The Role of Class II Molecules in Development of Insulin-Dependent Diabetes Mellitus in Mice, Rats and Humans

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


The major histocompatibility complex (MHC) represents a genetic risk factor for most known autoimmune diseases. More and more evidence implicates the class II region of the MHC in susceptibility in diseases such as insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis, and pemphigus vulgaris (for review see TODD et al. 1988). The gene products of this region are highly polymorphic and each individual expresses one or two alleles at each locus. Their function is the regulation of the immune response by binding fragments of proteins (peptides) with many different sequences and presenting them to the T cell receptor (TCR) which is expressed by T lymphocytes. Due to the polymorphism of class II molecules, each molecule binds a specific set of peptides (BUUS et al. 1987). These molecules are selective, but relatively nonspecific peptide receptors expressed on B lymphocytes, macrophages, and other cells collectively termed antigen presenting cells (APC’c) (UNANUE and ALLEN 1987). T cells expressing the surface marker CD4 represent the predominant type of T cells which interact with class II expressing cells. After formation of the trimolecular complex between TCR, MHC class II antigen, and peptide, T cell proliferation and differentiation is initiated.


Major Histocompatibility Complex Major Histocompatibility Complex Class Experimental Allergic Encephalomyelitis Major Histocompatibility Complex Molecule Major Histocompatibility Complex Antigen 
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  1. Acha-Orbea H, McDevitt HO (1986) The cDNA-sequence of the I-A major histocompatibility antigens of the non-obese diabetic mouse. In: Jaworsky MA, Molnar GD, Rajotte RV, Singh B (eds) Excerpta Medica international congress series: immunology of diabetes. Excerpta Medica, Amsterdam, pp 73–78Google Scholar
  2. Acha-Orbea H, McDevitt HO (1987) The first external domain of the non-obese diabetic mouse class II Ap chain is unique. Proc Natl Acad Sci USA 84: 2435–2439PubMedCrossRefGoogle Scholar
  3. Acha-Orbea H, Mitchell DJ, Timmermann L, Wraith DC, Tausch GS, Waldor MK, Zamvil SS, McDevit HO, Steinman L (1988) Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54: 263–273PubMedCrossRefGoogle Scholar
  4. Bell JI, Todd JA, McDevitt HO (1989) The molecular basis of HLA disease associations. In: Harris H, Hirschhanl K (eds) Advances of human genetics. Vol. 18 Plenum Press New York, pp 1–35CrossRefGoogle Scholar
  5. Bendelac A, Carnaud C, Boitard C, Bach JF (1987) Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirements for both L3T4 + and Lyt-2 + T cells. J Exp Med 166: 823–832PubMedCrossRefGoogle Scholar
  6. Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen JH, Dinarello CA, Svenson M (1986) Cytotoxicity of human pl7 interleukin-1 for pancreatic islets of langerhans. Science 232: 1545–1547PubMedCrossRefGoogle Scholar
  7. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC (1987a) The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329:512–518PubMedCrossRefGoogle Scholar
  8. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC (1987b) Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329: 506–512PubMedCrossRefGoogle Scholar
