Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus (original) (raw)

Abstract

Current knowledge of the phenotype of mononuclear cells accumulating in pancreatic islets in insulin-dependent diabetes (IDDM) and factors determining their homing into the pancreas is limited. Therefore, a pancreas obtained at the onset of IDDM was studied in detail. Cryostat sections were stained for mononuclear cell types, T cell receptor subtypes, and adhesion molecules of vascular endothelium and studied by immunofluorescence microscopy, and peripheral blood mononuclear cells were phenotyped using flow cytometry. Monocytes/macrophages (lysozyme- or CD 14-reactive cells) were identified among other mononuclear cell types in islet infiltrates. V beta 8-positive T cells were overrepresented, but T cells with other V beta s studied (V beta 5, V beta 5.1, V beta 6, V beta 12) were also found. The vascular endothelium of the islets and many small vessels nearby islets strongly expressed intercellular adhesion molecule-1, whereas vascular cell adhesion molecule-1 and E-selectin were totally absent. We conclude: (a) that increased expression of intercellular adhesion molecule-1 on vascular endothelium may increase endothelial adhesion of mononuclear cells and enhance their accumulation in the pancreas during diabetic insulitis; (b) that T cells with certain T cell receptors can be enriched in infiltrated pancreatic islets; and (c) that macrophages and antigen-specific CD 8-positive T cells are involved in pancreatic beta cell destruction at the onset of IDDM.

