. 1993 Jan 1;177(1):1–7. [PMC free article] [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Kinoshita T, Imamura J, Nagai H, Shimotohno K. Quantification of gene expression over a wide range by the polymerase chain reaction. Anal Biochem. 1992 Nov 1;206(2):231–235. [PubMed]
  • Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol. 1984 Aug;16(2):193–208. [PubMed]
  • Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol. 1984 Aug;16(2):209–215. [PubMed]
  • Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. III: Immunoelectron microscopy aspects of cell-mediated muscle fiber injury. Ann Neurol. 1986 Feb;19(2):112–125. [PubMed]
  • Wu Z, Podack ER, McKenzie JM, Olsen KJ, Zakarija M. Perforin expression by thyroid-infiltrating T cells in autoimmune thyroid disease. Clin Exp Immunol. 1994 Dec;98(3):470–477. [PMC free article] [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]
  • Kupfer A, Singer SJ. Cell biology of cytotoxic and helper T cell functions: immunofluorescence microscopic studies of single cells and cell couples. Annu Rev Immunol. 1989;7:309–337. [PubMed]
  • Podack ER, Kupfer A. T-cell effector functions: mechanisms for delivery of cytotoxicity and help. Annu Rev Cell Biol. 1991;7:479–504. [PubMed]
  • Yannelli JR, Sullivan JA, Mandell GL, Engelhard VH. Reorientation and fusion of cytotoxic T lymphocyte granules after interaction with target cells as determined by high resolution cinemicrography. J Immunol. 1986 Jan;136(2):377–382. [PubMed]
  • Kupfer A, Singer SJ, Dennert G. On the mechanism of unidirectional killing in mixtures of two cytotoxic T lymphocytes. Unidirectional polarization of cytoplasmic organelles and the membrane-associated cytoskeleton in the effector cell. J Exp Med. 1986 Mar 1;163(3):489–498. [PMC free article] [PubMed]
  • Felzen B, Berke G, Rosen D, Coleman R, Tschopp J, Young JD, Binah O. Effects of purified perforin and granzyme A from cytotoxic T lymphocytes on guinea pig ventricular myocytes. Cardiovasc Res. 1994 May;28(5):643–649. [PubMed]
  • Orimo S, Koga R, Goto K, Nakamura K, Arai M, Tamaki M, Sugita H, Nonaka I, Arahata K. Immunohistochemical analysis of perforin and granzyme A in inflammatory myopathies. Neuromuscul Disord. 1994 May;4(3):219–226. [PubMed]
  • Smyth MJ, Ortaldo JR, Shinkai Y, Yagita H, Nakata M, Okumura K, Young HA. Interleukin 2 induction of pore-forming protein gene expression in human peripheral blood CD8+ T cells. J Exp Med. 1990 Apr 1;171(4):1269–1281. [PMC free article] [PubMed]
  • Lundberg I, Brengman JM, Engel AG. Analysis of cytokine expression in muscle in inflammatory myopathies, Duchenne dystrophy, and non-weak controls. J Neuroimmunol. 1995 Dec;63(1):9–16. [PubMed]
  • Young LH, Joag SV, Zheng LM, Lee CP, Lee YS, Young JD. Perforin-mediated myocardial damage in acute myocarditis. Lancet. 1990 Oct 27;336(8722):1019–1021. [PubMed]
  • Hameed A, Olsen KJ, Cheng L, Fox WM, 3rd, Hruban RH, Podack ER. Immunohistochemical identification of cytotoxic lymphocytes using human perforin monoclonal antibody. Am J Pathol. 1992 May;140(5):1025–1030. [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]
  • Legros-Maïda S, Soulié A, Benvenuti C, Wargnier A, Vallée N, Berthou C, Guillet J, Sasportes M, Sigaux N. Granzyme B and perforin can be used as predictive markers of acute rejection in heart transplantation. Eur J Immunol. 1994 Jan;24(1):229–233. [PubMed]
  • Lipman ML, Stevens AC, Strom TB. Heightened intragraft CTL gene expression in acutely rejecting renal allografts. J Immunol. 1994 May 15;152(10):5120–5127. [PubMed]

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