Autoimmunity in Diabetes

  • H. Markholst
  • Å Lernmark
Part of the Developments in Medical Virology book series (DIMV, volume 2)


Before the turn of the century, insulin-independent diabetes mellitus (IDDM) was shown to develop in pancreatectomized dogs (1), thus linking the pathogenesis of the syndrome to the pancreas. Later, insulin was extracted from the pancreas and proved to ameliorate most of the diabetic symptoms(2). However, it became clear that insulin was not a cure. In 1965, Gepts reported (3), that the major morphologic alteration in the pancreas at the onset of IDDM was disruption of the architecture of the islets of Langerhans and a loss of cells. The number of B cells was reduced to less than 10% of normal values and in 68% of the pancreata examined, the islets were infiltrated by mononuclear cells. Islet inflammation, insulitis, is therefore thought to be of pathogenetic importance (3–6). Infiltration of the islets of Langerhans has also been associated with experimental diabetes introduced by immunization with insulin (7–8), by multiple injections of low dose streptozotocin (9) or following infection with diabetogenic viruses (10,11).


Major Histocompatibility Complex Islet Cell Islet Cell Antibody Islet Cell Surface Antibody 
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  1. 1.
    Mering J von, Minkowski O: Diabetes Mellitus nach Pankreasextirpation: Arch. Exp. Pathol. Pharmakol. 26: 371–387, 1889.Google Scholar
  2. 2.
    Banting FG, Best CB, Collip JB, Cambell WR, Fletcher AA: Pancreatic extract in the treatment of diabetes mellitus: Canad. Med. Ass. J. 2: 141–146, 1922.Google Scholar
  3. 3.
    Gepts W: Pathologic anatomy of the pancreas in juvenile diabetes mellitus: Diabetes 14: 619–633, 1965.PubMedGoogle Scholar
  4. 4.
    Foulis AK, Stewart JA: The pancreas in recent-onset Type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine acinar tissue: Diabetologia 26: 456–461, 1984.PubMedCrossRefGoogle Scholar
  5. 5.
    Bottazzo GF, Dean BM, McNally JM, McKay EH, Swift PGF, Gamble DR: In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis: New Engl. J. Med. 313: 353–360, 1985.PubMedCrossRefGoogle Scholar
  6. 6.
    Rahier J, Goebbels RM, Henquin JC: Cellular composition of the human diabetic pancreas: Diabetologia 24: 366–371, 1983.PubMedCrossRefGoogle Scholar
  7. 7.
    Lacy PE, Wright PH, Silverman JL: Eosinophilic infiltration in the pancreas of rats injected with anti-insulin serum: Fed. Proc. 22: 60, 1963.Google Scholar
  8. 8.
    Renold AE, Soeldner JS, Steincke J: Immunologic studies with homologous and heterologous pancreatic insulin in the cow: Ciba Foundations Colloquia 15: 122, 1964.Google Scholar
  9. 9.
    Like AA, Rossine AA: Streptozotocin - induced pancreatic insulitis: new model of diabetes mellitus: Science 193: 415–417, 1976.PubMedCrossRefGoogle Scholar
  10. 10.
    Craighead JE: The role of viruses in the pathogenesis of pancreatic disease and diabetes mellitus: Prog. Med. Virol. 19: 161–214, 1975.PubMedGoogle Scholar
  11. 11.
    Notkins AL: Virus-induced diabetes mellitus: Brief review: Arch. Virol. 54: 1–17, 1977.PubMedCrossRefGoogle Scholar
  12. 12.
    Nerup J, Andersen OO, Bendixen G, Egeberg J, Poulsen JE: Anti-pancreatic, cellular hypersensitivity in diabetes mellitus. Antigenic activity of fetal calf pancreas and correlation with clinical type of diabetes: Acta Allergol 28: 223–230, 1973.PubMedGoogle Scholar
  13. 13.
    Bottazzo GF, Florin-Christensen A, Doniach D: Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine defiencies: Lancet ii: 1279–1283, 1974.CrossRefGoogle Scholar
  14. 14.