1901

Images in this article

Selected References

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

  1. Acha-Orbea H., Mitchell D. J., Timmermann L., Wraith D. C., Tausch G. S., Waldor M. K., Zamvil S. S., McDevitt H. O., Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263–273. doi: 10.1016/0092-8674(88)90558-2. [DOI] [PubMed] [Google Scholar]
  2. Altmann D. M., Hogg N., Trowsdale J., Wilkinson D. Cotransfection of ICAM-1 and HLA-DR reconstitutes human antigen-presenting cell function in mouse L cells. Nature. 1989 Apr 6;338(6215):512–514. doi: 10.1038/338512a0. [DOI] [PubMed] [Google Scholar]
  3. Anderson D. C., Springer T. A. Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins. Annu Rev Med. 1987;38:175–194. doi: 10.1146/annurev.me.38.020187.001135. [DOI] [PubMed] [Google Scholar]
  4. Bendtzen K., Mandrup-Poulsen T., Nerup J., Nielsen J. H., Dinarello C. A., Svenson M. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science. 1986 Jun 20;232(4757):1545–1547. doi: 10.1126/science.3086977. [DOI] [PubMed] [Google Scholar]
  5. Bevilacqua M. P., Stengelin S., Gimbrone M. A., Jr, Seed B. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science. 1989 Mar 3;243(4895):1160–1165. doi: 10.1126/science.2466335. [DOI] [PubMed] [Google Scholar]
  6. Bottazzo G. F., Dean B. M., McNally J. M., MacKay E. H., Swift P. G., Gamble D. R. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med. 1985 Aug 8;313(6):353–360. doi: 10.1056/NEJM198508083130604. [DOI] [PubMed] [Google Scholar]
  7. Chluba J., Steeg C., Becker A., Wekerle H., Epplen J. T. T cell receptor beta chain usage in myelin basic protein-specific rat T lymphocytes. Eur J Immunol. 1989 Feb;19(2):279–284. doi: 10.1002/eji.1830190210. [DOI] [PubMed] [Google Scholar]
  8. Dustin M. L., Springer T. A. Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol. 1988 Jul;107(1):321–331. doi: 10.1083/jcb.107.1.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dustin M. L., Staunton D. E., Springer T. A. Supergene families meet in the immune system. Immunol Today. 1988 Jul-Aug;9(7-8):213–215. doi: 10.1016/0167-5699(88)91216-9. [DOI] [PubMed] [Google Scholar]
  10. Eisenbarth G. S. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med. 1986 May 22;314(21):1360–1368. doi: 10.1056/NEJM198605223142106. [DOI] [PubMed] [Google Scholar]
  11. Foulis A. K., Farquharson M. A. Aberrant expression of HLA-DR antigens by insulin-containing beta-cells in recent-onset type I diabetes mellitus. Diabetes. 1986 Nov;35(11):1215–1224. doi: 10.2337/diab.35.11.1215. [DOI] [PubMed] [Google Scholar]
  12. Foulis A. K., Farquharson M. A., Hardman R. Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1987 May;30(5):333–343. doi: 10.1007/BF00299027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Foulis A. K., McGill M., Farquharson M. A. Insulitis in type 1 (insulin-dependent) diabetes mellitus in man--macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol. 1991 Oct;165(2):97–103. doi: 10.1002/path.1711650203. [DOI] [PubMed] [Google Scholar]
  14. Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 1965 Oct;14(10):619–633. doi: 10.2337/diab.14.10.619. [DOI] [PubMed] [Google Scholar]
  15. Happ M. P., Heber-Katz E. Differences in the repertoire of the Lewis rat T cell response to self and non-self myelin basic proteins. J Exp Med. 1988 Feb 1;167(2):502–513. doi: 10.1084/jem.167.2.502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Haskard D., Cavender D., Beatty P., Springer T., Ziff M. T lymphocyte adhesion to endothelial cells: mechanisms demonstrated by anti-LFA-1 monoclonal antibodies. J Immunol. 1986 Nov 1;137(9):2901–2906. [PubMed] [Google Scholar]
  17. Haskins K., Hannum C., White J., Roehm N., Kubo R., Kappler J., Marrack P. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. VI. An antibody to a receptor allotype. J Exp Med. 1984 Aug 1;160(2):452–471. doi: 10.1084/jem.160.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hutchings P., Rosen H., O'Reilly L., Simpson E., Gordon S., Cooke A. Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages. Nature. 1990 Dec 13;348(6302):639–642. doi: 10.1038/348639a0. [DOI] [PubMed] [Google Scholar]
  19. Jalkanen S. T., Bargatze R. F., Herron L. R., Butcher E. C. A lymphoid cell surface glycoprotein involved in endothelial cell recognition and lymphocyte homing in man. Eur J Immunol. 1986 Oct;16(10):1195–1202. doi: 10.1002/eji.1830161003. [DOI] [PubMed] [Google Scholar]
  20. Kontiainen S., Toomath R., Lowder J., Feldmann M. Selective activation of T cells in newly diagnosed insulin-dependent diabetic patients: evidence for heterogeneity of T cell receptor usage. Clin Exp Immunol. 1991 Mar;83(3):347–351. doi: 10.1111/j.1365-2249.1991.tb05641.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lawrence M. B., Smith C. W., Eskin S. G., McIntire L. V. Effect of venous shear stress on CD18-mediated neutrophil adhesion to cultured endothelium. Blood. 1990 Jan 1;75(1):227–237. [PubMed] [Google Scholar]
  22. Lee K. U., Amano K., Yoon J. W. Evidence for initial involvement of macrophage in development of insulitis in NOD mice. Diabetes. 1988 Jul;37(7):989–991. doi: 10.2337/diab.37.7.989. [DOI] [PubMed] [Google Scholar]
