Major Histocompatibility Complex Molecules and the Beta Cell: Inferences from Transgenic Models

Conference paper
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 156)


Type 1 or insulin-dependent diabetes mellitus is a syndrome of chronic hyperglycaemia secondary to insulin deficiency due to the selective destruction of the pancreatic islet β cells. The molecular pathology of the disease in humans is still poorly understood, but a substantial body of evidence favours the view that the β cells are destroyed by an autoimmune process initiated in genetically predisposed individuals by environmental agents such as viruses or chemotoxins (EISENBARTH 1986; ROSSINI et al. 1988; CAMPBELL and HARRISON 1989). Evidence in humans for the autoimmune basis of type 1 diabetes includes the following: (a) the presence of circulating autoantibodies to islet cells and/or insulin in the majority of newly diagnosed patients (GLEICHMANN and BOTTAZZO 1987), (b) mononuclear cell infiltration or “insulitis” of islets seen in the pancreas obtained at autopsy from newly diagnosed subjects (GEPTS and LE COMPTE 1981; FOULIS et al. 1986), (c) recurrence of diabetes associated with insulitis in recipients of pancreas isografts from major histocompatibility complex (MHC) identical siblings (SIBLEY et al. 1985) and (d) an increase in the frequency and duration of remissions from insulin dependence in newly diagnosed patients treated with immunosuppressive agents (HARRISON et al. 1985; ASSAN et al. 1985).


Beta Cell Major Histocompatibility Complex Class Major Histocompatibility Complex Molecule Major Histocompatibility Complex Protein Human Islet Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams TE, Alpert S, Hanahan D (1987) Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic β cells. Nature 325: 223–228PubMedCrossRefGoogle Scholar
  2. Allison J, Campbell IL, Morahan G, Mandel TE, Harrison LC, Miller JFAP (1988) Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic P cells. Nature 333: 529–533PubMedCrossRefGoogle Scholar
  3. Alpert S, Hanahan D, Teitelman G (1988) Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell 53: 295–308PubMedCrossRefGoogle Scholar
  4. Andersson M, Pääbo S, Nilsson T, Peterson P (1985) Impaired intracellular transport of class I MHC antigens as a possible means for adnenovirus to evade immune surveillance. Cell 43: 215–222PubMedCrossRefGoogle Scholar
  5. Assan R, Feutren G, Debray-Sachs M, Quiniou-Debrie MC, Laborie C, Thomas G, Chatenoud L, Bach JF (1985) Metabolic and immunological effects of cyclosporin in recently diagnosed type 1 diabetes mellitus. Lancet 1: 67–71PubMedCrossRefGoogle Scholar
  6. Baekkeskov S, Kanatsuna T, Klareskog L, Nielsen DA, Peterson A, Rubenstein AH, Steiner DF, Lernmark A (1981) Expression of major histocompatibility antigens on pancreatic islet cells. Proc Natl Acad Sci USA 78: 6456–6460PubMedCrossRefGoogle Scholar
  7. Bendelac A, Carnaud C, Boitard C, Bach JF (1987) Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2 + T cells. J Exp Med 166: 823–832PubMedCrossRefGoogle Scholar
  8. Billingham RE, Breur L, Medawar PB (1953) “Actively acquired tolerance” of foreign cells. Nature 172: 603–606PubMedCrossRefGoogle Scholar
  9. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC (1987) The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329: 512–518PubMedCrossRefGoogle Scholar