    Lernmark Å, Freedman ZR, Hofmann C, Rubenstein AH, Steiner DF, Jackson RL, Winter RJ, Traisman HS: Islet cell surface antibodies in juvenile diabetes mellitus: N. Engl. J. Med. 299: 375–380, 1978.PubMedCrossRefGoogle Scholar
  15. 15.
    Platz P, Jackson BK, Morling M, Ryder LP, Svejgaard A, Thomsen M, Christy M, Kromann H, Benn J, Nerup J, Green A, Hauge M: HLA-D and DR-antigens in genetic analysis of insulin-dependent diabetes mellitus: Diabetologia 21: 100–115, 1981.CrossRefGoogle Scholar
  16. 16.
    Barbosa J, Chavers B, Dunsworth T, Michael A: Islet cell antibodies and histocompatibility antigens (HLA) in insulin-dependent diabetes and their first degree relatives: Diabetes 31: 585–588, 1982.PubMedGoogle Scholar
  17. 17.
    Owerbach D, Lernmark Å, Platz P, Ryder LP, Rask L, Peterson PA, Ludvigson J: HLA-D region 3-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals: Nature 303: 815–817, 1983.PubMedCrossRefGoogle Scholar
  18. 18.
    Andreani D, DiMario U, Federlin KF, Heding LG (eds): Immunulogy in Diabetes: Kimpton Medical Publications, London, 1984.Google Scholar
  19. 19.
    Todd I, Bottazzo GF: Laboratory investigation of autoimmune endocrine diseases: Clinics in Immunol, and Allergy 5: 613–638, 1985.Google Scholar
  20. 20.
    Rossini AA, Mordes JP, Like AA: Immunology of insulin-dependent diabetes mellitus: Ann. Rev. Immunol. 3: 289–320, 1985.CrossRefGoogle Scholar
  21. 21.
    Honjo T: Origin of immune diversity: genetic variation and selection: Ann. Rev. Biochem. 54: 803–830, 1985.PubMedCrossRefGoogle Scholar
  22. 22.
    Jerne NK: Towards a network theory of the immune system: Ann. Immunal. (Paris) 125: 373–382, 1974.Google Scholar
  23. 23.
    Wasserman NH, Penn AS, Freimuth PI, Treptow N, Wentzel S, Cleveland WL and Erlanger BF: Anti-idiotypic route to anti-acetylcholine receptor antibodies and experimental myasthenia gravis: Proc. Natl. Acad. Sci. USA 79: 4810–4816, 1982.CrossRefGoogle Scholar
  24. 24.
    McConnell I, Munro A, Waldmann H: Autoimmune Disease in the immune system — a course on the molecular and cellular basis of immunity, 2nd ED: Blackwell Scientific Publ. London, p. 273, 1981.Google Scholar
  25. 25.
    Ayoub EM, Barret DJ, MacLaren NK, Krischer JP: Association of Class II Human Histocompatibility Leykocyte antigens with rheumatic fever: J. Clin. Invest. 77: 2019–2026, 1986.PubMedCrossRefGoogle Scholar
  26. 26.
    Weiss M, Ingbar SH, Winblad S, Kaspar DL: Demonstration of a saturable binding site for thyrotropin in Yersinia enterocolitica: Science 219: 1331–1333, 1983.PubMedCrossRefGoogle Scholar
  27. 27.
    Waldmann TA, Broder S: Polyclonal B-cell activators in the study of the regulation of immunoglobulin synthesis in the human system: Adv. Immunol. 48: 196–200, 1982.Google Scholar
  28. 28.
    Walls KW, Smith JW: Serology of parasite infections: Int. J. Parasitol. 10: 329–340, 1979.Google Scholar
  29. 29.
    Perrin LH, Mackey LJ, Lambert PH: Immunology of malaria: In: Clinical Immunal. Update (Rosse WF, ed) Elsevier, N.Y. pp. 234–264, 1985.Google Scholar
  30. 30.
    Owerbach D, Lernmark Å, Rask L, Peterson PA, Platz P, Svejgaard A: Detection of HLA-D/DR-related DNA polymorphism in HLA-D homozygous typing cells: Proc. Natl. Acad. Sci. USA 80: 3758–3761, 1983.PubMedCrossRefGoogle Scholar
  31. 31.