  23. Lee K. U., Pak C. Y., Amano K., Yoon J. W. Prevention of lymphocytic thyroiditis and insulitis in diabetes-prone BB rats by the depletion of macrophages. Diabetologia. 1988 Jun;31(6):400–402. doi: 10.1007/BF02341511. [DOI] [PubMed] [Google Scholar]
  24. Luscinskas F. W., Brock A. F., Arnaout M. A., Gimbrone M. A., Jr Endothelial-leukocyte adhesion molecule-1-dependent and leukocyte (CD11/CD18)-dependent mechanisms contribute to polymorphonuclear leukocyte adhesion to cytokine-activated human vascular endothelium. J Immunol. 1989 Apr 1;142(7):2257–2263. [PubMed] [Google Scholar]
  25. Munro J. M., Pober J. S., Cotran R. S. Tumor necrosis factor and interferon-gamma induce distinct patterns of endothelial activation and associated leukocyte accumulation in skin of Papio anubis. Am J Pathol. 1989 Jul;135(1):121–133. [PMC free article] [PubMed] [Google Scholar]
  26. Nakano N., Kikutani H., Nishimoto H., Kishimoto T. T cell receptor V gene usage of islet beta cell-reactive T cells is not restricted in non-obese diabetic mice. J Exp Med. 1991 May 1;173(5):1091–1097. doi: 10.1084/jem.173.5.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. O'Reilly L. A., Hutchings P. R., Crocker P. R., Simpson E., Lund T., Kioussis D., Takei F., Baird J., Cooke A. Characterization of pancreatic islet cell infiltrates in NOD mice: effect of cell transfer and transgene expression. Eur J Immunol. 1991 May;21(5):1171–1180. doi: 10.1002/eji.1830210512. [DOI] [PubMed] [Google Scholar]
  28. Ohashi P. S., Oehen S., Buerki K., Pircher H., Ohashi C. T., Odermatt B., Malissen B., Zinkernagel R. M., Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991 Apr 19;65(2):305–317. doi: 10.1016/0092-8674(91)90164-t. [DOI] [PubMed] [Google Scholar]
  29. Osborn L. Leukocyte adhesion to endothelium in inflammation. Cell. 1990 Jul 13;62(1):3–6. doi: 10.1016/0092-8674(90)90230-c. [DOI] [PubMed] [Google Scholar]
  30. Parkkonen P., Hyöty H., Koskinen L., Leinikki P. Mumps virus infects beta cells in human fetal islet cell cultures upregulating the expression of HLA class I molecules. Diabetologia. 1992 Jan;35(1):63–69. doi: 10.1007/BF00400853. [DOI] [PubMed] [Google Scholar]
  31. Pipelleers D. G., in 't Veld P. A., Pipeleers-Marichal M. A., Gepts W., van de Winkel M. Presence of pancreatic hormones in islet cells with MHC-class II antigen expression. Diabetes. 1987 Jul;36(7):872–876. doi: 10.2337/diab.36.7.872. [DOI] [PubMed] [Google Scholar]
  32. Pober J. S., Cotran R. S. The role of endothelial cells in inflammation. Transplantation. 1990 Oct;50(4):537–544. doi: 10.1097/00007890-199010000-00001. [DOI] [PubMed] [Google Scholar]
  33. Pober J. S., Gimbrone M. A., Jr, Cotran R. S., Reiss C. S., Burakoff S. J., Fiers W., Ault K. A. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon. J Exp Med. 1983 Apr 1;157(4):1339–1353. doi: 10.1084/jem.157.4.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pober J. S. Warner-Lambert/Parke-Davis award lecture. Cytokine-mediated activation of vascular endothelium. Physiology and pathology. Am J Pathol. 1988 Dec;133(3):426–433. [PMC free article] [PubMed] [Google Scholar]
  35. Rice G. E., Munro J. M., Corless C., Bevilacqua M. P. Vascular and nonvascular expression of INCAM-110. A target for mononuclear leukocyte adhesion in normal and inflamed human tissues. Am J Pathol. 1991 Feb;138(2):385–393. [PMC free article] [PubMed] [Google Scholar]
  36. Schönrich G., Kalinke U., Momburg F., Malissen M., Schmitt-Verhulst A. M., Malissen B., Hämmerling G. J., Arnold B. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell. 1991 Apr 19;65(2):293–304. doi: 10.1016/0092-8674(91)90163-s. [DOI] [PubMed] [Google Scholar]
  37. Shizuru J. A., Taylor-Edwards C., Livingstone A., Fathman C. G. Genetic dissection of T cell receptor V beta gene requirements for spontaneous murine diabetes. J Exp Med. 1991 Sep 1;174(3):633–638. doi: 10.1084/jem.174.3.633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sibley R. K., Sutherland D. E., Goetz F., Michael A. F. Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest. 1985 Aug;53(2):132–144. [PubMed] [Google Scholar]
  39. Smith C. W., Marlin S. D., Rothlein R., Toman C., Anderson D. C. Cooperative interactions of LFA-1 and Mac-1 with intercellular adhesion molecule-1 in facilitating adherence and transendothelial migration of human neutrophils in vitro. J Clin Invest. 1989 Jun;83(6):2008–2017. doi: 10.1172/JCI114111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
  41. Wellicome S. M., Thornhill M. H., Pitzalis C., Thomas D. S., Lanchbury J. S., Panayi G. S., Haskard D. O. A monoclonal antibody that detects a novel antigen on endothelial cells that is induced by tumor necrosis factor, IL-1, or lipopolysaccharide. J Immunol. 1990 Apr 1;144(7):2558–2565. [PubMed] [Google Scholar]
  42. Yoon J. W. The role of viruses and environmental factors in the induction of diabetes. Curr Top Microbiol Immunol. 1990;164:95–123. doi: 10.1007/978-3-642-75741-9_6. [DOI] [PubMed] [Google Scholar]
  43. Zamvil S. S., Mitchell D. J., Lee N. E., Moore A. C., Waldor M. K., Sakai K., Rothbard J. B., McDevitt H. O., Steinman L., Acha-Orbea H. Predominant expression of a T cell receptor V beta gene subfamily in autoimmune encephalomyelitis. J Exp Med. 1988 May 1;167(5):1586–1596. doi: 10.1084/jem.167.5.1586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]