  9. Boitard C, Michie S, Serrurier P, Butcher GW, Larkins AP, McDevitt HO (1985) In vivo prevention of thyroid and pancreatic autoimmunity in the BB rat by antibody to class II major histocompatibility complex gene products. Proc Natl Acad Sci USA 82: 6627–6631PubMedCrossRefGoogle Scholar
  10. Boitard C, Bendelac A, Richard MF, Carnaud C, Bach JF (1988) Prevention of diabetes in non obese diabetic mice by abti-I-A monoclonal antibodies; transfer of protection by splenic T cells. Proc Natl Acad Sci USA 85: 9719–9723PubMedCrossRefGoogle Scholar
  11. Bougeneres PF, Carel JC, Castaneo L, Boitard C, Gardin JP, Laandais P, Hors J, Mihatsch MJ, Paillard M, Chaussain JL, Bach JF (1988) Factors associated with early remission of type I diabetes in children treated with cyclosporine. N Engl J Med 318: 663–670CrossRefGoogle Scholar
  12. Brown JH, Jardetzky T, Saper MA, Samraoui B, Bjorkman PJ, Wiley DC (1988) A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature 332: 845–850PubMedCrossRefGoogle Scholar
  13. Buus S, Sette A, Grey HM (1987) The interaction between protein derived immunogenic peptides and la. Immunol Rev 98: 115–141PubMedCrossRefGoogle Scholar
  14. Campbell IL, Iscaro A, Harrison LC (1988) Ifn-γ and tumor necrosis factor-α. Cytotoxicity to murine islets of langerhans. J Immunol 141: 2325–2329PubMedGoogle Scholar
  15. Carnaud C, Bendelac A, Boitard C, Bach JF (1988) Failure to induce neonatal tolerance in the autoimmune nonobese diabetic (NOD) mouse strain. Diabetes 37: 1AGoogle Scholar
  16. Carroll MC, Katzman P, Alicot EM, Koller BH, Geraghty DE, Orr HT, Strominger SL, Spies T (1987) Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes. Proc Natl Acad Sci USA 84: 8535–8539PubMedCrossRefGoogle Scholar
  17. Chao NJ, Timmerman L, McDevitt HO, Jacob CO (1989) Molecular characterization of MHC class II antigens domain) in the BB diabetes prone and resistant rat. Immunogenetics 29: 231–234PubMedCrossRefGoogle Scholar
  18. Colle E, Gurrmann RD, Seemayer T (1981) Spontaneous diabetes mellitus syndrome in the rat I. Association with the major histocompatibility complex. J Exp Med 154: 1237–1242PubMedCrossRefGoogle Scholar
  19. Colle E, Guttmann RD, Seemayer TA, Michel F (1983) Spontaneous diabetes mellitus syndrome in the rat IV. Immunogenetic interactions of MHC and non-MHC components in the syndrome. Metabolism 32: 54–61PubMedCrossRefGoogle Scholar
  20. Colle E, Ono SJ, Fuks A, Guttmann RD, Seemayer TA (1988) Association of susceptibility to spontaneous diabetes in rat with genes of major histocompatibility complex. Diabetes 37: 1438–1443PubMedCrossRefGoogle Scholar
  21. Engelman EG, Sonnenfeld G, Dauphinee M, Greenspan JS, Talal J, Mevitt HO (1981) Treatment of NZB/NZW F1 mice with mycobacterium bovis strain BCG or type II interferon preparations accelerates autoimmune disease. Arthritis Rheum 24: 1396CrossRefGoogle Scholar
  22. Festenstein H, Oilier B (1987) Cellulasr typing and functional heterogeneity of MHC-encoded products. Br Med Bull 43: 122–155PubMedGoogle Scholar
  23. Greiner DL, Handler ES, Nakano K, Mordes JP, Rossini AA (1986) Absence of the RT-6 T-cell subset in diabetes prone BB/W rats. J Immunol 136: 148–151PubMedGoogle Scholar
  24. Greiner DL, Mordes JP, Handler ES, Angelillo M, Nakamura N, Rossini A A (1987) Depletion of RT6.1 + T lymphocytes induces diabetes in resistant biobreeding/Worcester (BB/W) rats. J Exp Med 166:461–475PubMedCrossRefGoogle Scholar
  25. Guillet JG, Lai MZ, Briner TJ, Buus S, Sette A, Grey HM, Smith JA, Gefter ML (1987) Immunological self, non-self discrimination. Science 235: 865–870PubMedCrossRefGoogle Scholar