    Owerbach D, Hägglöff B, Lernmark Å, Holmgren G: Susceptibility to insulin-dependent diabetes defined by restriction enzyme polymorphism of HLA-D region genomic DNA: Diabetes 33: 958–965, 1984.PubMedCrossRefGoogle Scholar
  32. 32.
    Cohen-Haguenauer O, Robbins E, Massart C, Busson M, Deschamps I, Hors J, Lalouel JM, Dausset J, Cohen D: A systematic study of HLA class II-β DNA restriction fragments in insulin-dependent diabetes mellitus: Proc. Natl. Acad. Sci. USA, 82: 3335–3339, 1985.PubMedCrossRefGoogle Scholar
  33. 33.
    Böhme J, Carlsson B, Wallin J, Möller E, Persson B, Peterson PA, Rask L: Only one of each DR specificity is associated with insulin-dependent diabetes: J. Immunol. 137: 941–947, 1986.PubMedGoogle Scholar
  34. 34.
    Michelsen B, Kastern W, Lernmark Å, Owerbach D: Identification of an HLA-DC β-chain related genomic sequence associated with insulin-dependent diabetes: Biomed. Biochim. Acta 44, 1: 33–36, 1985.PubMedGoogle Scholar
  35. 35.
    Michelsen B, Lernmark Å: HLA-DQ gene polymorphism in insulin-dependent diabetes: Proc. of the Satelite Symposium Immunology in Diabetes, Edmonton, in press, 1986.Google Scholar
  36. 36.
    Boss JM, Stromminger JL: Cloning and sequence analysis of the human major histocompatibility complex gene DC-33: Proc. Natl. Acad. Sci. USA. 81: 5199–5203, 1985.CrossRefGoogle Scholar
  37. 37.
    Rotter JI, Rimoin DL: The genetics of the glucose intolerance disorders: Am. J. Med. 70: 116–126, 1981.PubMedCrossRefGoogle Scholar
  38. 38.
    Barnett AH, Eff C, Leslie RDG, Pyke DA: Diabetes in identical twins: a study of 200 pairs: Diabetologia 20: 87–93, 1981.PubMedCrossRefGoogle Scholar
  39. 39.
    Dahlquist G, Blom L, Holmgren G, Hägglöff B, Larson Y, Sterky G, Wall S: The epidemiology of diabetes in Swedish Children 0–14 years — A six-year prospective study. Diabetologia 28: 802–808, 1985.PubMedCrossRefGoogle Scholar
  40. 40.
    Nakhooda AF, Like AA, Chappel CI, Murray FT, Marliss EB: The spontaneously diabetic Wistar rat. Metabolic and morphologic studies: Diabetes 26: 100–112, 1977.PubMedCrossRefGoogle Scholar
  41. 41.
    The juvenile Diabetes Foundation workshop on the spontaneously diabetic BB rat: Its potential for insight into human juvenile diabetes: Marliss EB (ed): Metabolism, 32 suppl 1: 1–166, 1983.Google Scholar
  42. 42.
    Ono SJ, Colle E, Guttmann RD, Fuks A: MHC association of IDDM in the BB rat maps to permissive immune response genes. In “Immunology of diabetes”, Molnar GD, Jaworski MA, eds: Elsevier publ., New York, (in press), 1986.Google Scholar
  43. 43.
    Jackson RA, Buse JB, Rifai R, Pelletier D, Milford EL, Carpenter CB, Eisenbarth GS: Diabetes in BB rats: J. Exp. Med. 159: 1629–1636, 1984.PubMedCrossRefGoogle Scholar
  44. 44.
    Kastern W, Dyrberg T, Schöller J, Kryspin-Sørensen I: Restriction fragment polymorphisms in the major histocompatibility complex of diabetic BB rats: Diabetes 33: 807–809, 1984.PubMedCrossRefGoogle Scholar
  45. 45.
    Björck L, Kryspin-Sørensen I, Dyrberg T, Lernmark Å, Kastern W:A deletion in a rat major histocompatibility complex class I gene is linked to the absence of β2-microglobulin — containing serum molecules: Proc. Natl. Acad. Sci. USA (in press), 1986.Google Scholar
  46. 46.