  10. Bottazzo GF, Pujol-Borrell R, Hanafusa T, Feldmann M (1983) Hypothesis: role of aberrant HLA- DR expression and antigen presentation in the induction of endocrine autoimmunity. Lancet 2: 1115PubMedCrossRefGoogle Scholar
  11. Bottazzo GF, Dean BM, McNally JM, Mackay EH, Swift PGF, Gamble DR (1985) In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 31: 353–360CrossRefGoogle Scholar
  12. Brinster RL, Chen HY, Trumbauer ME, Yagle MK, Palmiter RD (1985) Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci USA 82: 4438–4442PubMedCrossRefGoogle Scholar
  13. Campbell IL, Harrison LC (1989) Molecular pathology of type 1 diabetes. Mol Biol Med (in press)Google Scholar
  14. Campbell IL, Wong GHW, Schräder JW, Harrison LC (1985) Interferon-γ enhances the expression of the major histocompatibility class I antigens on mouse pancreatic beta cells. Diabetes 34: 1205–1209PubMedCrossRefGoogle Scholar
  15. Campbell IL, Harrison LC, Ashcroft RG, Jack I (1988a) Reo virus infection enhances expression of class I MHC proteins on human ß-cell and rat RINm5F cell. Diabetes 37: 362–365PubMedCrossRefGoogle Scholar
  16. Campbell IL, Oxbrow L, West J, Harrison LC (1988b) Regulation of MHC protein expression in pancreatic beta cells by interferon-y and tumor necrosis factor-α. Mol Endocrinol 2: 101–107PubMedCrossRefGoogle Scholar
  17. Campbell IL, Iscaro A, Harrison LC (1988c) Interferon-γ and tumor necrosis factor-α: cytotoxicity to murine islets of Langerhans. J Immunol 141: 2325–2329PubMedGoogle Scholar
  18. Campbell IL, Cutri A, Wilkinson D, Boyd AW, Harrison LC (1989a) Intercellular adhesion molecule-1 is induced on endocrine islet cells by cytokines but not by reovirus infection. Proc Natl Acad Sci USA 86: 4282–4286PubMedCrossRefGoogle Scholar
  19. Campbell IL, Cutri A, Wilson A, Harrison LC (1989b) Evidence of interleukin-6 production by and effects on the pancreatic beta cell. J Immunol 143: 1188–1191PubMedGoogle Scholar
  20. Eisenbarth GS (1986) Type 1 diabetes mellitus. A chronic autoimmune disease. N Engl J Med 314:1360–1368PubMedCrossRefGoogle Scholar
  21. Foulis AK, Liddle CN, Farquharson MA, Richmond JA (1986) The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 29: 267–274PubMedCrossRefGoogle Scholar
  22. Foulis AK, Farquharson MA, Hardman R (1987a) Aberrant expression of class II major histocompatibility complex molecules by ß cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30: 333–343PubMedCrossRefGoogle Scholar
  23. Foulis AK, Farquharson MA, Meager A (1987b) Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 2: 1423–1427PubMedCrossRefGoogle Scholar
  24. Garman RD, Jacobs KA, Clark SC, Raulet DH (1987) B-cell stimulating factor 2 (ß2 interferon) functions as a second signal for interleukin-2 production by mature murine T cells. Proc Natl Acad Sci USA 84: 7629–7633PubMedCrossRefGoogle Scholar
  25. Gepts W, Lecompte PM (1981) The pancreatic islets in diabetes. Am J Med 70: 105–115PubMedCrossRefGoogle Scholar
  26. Gleichman H, Bottazzo GF (1987) Islet cell and insulin autoantibodies in diabetes. Immunol Today 8:167–168CrossRefGoogle Scholar
  27. Gorsuch AN, Lister J, Dean BM, Spencer KM, McNally JM, Bottazzo GF, Cudworth AG (1981) Evidence for a long prediabetic period in type 1 (insulin-dependent) diabetes mellitus. Lancet 2:1363–1365PubMedCrossRefGoogle Scholar
