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. 1998 Jan;152(1):261–268.

Activated CD4+ and CD8+ cytotoxic cells are present in increased numbers in the intestinal mucosa from patients with active inflammatory bowel disease.

S Müller 1, J Lory 1, N Corazza 1, G M Griffiths 1, K Z'graggen 1, L Mazzucchelli 1, A Kappeler 1, C Mueller 1
PMCID: PMC1858122  PMID: 9422543

Abstract

The contribution of cell-mediated cytotoxicity to the pathogenesis of inflammatory bowel disease (IBD) is controversial, and results of in vitro assays vary according to experimental procedures. Therefore, we compared the frequency of cytotoxic effector cells in situ. On tissue sections of controls (n = 11), low frequencies of granzyme A and perforin mRNA-expressing cells are found in the lamina propria (1.77 +/- 0.15% and 1.46 +/- 0.12%, respectively) and in the epithelial cell layer (0.76 +/- 0.12% and 0.66 +/- 0.10%, respectively). In patients with IBD (n = 33), corresponding values were significantly (P < 0.02) higher, 6.1 +/- 0.40% and 5.92 +/- 0.57% for granzyme A and perforin expression in the lamina propria and 2.50 +/- 0.19% and 2.59 +/- 0.28%, respectively, in the epithelial compartment. Differences between ulcerative colitis and Crohn's disease are statistically not significant (P > 0.33). Activated cytotoxic cells are preferentially found at sites facing the intestinal lumen. Perforin mRNA-expressing cells are mainly CD8+ T cells. CD4+ T cells expressing perforin mRNA are mainly isolated from affected areas of patients with Crohn's disease. Immunostaining for perforin protein generally coincides with perforin mRNA in situ. These data demonstrate that cytotoxic cells are vigorously activated in situ in the intestinal mucosa of patients with active IBD.