    Christau B, Kromann H, Ortved Andersen O, Christy M, Bushard K, Armung K: Seasonal and geographical patterns of juvenile-onset insulin-dependent diabetes in Denmark: Diabetologia 13: 281–284, 1977.PubMedCrossRefGoogle Scholar
  47. 47.
    Weringer EJ, Like AA: Immune attack on pancreatic islet transplant in the spontaneously diabetic Biobreeding/Worcester (BB/W) rat is not MHC restricted: J. Immunol. 134: 2383–2386, 1985.PubMedGoogle Scholar
  48. 48.
    Bækkeskov S, Dyrberg T, Lernmark Å: Autoantibodies against a Mr 64000 islet cellprotein precede the onset of spontaneous diabetes: Science 224: 1348–1350, 1984.PubMedCrossRefGoogle Scholar
  49. 49.
    Bækkeskov S, Nielsen JH, Marner B, Bilde T, Ludvigson J, Lernmark Å: Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins: Nature 298: 167–169, 1982.PubMedCrossRefGoogle Scholar
  50. 50.
    Bækkeskov S, Bruining S, Srikanta T, Mandrup-Poulsen T, Beaufort C, Eisenbarth GS, Lernmark Å: Antibodies to a M 64000 human islet cell protein in the prediabetic period of IDDM patients: Ann. N.Y. Acad. Sci. 475: 415–417, 1986.CrossRefGoogle Scholar
  51. 51.
    Kanatsuna T, Bækkeskov S, Lernmark Å, Ludvigson J: Immunoglobulin from insulin-dependent diabetic children inhibits glucose-induced insulin release: Diabetes 32: 520–524, 1983.PubMedCrossRefGoogle Scholar
  52. 52.
    Bækkeskov S, Kanatsuna T, Klareskog L, Nielsen DA, Peterson PA, Rubenstein AH, Steiner DF, Lernmark Å: Expression of major histocompatibility antigens on pancreatic islet cells: Proc. Natl. Acad. Sci. USA 78: 6456–6460, 1981.PubMedCrossRefGoogle Scholar
  53. 53.
    Faustman D, Hauptfeld V, Davie JM, Lacy PE, Schreffler DC: Murine pancreatic-cells express H-2K and H-2D but not Ia antigens: J. Exp. Med. 151: 1563–1568, 1980.PubMedCrossRefGoogle Scholar
  54. 54.
    Dean BM, Walker R, Bone AJ, Baird JD, Cooke A: Pre-diabetes in the spontaneously diabetic BB/E rat: lymphocyte subpopulations in the pancreatic infiltrate and expression of MHC class II molecules in endocrine cells: Diabetologia 28: 464–466, 1985.PubMedCrossRefGoogle Scholar
  55. 55.
    Agger R, Petersen J, Dinesen B, Wiik A, Andersen A: Production and secretion of immunolobulins by in vitro activated lymphocytes: Allergy 37: 179–185, 1982.PubMedCrossRefGoogle Scholar
  56. 56.
    Horita M, Suzuki H, Onodera T, Ginsberg-Fellner F, Fanci AS, Notkins AL: Abnormalities of immunoregulatory T cell subsets in patients with insulin-dependent diabetes mellitus: J. Immunol 129: 1426–1429, 1982.PubMedGoogle Scholar
  57. 57.
    Papadopoulos G, Petersen J, Andersen V, Lernmark Å, Marner B, Nerup J, Binder C: Spontaneous in vitro immunoglobulin secretion at the diagnosis of insulin-dependent diabetes: Acta endocrinol. 105: 521–527, 1984.PubMedGoogle Scholar
  58. 58.
    Madsen OD, Landin-Olsson M, Bille G, Sundkvist G, Lernmark Å, Dahlquist G, Ludvigson J: A two-colour immunofluorescence test with 1 monoclonal human proinsulin antibody improves the assay for islet cell antibodies: Diabetologia 29: 115–118, 1986.PubMedCrossRefGoogle Scholar
  59. 59.