  28. Hanahan D (1985) Heritable formation of pancreatic β-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315: 115–122PubMedCrossRefGoogle Scholar
  29. Harrison LC, Kay TWH (1989) Strategies for intervention therapy in type 1 diabetes. In: Andreani D, Kolb H, Pozzilli P (eds) Immunotherapy of type 1 diabetes. Wiley, Chichester, pp 93–110Google Scholar
  30. Harrison LC, Colman PG, Dean B, Baxter R, Martin FIR (1985) Increase in remission rate in newly diagnosed type 1 diabetic subjects treated with azathioprine. Diabetes 34: 1306–1308PubMedCrossRefGoogle Scholar
  31. Harrison LC, Campbell IL, Allison J, Miller JFAP (1989) MHC molecules and beta cell destruction: immune and non-immune mechanisms. Diabetes 38: 815–818PubMedCrossRefGoogle Scholar
  32. Koevary S, Rossini A, Stoller W, Chick W, Williams RM (1983) Passive transfer of diabetes in the BB/W rat. Science 220: 727–728PubMedCrossRefGoogle Scholar
  33. Kolb-Bachofen V, Kolb H (1989) A role for macrophages in the pathogenesis of type 1 diabetes. Autoimmunity 3: 145–155PubMedCrossRefGoogle Scholar
  34. Lafferty KJ, Andrus L, Prowse SJ (1980) Role of lymphokine and antigen in the control of specific T cell responses. Immunol Rev 51: 279–314PubMedCrossRefGoogle Scholar
  35. Lambert ME, Ronai ZA, Weinstein IB, Garrels JI (1989) Enhancement of major histocompatibility class I protein synthesis by DNA damage in cultured human fibroblasts and keratinocytes. Mol Cell Biol 9: 847–850PubMedGoogle Scholar
  36. Leiter EH, Prochazka M, Coleman DL (1987) The non-obese diabetic (NOD) mouse. Am J Pathol 128:380–393PubMedGoogle Scholar
  37. Like A A, Biron CA, Weringer EJ, Byman K, Srocznski E, Guberski DL (1986) Prevention of diabetes in BioBreeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells. J Exp Med 164: 1145–1159PubMedCrossRefGoogle Scholar
  38. Lo D, Burkly LC, Widera G, Cowing C, Flavell RA, Palmiter R, Brinster RL (1988) Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell 53:159–168PubMedCrossRefGoogle Scholar
  39. Lotz M, Jirik F, Kabouridis P, Tsoukas C, Hirano T, Kishimoto T, Carson DA (1988) B cell stimulating factor 2/interleukin-6 is a co-stimulant for human thyrocytes and T lymphocytes. J Exp Med 167: 1253–1258PubMedCrossRefGoogle Scholar
  40. Markmann J, Lo D, Naji A, Palmiter RD, Brinster RL, Heber-Katz E (1988) Antigen presenting function of class II MHC expressing pancreatic beta cells. Nature 336: 476–479PubMedCrossRefGoogle Scholar
  41. Marliss EB, Nakhooda AF, Poussier P (1983) Clinical forms and natural history of the diabetic syndrome and insulin and glucagon secretion in the BB rat. Metabolish 32 [Suppl 1]: 11–16CrossRefGoogle Scholar
  42. Massa PT, Dorries R, ter Meulen V (1986) Viral particles induce la antigen expression on astrocytes. Nature 320: 543–546PubMedCrossRefGoogle Scholar
  43. Morahan G, Allison J, Miller JFAP (1989) Tolerance of class I histocompatibility antigens expressed extrathymically. Nature 339: 622–624PubMedCrossRefGoogle Scholar
  44. Neufeld DS, Platzer M, Da vies TF (1989) Reo virus induction of MHC class II antigen in rat thyroid cells. Endocrinology 124: 543–545PubMedCrossRefGoogle Scholar
  45. Oxbrow L, Campbell IL, Harrison LC (1988) Expression of islet cell differentiation antigens and major histocompatibility antigens on human insulinoma cells. Diabetes Res Clin Prac 5 [Suppl 1]:S140Google Scholar
  46. Palmiter RD (1986) Germ-line transformation of mice. Annu Rev Genet 20: 465–499PubMedCrossRefGoogle Scholar
