1932

Abstract

This paper reviews the presentation of peptides by major histocompatibility complex (MHC) class II molecules in the autoimmune diabetes of the nonobese diabetic (NOD) mouse. Islets of Langerhans contain antigen-presenting cells that capture the proteins and peptides of the beta cells' secretory granules. Peptides bound to I-Ag7, the unique MHC class II molecule of NOD mice, are presented in islets and in pancreatic lymph nodes. The various beta cell–derived peptides interact with selected CD4 T cells to cause inflammation and beta cell demise. Many autoreactive T cells are found in NOD mice, but not all have a major role in the initiation of the autoimmune process. I emphasize here the evidence pointing to insulin autoreactivity as a seminal component in the diabetogenic process.

[Erratum, Closure]

An erratum has been published for this article:
Antigen Presentation in the Autoimmune Diabetes of the NOD Mouse
Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-032712-095941
2014-03-21
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/immunol/32/1/annurev-immunol-032712-095941.html?itemId=/content/journals/10.1146/annurev-immunol-032712-095941&mimeType=html&fmt=ahah

Literature Cited

  1. Kikutani H, Makino S. 1.  1992. The murine autoimmune diabetes model: NOD and related strains. Adv. Immunol. 51:285–322 [Google Scholar]
  2. Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K. 2.  et al. 1980. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu 29:1–13 [Google Scholar]
  3. Miyazaki T, Uno M, Uehira M, Kikutani T, Kimoto M. 3.  et al. 1990. Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice. Nature 345:722–24 [Google Scholar]
  4. Miyazaki A, Hanafusa T, Yamada K, Miyagawa J, Fujino-Kurihara J. 4.  et al. 1985. Predominance of T lymphocytes in pancreatic islets and spleen of pre-diabetic non-obese diabetic (NOD) mice: a longitudinal study. Clin. Exp. Immunol. 60:622–30 [Google Scholar]
  5. Hattori M, Buse JB, Jackson RA, Glimcher L, Dorf ME. 5.  et al. 1986. The NOD mouse: recessive diabetogenic gene in the major histocompatibility complex. Science 231:733–35 [Google Scholar]
  6. Todd JA, Bell JI, McDevitt HO. 6.  1987. HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329:599–604 [Google Scholar]
  7. Acha-Orbea H, McDevitt HO. 7.  1987. The first external domain of the nonobese diabetic mouse class II I-A β chain is unique. Proc. Natl. Acad. Sci. USA 84:2435–39 [Google Scholar]
  8. Corper AL, Stratmann T, Apostolopoulos V, Scott CA, Garcia KC. 8.  et al. 2000. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 288:505–11 [Google Scholar]
  9. Latek RR, Suri A, Petzold SJ, Nelson CA, Kanagawa O. 9.  et al. 2000. Structural basis of peptide binding and presentation by the type 1 diabetes-associated MHC class II molecule of NOD mice. Immunity 12:699–710 [Google Scholar]
  10. Lee KH, Wucherpfenning KW, Wiley DC. 10.  2001. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat. Immunol. 2:501–7 [Google Scholar]
  11. Suri A, Walters JJ, Gross M, Unanue ER. 11.  2005. Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity. J. Clin. Investig. 115:2268–76 [Google Scholar]
  12. Chang KY, Unanue ER. 12.  2009. Prediction of HLA-DQ8β cell peptidome using a computational program and its relationship to autoreactive T cells. Int. Immunol. 21:705–13 [Google Scholar]
  13. Godkin A, Friede T, Davenport M, Stevanovic S, Willis A. 13.  et al. 1997. Use of eluted peptide sequence data to identify the binding characteristics of peptides to the insulin-dependent diabetes susceptibility allele HLA-DQ8 (DQ 3.2). Int. Immunol. 9:905–11 [Google Scholar]
  14. Reich EP, von Grafenstein H, Barlow A, Swenson KE, Williams K, Janeway CA Jr. 14.  1994. Self peptides isolated from MHC glycoproteins of non-obese diabetic mice. J. Immunol. 152:2279–88 [Google Scholar]
  15. Calderon B, Unanue ER. 15.  2012. Antigen presentation events in autoimmune diabetes. Curr. Opin. Immunol. 24:119–28 [Google Scholar]
  16. Mohan JF, Unanue ER. 16.  2012. Unconventional recognition of peptides by T cells and the implications for autoimmunity. Nat. Rev. Immunol. 12:721–28 [Google Scholar]
  17. Calderon B, Suri A, Miller M, Unanue ER. 17.  2008. Dendritic cells in islets of Langerhans constitutively present β cell-derived peptides bound to their class II MHC molecules. Proc. Natl. Acad. Sci. USA 105:6121–26 [Google Scholar]
  18. Melli K, Friedman RS, Martin AE, Finger EB, Miao G. 18.  et al. 2009. Amplification of autoimmune response through induction of dendritic cell maturation in inflamed tissues. J. Immunol. 182:2590–600 [Google Scholar]
  19. Ginhoux F, Liu K, Heift J, Bogunovic M, Greter M. 19.  et al. 2009. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206:3115–30 [Google Scholar]