    Gorsuch AN, Spencer KM, Lister J, McNally JM, Dean BM, Bottazzo GF, Cudworth AG: The natural history of type 1 (insulin-dependent) diabetes mellitus: Evidence for a prolonged prediabetic period: Lancet ii: 1363–1365, 1981.CrossRefGoogle Scholar
  60. 60.
    Srikanta S, Gimda O, Eisenbarth G, Soeldner JS: Islet cell antibodies and beta cell function in monozygotic triplets and twins initially discordant for type 1 diabetes mellitus: N. Engl. J. Med. 308: 322–325, 1983.PubMedCrossRefGoogle Scholar
  61. 61.
    Marner B, Agner T, Binder C, Lernmark Å, Nerup J, Mandrup-Poulsen T, Walldorf S: Increased reduction in fasting C-peptide is associated with islet cell antibodies in Type 1 (insulin-dependent) diabetic patients: Diabetologia 28: 875–880, 1985.PubMedCrossRefGoogle Scholar
  62. 62.
    Mandrup-Poulsen T, Nerup J, Stiller CR, Marner B, Bille G, Heinrichs D, Marstell R, Dupse J, Keown PA, Jenner MR, Rodger NW, Wolfe B, Graffenried BV, Binder C: Disappearance and reappearance of islet cell cytoplasmic antibodies in cyclosporin — treated insulin-dependent diabetics: Lancet i: 599–602, 1985.CrossRefGoogle Scholar
  63. 63.
    Winkel van de M, Smets G, Gepts W, Pipeleers DG: Islet cell surface antibodies from insulin-dependent diabetics bind specifically to pancreatic B-cells: J. Clin. Invest. 70: 41–49, 1982.CrossRefGoogle Scholar
  64. 64.
    Huen A, Haneda M, Freedman Z, Lernmark Å, Rubenstein AH: Quantitative determinations of islet cell surface antibodies using 125I-protein A: Diabetes 32: 460–465, 1983.PubMedCrossRefGoogle Scholar
  65. 65.
    Dyrberg T, Poussier P, Nakhooda F, Marliss EB, Lernmark Å: Islet cell surface and lymphocyte antibodies often precede the spontaneous diabetes in the BB rat: Diabetologia 26: 159–165, 1984.PubMedCrossRefGoogle Scholar
  66. 66.
    Pipeleers D, Winkel van de M, Dyrberg T, Lernmark Å: The spontaneously diabetic BB rats have age-dependent B cell specific surface antibodies at the time of onset: (Submitted for publication), 1986.Google Scholar
  67. 67.
    Martin DR, Logothetopoulos J: Complement-fixing islet cell antibodies in the spontaneously diabetic BB rat: Diabetes 33: 93–96, 1984.PubMedCrossRefGoogle Scholar
  68. 68.
    Dobersen MJ, Scharff JE, Ginsberg-Fellner FBS, Notkins AL: Cytotoxic autoantibodies to beta cells in the serum of patients with insulin-dependent diabetes mellitus: N. Engl. J. Med. 303: 1493–1498, 1980.PubMedCrossRefGoogle Scholar
  69. 69.
    Hartling SG, Lindgren F, Dahlquist G, Thalme B, Möller E, Efendic S, Persson B, Binder C: Proinsulin — a possible subclinical indicator for B-cell dysfunction: Diabetologie 29: 202 A, 1986.Google Scholar
  70. 70.
    Lernmark Å, Kanatsuna T, Rubenstein AH, Steiner DF: Detection and possible functional influence of antibodies directed against pancreatic islet cell surface: Adv. Exp. Med. Biol. 119: 157–163, 1979.PubMedGoogle Scholar
  71. 71.
    Like AA, Appel MC, Rossini AA: Autoantibodies in the BB/W rat: Diabetes 31: 313–318, 1982.CrossRefGoogle Scholar
  72. 72.
    Elders M, MacLaren NK: Identification of profound peripheral T lymphocyte immunodeficiencies in the spontaneously diabetic BB rat: J. Immunol. 130: 1723–1731, 1983.Google Scholar
  73. 73.
    Contreas G, Lernmark Å, Mathiasen ER, Deckert T: Immune complexes in insulin-dependent diabetes: Biomed. Acta 44, 1: 129–132, 1985.Google Scholar
  74. 74.