  47. Palmiter RD, Chen HY, Brinster RL (1982) Differential regulation of metallothionein-thymidine kinase fusion genes in transgenic mice and their offspring. Cell 29: 701–710PubMedCrossRefGoogle Scholar
  48. Parham P (1988) Intolerable secretion in tolerant transgenic mice. Nature 333: 500–503PubMedCrossRefGoogle Scholar
  49. Pujol-Borrell T, Todd I, Mala Doshi D, Gray M, Feldmann M, Bottazzo GF (1986) Differential expression and regulation of MHC products in the endocrine and exocrine cells of the human pancreas. Clin Exp Immunol 65: 128–139PubMedGoogle Scholar
  50. Pujol-Borrell R, Todd I, Doshi M, Bottazzo GF, Sutton R, Gray R, Adolf GR, Feldmann M (1987) HLA class II induction in human islet cells by interferon-gamma plus tumour necrosis factor or lymphotoxin. Nature 326: 304–306PubMedCrossRefGoogle Scholar
  51. Rossini AA, Mordes JP, Handler ES (1988) Perspectives in diabetes: speculations on etiology of diabetes mellitus. Diabetes 37: 257–261PubMedCrossRefGoogle Scholar
  52. Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart TA (1988) Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 52: 773–782PubMedCrossRefGoogle Scholar
  53. Severinsson L, Peterson PA (1984) β2-microglobulin induces intracellular transport of human class I transplantation antigen heavy chains in xenopus laevis oocytes. J Cell Biol 99: 226–232PubMedCrossRefGoogle Scholar
  54. Sibley RK, Sutherland DER, Goetz F, Michael AF (1985) Recurrent diabetes mellitus in the pancreas iso- and allograft. Lab Invest 53: 132–144PubMedGoogle Scholar
  55. Simonsen M, Skjødt K, Crone M, Sanderson A, Fujita-Yamaguchi Y, Due C, Rønne E, Linnet K, Olsson L (1985) Compound receptors in the cell membrane: ruminations from the borderland of immunology and physiology. Prog Allergy 36: 151–176PubMedGoogle Scholar
  56. Srikanta S, Granda OP, Rabizadeh A, Soeldner JS, Eisenbarth GS (1985) First-degree relatives of patients with type 1 diabetes mellitus. Islet cell antibodies and abnormal insulin secretion. N Engl J Med 313:461–464PubMedCrossRefGoogle Scholar
  57. Tarn AC, Smith CP, Spencer KM, Bottazzo GF, Gale EAM (1987) Type 1 (insulin-dependent) diabetes: a disease of slow clinical onset? B Med J 294: 342–345CrossRefGoogle Scholar
  58. Unanue ER, Allen PM (1987) The basis for the immuno-regulatory role of macrophages and other accessory cells. Science 236: 551–559PubMedCrossRefGoogle Scholar
  59. Walker MD, Edlund T, Boulet AM, Rutter WJ (1983) Cell-specific expression controlled by the 5’ flanking region of insulin and chymotrypsin genes. Nature 306: 557–561PubMedCrossRefGoogle Scholar
  60. Wawryk SO, Novotny JR, Wicks IP, Wilkinson D, Maher D, Salvaris E, Welch K, Fecondo J, Boyd AW (1989) The role of the LFA-l/ICAM-1 interaction in human leukocyte homing and adhesion. Immunol Rev 108: 135–161PubMedCrossRefGoogle Scholar
  61. Wicker LS, Miller BJ, Muller Y (1986) Transfer of autoimmune diabetes mellitus with splenocytes from non-obese diabetic (NOD) mice. Diabetes 35: 855–860PubMedCrossRefGoogle Scholar
  62. Wilkie TM, Brinster RL, Palmiter RD (1986) Germline and somatic mosaicism in transgenic mice. Dev Biol 118:9–18PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1990

Authors and Affiliations

  1. 1.The Walter and Eliza Hall Institute of Medical ResearchParkvilleAustralia

Personalised recommendations