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Selected References

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

  1. Baetz K., Isaaz S., Griffiths G. M. Loss of cytotoxic T lymphocyte function in Chediak-Higashi syndrome arises from a secretory defect that prevents lytic granule exocytosis. J Immunol. 1995 Jun 1;154(11):6122–6131. [PubMed] [Google Scholar]
  2. Eckmann L., Jung H. C., Schürer-Maly C., Panja A., Morzycka-Wroblewska E., Kagnoff M. F. Differential cytokine expression by human intestinal epithelial cell lines: regulated expression of interleukin 8. Gastroenterology. 1993 Dec;105(6):1689–1697. doi: 10.1016/0016-5085(93)91064-o. [DOI] [PubMed] [Google Scholar]
  3. Eckmann L., Kagnoff M. F., Fierer J. Epithelial cells secrete the chemokine interleukin-8 in response to bacterial entry. Infect Immun. 1993 Nov;61(11):4569–4574. doi: 10.1128/iai.61.11.4569-4574.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Egawa S., Hiwatashi N. Natural killer cell activity in patients with inflammatory bowel disease. J Clin Lab Immunol. 1986 Aug;20(4):187–192. [PubMed] [Google Scholar]
  5. 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]
  6. Ginsburg C. H., Dambrauskas J. T., Ault K. A., Falchuk Z. M. Impaired natural killer cell activity in patients with inflammatory bowel disease: evidence for a qualitative defect. Gastroenterology. 1983 Oct;85(4):846–851. [PubMed] [Google Scholar]
  7. Griffiths G. M., Mueller C. Expression of perforin and granzymes in vivo: potential diagnostic markers for activated cytotoxic cells. Immunol Today. 1991 Nov;12(11):415–419. doi: 10.1016/0167-5699(91)90145-J. [DOI] [PubMed] [Google Scholar]
  8. Henkart P. A. Lymphocyte-mediated cytotoxicity: two pathways and multiple effector molecules. Immunity. 1994 Aug;1(5):343–346. doi: 10.1016/1074-7613(94)90063-9. [DOI] [PubMed] [Google Scholar]
  9. Holländer G. A., Simpson S. J., Mizoguchi E., Nichogiannopoulou A., She J., Gutierrez-Ramos J. C., Bhan A. K., Burakoff S. J., Wang B., Terhorst C. Severe colitis in mice with aberrant thymic selection. Immunity. 1995 Jul;3(1):27–38. doi: 10.1016/1074-7613(95)90156-6. [DOI] [PubMed] [Google Scholar]
  10. Kühn R., Löhler J., Rennick D., Rajewsky K., Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
  11. Lichtenheld M. G., Olsen K. J., Lu P., Lowrey D. M., Hameed A., Hengartner H., Podack E. R. Structure and function of human perforin. Nature. 1988 Sep 29;335(6189):448–451. doi: 10.1038/335448a0. [DOI] [PubMed] [Google Scholar]
  12. Mazzucchelli L., Hauser C., Zgraggen K., Wagner H., Hess M., Laissue J. A., Mueller C. Expression of interleukin-8 gene in inflammatory bowel disease is related to the histological grade of active inflammation. Am J Pathol. 1994 May;144(5):997–1007. [PMC free article] [PubMed] [Google Scholar]
  13. Mombaerts P., Mizoguchi E., Grusby M. J., Glimcher L. H., Bhan A. K., Tonegawa S. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell. 1993 Oct 22;75(2):274–282. doi: 10.1016/0092-8674(93)80069-q. [DOI] [PubMed] [Google Scholar]
  14. Monteleone G., Biancone L., Marasco R., Morrone G., Marasco O., Luzza F., Pallone F. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology. 1997 Apr;112(4):1169–1178. doi: 10.1016/s0016-5085(97)70128-8. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Okazaki K., Morita M., Nishimori I., Sano S., Toyonaga M., Nakazawa Y., Yamamoto Y., Yamamoto Y. Major histocompatibility antigen-restricted cytotoxicity in inflammatory bowel disease. Gastroenterology. 1993 Feb;104(2):384–391. doi: 10.1016/0016-5085(93)90405-2. [DOI] [PubMed] [Google Scholar]
  17. Parronchi P., Romagnani P., Annunziato F., Sampognaro S., Becchio A., Giannarini L., Maggi E., Pupilli C., Tonelli F., Romagnani S. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease. Am J Pathol. 1997 Mar;150(3):823–832. [PMC free article] [PubMed] [Google Scholar]
  18. Rouvier E., Luciani M. F., Golstein P. Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity. J Exp Med. 1993 Jan 1;177(1):195–200. doi: 10.1084/jem.177.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rudolph U., Finegold M. J., Rich S. S., Harriman G. R., Srinivasan Y., Brabet P., Boulay G., Bradley A., Birnbaumer L. Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice. Nat Genet. 1995 Jun;10(2):143–150. doi: 10.1038/ng0695-143. [DOI] [PubMed] [Google Scholar]
  20. Rüthlein J., Heinze G., Auer I. O. Anti-CD2 and anti-CD3 induced T cell cytotoxicity of human intraepithelial and lamina propria lymphocytes. Gut. 1992 Dec;33(12):1626–1632. doi: 10.1136/gut.33.12.1626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sadlack B., Merz H., Schorle H., Schimpl A., Feller A. C., Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993 Oct 22;75(2):253–261. doi: 10.1016/0092-8674(93)80067-o. [DOI] [PubMed] [Google Scholar]
  22. Schuerer-Maly C. C., Eckmann L., Kagnoff M. F., Falco M. T., Maly F. E. Colonic epithelial cell lines as a source of interleukin-8: stimulation by inflammatory cytokines and bacterial lipopolysaccharide. Immunology. 1994 Jan;81(1):85–91. [PMC free article] [PubMed] [Google Scholar]
  23. Simpson S. J., Mizoguchi E., Allen D., Bhan A. K., Terhorst C. Evidence that CD4+, but not CD8+ T cells are responsible for murine interleukin-2-deficient colitis. Eur J Immunol. 1995 Sep;25(9):2618–2625. doi: 10.1002/eji.1830250932. [DOI] [PubMed] [Google Scholar]
  24. Stalder T., Hahn S., Erb P. Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. J Immunol. 1994 Feb 1;152(3):1127–1133. [PubMed] [Google Scholar]
  25. Walz A., Burgener R., Car B., Baggiolini M., Kunkel S. L., Strieter R. M. Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin 8. J Exp Med. 1991 Dec 1;174(6):1355–1362. doi: 10.1084/jem.174.6.1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Williams N. S., Engelhard V. H. Identification of a population of CD4+ CTL that utilizes a perforin- rather than a Fas ligand-dependent cytotoxic mechanism. J Immunol. 1996 Jan 1;156(1):153–159. [PubMed] [Google Scholar]
  27. Z'Graggen K., Walz A., Mazzucchelli L., Strieter R. M., Mueller C. The C-X-C chemokine ENA-78 is preferentially expressed in intestinal epithelium in inflammatory bowel disease. Gastroenterology. 1997 Sep;113(3):808–816. doi: 10.1016/s0016-5085(97)70175-6. [DOI] [PubMed] [Google Scholar]

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