    Boitard C, Debray-Sachs M, Pouplard A, Assan R, Hamburger J: Lymphocytes from diabetics suppress insulin release in vitro: Diabetologia 21: 41–46, 1981.PubMedGoogle Scholar
  75. 75.
    Sensi M, Pozzilli P, Gorsuch AN, Bottazzo GF, Cudworth AG: Increased killer cell activity in insulin-dependent (Type 1) diabetes mellitus: Diabetologia 20: 106–109, 1981.PubMedCrossRefGoogle Scholar
  76. 76.
    Wilson RG, Anderson J, Shenton BK, White MD, Taylor RMR, Proud G: Natural killer cells in insulin-dependent diabetes mellitus: Br. Med. J. 293: 244, 1986.CrossRefGoogle Scholar
  77. 77.
    MacKay P, Boulton A, Rabinovitch A: Lymphoid cells of BB/W diabetic rats are cytotoxic to islet beta cells in vitro: Diabetes 34: 706–709, 1985.PubMedCrossRefGoogle Scholar
  78. 78.
    Koevary S, Rossini AA, Stollen W, Chick WL: Passive transfer of diabetes in the BB/W rat: Science 220: 727–728, 1983.PubMedCrossRefGoogle Scholar
  79. 79.
    Handler ES, Mordes JP, Seals J, Koevary S, Like AA, Nakano K, Rossini AA: Diabetes in the Biobreeding/Worcester rat. Induction and acceleration by spleen cell-conditioned media: J. Clin. Invest. 76: 1692–1694, 1985.PubMedCrossRefGoogle Scholar
  80. 80.
    Mordes JP, Handler ES, Like AA, Nakano K, Rossini AA: Irradiated lymphocytes do not adoptively transfer diabetes or prevent spontaneous disease in the BB/W rat: Metabolism 35: 552–554, 1986.PubMedCrossRefGoogle Scholar
  81. 81.
    Feutren G, Assan R, Karsenty G, Du Rostu H, Sirmai J, Papoz L, Vialettes B, Vexiau P, Rodier M, Lallemand A, Bach J-F: Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset: Lancet ii: 119–123, 1986.CrossRefGoogle Scholar
  82. 82.
    Jaworski MA, Honore L, Jewell LD, Metha JG, McGuire-Clark P, Schouls JJ, Yap WY: Cyclosporin prophylaxis induces long-term prevention of diabetes, and inhibits lymphocytic infiltration in multiple target tissues in the high-risk BB rat: Diabetes Research 3: 1–6, 1986.PubMedGoogle Scholar
  83. 83.
    Stiller CR, Laupacis A, Keown PA, Gardell C, Dupre J, Thibert P, Wall W: Cyclosporin: Action, pharmacokinetics and effect in the BB rat model: Metabolism 32 suppl. 1: 69–72, 1983.CrossRefGoogle Scholar
  84. 84.
    Like AA, Kislauskis E, Williams RM, Rossini AA: Neonatal thymectomy prevents diabetes mellitus in the BB/W rat: Science 216: 644–646, 1982.PubMedCrossRefGoogle Scholar
  85. 85.
    Naji A, Silvers WK, Bellgrau D, Anderson AO, Plotkin S, Barker CF: Prevention of diabetes in rats by bone marrow transplantation: Ann. Surg. 194: 328–338, 1981.Google Scholar
  86. 86.
    Brayman KL, Markmann J, Silvers WK, Barker CF, Naji A: Neonatal bone marrow transplantation and the prevention of diabetes in BB rats: Immunology of Diabetes, Edmonton, Canada: S39, 1986.Google Scholar
  87. 87.
    Rossini AA, Faustman D, Woda BA, Like AA, Szymanski I, Mordes J: Lymphocyte transfusions prevent diabetes in the Bio-Breeding/Worcester rat J. Clin. Invest. 74: 39–46, 1984.PubMedCrossRefGoogle Scholar

Copyright information

© Martinus Nijhoff Publishing, Boston 1987

Authors and Affiliations

  • H. Markholst
    • 1
  • Å Lernmark
    • 1
  1. 1.Hagedorn Research LaboratoryGentofteDenmark

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