  26. Hattori M, Buse JB, Jackson RA, Glimcher L, Dorf ME, Minami M, Makinö S, Moriwaki K, Kuzuya H, Imura H, Strauss WM, Scidman JG, Eisenbarth GS (1986) The NOD mouse: recessive diabetogenic gene in the major histocompatibility complex. Science 231: 733–735PubMedCrossRefGoogle Scholar
  27. Hirayama K, Matsushita S, Kihashi I, Iuchi M, Ohta N, Sasazuki T (1987) HLA-DQ is epistatic to HLA-DR in controlling the immune response to schistosomal antigen in humans. Nature 327:426–430PubMedCrossRefGoogle Scholar
  28. Jackson RA, Buse JB, Rifai R, Pelletier D, Milford EL, Carpenter CB, Eisenbarth GS, Williams M (1984) Two genes required for fiabetes in BB rats. Evidence from cyclical intercrosses and backcrosses. J Exp Med 159: 1629–1636PubMedCrossRefGoogle Scholar
  29. Jacob CO, Mevitt HO (1988) Tumor necrosis factor-a in murine autoimmune “lupus” nephritis. Nature 331:356–358PubMedCrossRefGoogle Scholar
  30. Jacob CO, Aiso S, Michie SA, Mevitt HO, Acha-Orbea H (1990) Tumor necrosis factor in autoimmunity: protective effect on non-obese diabetic mice. Proc Natl Acad Sci US, in pressGoogle Scholar
  31. Kappler JW, Roehm N, Marrack P (1987) T cell tolerance by clonal elimination in the thymus. Cell 49: 273–280PubMedCrossRefGoogle Scholar
  32. Kelley VE, Gaulton GN, Hattori M, Ikegami H, Eisenbarth G, Strom TB (1988) Anti-interleukin 2 receptor antibody suppresses murine diabetic insulitis and lupus nephritis. J Immunol 140: 59–61PubMedGoogle Scholar
  33. Kisielow P, Teh HS, Bluethmann H, vooehmer H (1988) Positive selection of antigen apecific T cells by restricting MHC molecules. Nature 335: 730–733PubMedCrossRefGoogle Scholar
  34. Koevary S, Rossini A A, Stoller W, Chick WL, Williams RM (1983) Passive transfer of diabetes in the BB/W rat. Science 220: 727–728PubMedCrossRefGoogle Scholar
  35. Like AA, Guberski DL, Butler L (1986) Diabetic Biobreeding/Worcester (BB/Wor) rats need not to be lymphopenic. J Immunol 136: 3254–3258PubMedGoogle Scholar
  36. Lorenz RG, Allen P (1988) Direct evidence for functional self-protein/la-molecule complexes in vivo. Proc Natl Acad Sci USA 85: 5220–5223PubMedCrossRefGoogle Scholar
  37. Massa PT, Teeulen V, Fontana A (1987) Hyperinducibility of la antigen on astrocytes correlates with satrain-specific susceptibility to experimental allergic encephalomyelitis. Proc Natl Acad Sci USA 84: 4219–4223PubMedCrossRefGoogle Scholar
  38. Miller BJ, Appel MC, O’Neill JJ, Wicker LS (1988) Both the Lyt-2 + and L3T4 + T-cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J Immunol 140: 52–58PubMedGoogle Scholar
  39. Moeller, G (ed) (1985) Molecular genetics of class I and II MHC antigens. Immunol Rev 84 and 85Google Scholar
  40. Mordes JP, Gallina DL, Handler ES, Greiner DL, Nakamura N, Pelletier A, Rossini AA (1987) Transfusions enriched for W3/25 + helper/inducer T lymphocytes prevent spontaneous diabetes in the BB/W rat. Diabetologia 30: 22–26PubMedCrossRefGoogle Scholar
  41. Morel PA, Dorman JS, Todd JA, Mevitt HO, Trucco M (1988) Aspartic acid at position 57 of the HLA-DQ ß chain protects against type I diabetes: a family story. Proc Natl Acad Sci USA 85: 8111–8115PubMedCrossRefGoogle Scholar
  42. Mueller U, Jongeneel CV, Nedospasov SA, Fisher Lindahl K, Steinmetz M (1987) Tumor necrosis factor lymphotoxin genes map close to H-2D in the mouse major histocompatibility complex. Nature 325: 265–267CrossRefGoogle Scholar
  43. Naparstek Y, Baur K, Reis MD, Breitman L, Mak TW, Schwartz RS, Madaio MP (1988) Autoreactive T cells with a typical MHC restiction for MLR-lpr/lpr mice: forbidden clones revisited J Mol Cell Immunol 4: 35–43Google Scholar
  44. Nishimoto H, Kikutani H, Yamamura KI, Kishimoto T (1987) Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. Nature 328: 432–434PubMedCrossRefGoogle Scholar
  45. Parsitol HS, Hirsch RL, Haley AS, Johnson KP (1986) Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1: 893–894Google Scholar
  46. Prochazka M, Leiter EH, Serreze DV, Coleman DL (1987) Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science 237: 286–289PubMedCrossRefGoogle Scholar
  47. Pujol-Borrell R, Todd, Doslin M, Botazzo GF, Sutton R, Gray D, Adolf GR, Feldmann M (1987) HLA class II induction tumor islet cells by interferon-y plus tumor necrosis factor or lymphotoxin. Nature 326: 304–307PubMedCrossRefGoogle Scholar
  48. Rossini A A, Mordes JP, Like A A (1985) Immunology of insulin-dependent diabetes mellitus. Annu Rev Immunol 3: 289PubMedCrossRefGoogle Scholar
  49. Rotter JI, Landau EM (1984) Measuring the genetic contribution of a single locus to a multilocus disease. Clin Genet 26: 529–542PubMedCrossRefGoogle Scholar
  50. Segiescu D, Cerutti I, Efthymiou E, Kahan A, Chany C (1979) Adverse effects of interferon treatment on the life span of NZB mice. Biomed Exp 31: 48Google Scholar
  51. Serreze DV, Leiter E (1988) Defective activation of T suppressor cell function in nonobese diabetic mice. Potential relation to cytokine deficiencies. J Immunol 140: 3801–3807PubMedGoogle Scholar
  52. Shizuru J A, Taylor-Edwards C, Banks BA, Gregory AK, Fathman CG (1988) Immunotherapy of the nonobese diabetic mouse: treatment with an antibody to T-helper lymphocytes. Science 240: 659–662PubMedCrossRefGoogle Scholar
  53. Todd J A, Bell JI, Mevitt HO (1987) HLA-DQ gene contributes to susceptibility and resistance to insulin-dependant diabetes mellitus. Nature 329: 599–604PubMedCrossRefGoogle Scholar
  54. Todd JA, Acha-Orbea H, Bell JI, Chao N, Fronek Z, Jacob CO, Mermott M, Sinha AA, Timmerman L, Steinman L, Mevitt HO (1988) A molecular basis for MHC class II-associated autoimmunity. Science 240: 1003–1009PubMedCrossRefGoogle Scholar
  55. Todd J A, Mijovic C, Fletcher J, Jenkins D, Bradwell AR, Barnett AH (1989) Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature 338: 587–589PubMedCrossRefGoogle Scholar
  56. Unanue ER, Allen PM (1987) The basis for the immunoregulatory role of macrophages and other accessory cells. Science 236: 551–557PubMedCrossRefGoogle Scholar
  57. Wicker LS, Miller BJ (1988) The MHC-linked gene in the NOD mouse is not absolutely recessive. Diabetes 37: 10AGoogle Scholar
  58. Wicker LS, Miller BJ, Coker LZ, Mally SE, Scott S, Mullen Y, Appel MC (1987) Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse. J Exp Med 165: 1639–1654PubMedCrossRefGoogle Scholar
  59. Woda BA, Biron CA (1986) Natural killer cell number and function in the spontaneously diabetic BB/W rat. J Immunol 137: 1860–1866PubMedGoogle Scholar
  60. Zinkernagel RM, Dohertly PC (1979) 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 27: 52–177Google Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1990

Authors and Affiliations

  1. 1.Dept. of Medical Microbiology, Immunology and MedicineStanford University School of MedicineStanfordUSA
  2. 2.Ludwig Institute for Cancer ResearchEpalinges S. LausanneSwitzerland

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