  20. Yin N, Xu J, Ginhoux F, Randolph GJ, Merad M. 20.  et al. 2012. Functional specialization of islet dendritic cell subsets. J. Immunol. 188:4921–30 [Google Scholar]
  21. Wynn TA, Chawla A, Pollard JW. 21.  2013. Macrophage biology in development, homeostasis and disease. Nature 496:445–55 [Google Scholar]
  22. Banaei-Bouchareb L, Gouon-Evans V, Samara-Boustani D, Castellotti MC, Czernichow P. 22.  et al. 2004. Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. J. Leukoc. Biol. 76:359–67 [Google Scholar]
  23. Mohan JF, Levisetti MG, Calderon B, Herzog JW, Petzold SJ, Unanue ER. 23.  2010. Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat. Immunol. 11:350–54 [Google Scholar]
  24. Gagnerault MC, Luan JJ, Lotton C, Lepault F. 24.  2001. Pancreatic lymph nodes are required for priming of β cell reactive T cells in NOD mice. J. Exp. Med. 196:369–77 [Google Scholar]
  25. Levisetti MG, Suri A, Frederick K, Unanue ER. 25.  2004. Absence of lymph nodes in NOD mice treated with lymphotoxin-β receptor immunoglobulin protects from diabetes. Diabetes 53:3115–19 [Google Scholar]
  26. Qu P, Ji RC, Kato S. 26.  2003. Histochemical analysis of lymphatic endothelial cells in the pancreas of non-obese diabetic mice. J. Anat. 203:523–30 [Google Scholar]
  27. Lennon GP, Bettini M, Burton AR, Vincent E, Arnold PY. 27.  et al. 2009. T cell islet accumulation in type 1 diabetes is a tightly regulated, cell-autonomous event. Immunity 31:643–53 [Google Scholar]
  28. Calderon B, Carrero JA, Miller MJ, Unanue ER. 28.  2011. Cellular and molecular events in the localization of diabetogenic T cells to islets of Langerhans. Proc. Natl. Acad. Sci. USA 108:1561–66 [Google Scholar]
  29. Calderon B, Carrero JA, Miller MJ, Unanue ER. 29.  2011. Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response. Proc. Natl. Acad. Sci. USA 108:567–72 [Google Scholar]
  30. Katz JD, Wang B, Haskins K, Benoist C, Mathis D. 30.  1993. Following a diabetogenic T cell receptor from genesis through pathogenesis. Cell 74:1089–100 [Google Scholar]
  31. Bendelac A, Carnaud C, Boitard C, Bach JF. 31.  1987. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates: requirement for both L3T4+ and Lyt2+ T cells. J. Exp. Med. 166:823–32 [Google Scholar]
  32. Miller BJ, Appel MC, O'Neil JJ, Wicker LS. 32.  1988. Both the Lyt2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J. Immunol. 140:52–58 [Google Scholar]
  33. Wang Y, Hao L, Gill RG, Lafferty KJ. 33.  1987. Autoimmune diabetes in NOD mouse is L3T4 T-lymphocyte dependent. Diabetes 36:535–38 [Google Scholar]
  34. Thivolet C, Bendelac A, Bedossa P, Bach JF, Carnaud C. 34.  1991. CD8+ T cell homing to the pancreas in the nonobese diabetic mouse is CD4+ T cell-dependent. J. Immunol. 146:85–88 [Google Scholar]
  35. Christianson SW, Shultz LD, Leiter EH. 35.  1993. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes 42:44–55 [Google Scholar]
  36. Haskins K, Portas M, Bradley B, Wegmann D, Lafferty K. 36.  1988. T-lymphocyte clone specific for pancreatic islet antigen. Diabetes 37:1444–48 [Google Scholar]
  37. Haskins K, Portas M, Bergman B, Lafferty K, Bradley B. 37.  1989. Pancreatic islet-specific T-cell clones from nonobese diabetic mice. Proc. Natl. Acad. Sci. USA 86:8000–4 [Google Scholar]
  38. Haskins K, McDuffie M. 38.  1990. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 249:1433–36 [Google Scholar]
  39. Haskins K. 39.  2005. Pathogenic T-cell clones in autoimmune diabetes: more lessons from the NOD mouse. Adv. Immunol. 87:123–62 [Google Scholar]
  40. Peterson JD, Pike B, McDuffie M, Haskins K. 40.  1994. Islet-specific T-cell clones transfer diabetes to nonobese diabetic (NOD) F1 mice. J. Immunol. 153:2800–6 [Google Scholar]
  41. Shimizu J, Carrasco-Marin E, Kanagawa O, Unanue ER. 41.  1995. Relationship between beta cell injury and antigen presentation in NOD mice. J. Immunol. 155:4095–99 [Google Scholar]
  42. Suri A, Walters JJ, Rohrs HW, Gross ML, Unanue ER. 42.  2008. First signature of islet β-cell-derived naturally processed peptides selected by diabetogenic class II MHC molecules. J. Immunol. 180:3849–56 [Google Scholar]
  43. Wegmann DR, Eisenbarth GS. 43.  2000. It's insulin. J. Autoimmun. 15:286–91 [Google Scholar]
  44. Wright PH. 44.  1961. The production of experimental diabetes by means of insulin antibodies. Am. J. Med. 31:892–900 [Google Scholar]
  45. Gregor WH, Martin JM, Williamson JR, Lacy PE, Kipnis DM. 45.  1963. A study of the diabetic syndrome produced in rats by anti-insulin serum. Diabetes 12:73–81 [Google Scholar]
  46. Frikke MJ, Gingerich RL, Stranahan PD, Carter G, Bauman AK. 46.  et al. 1974. Distribution of injected insulin and insulin-antibody complexes in normal and insulin-immunized animals. Diabetologia 10:345–51 [Google Scholar]
  47. Lacy PE, Wright PH. 47.  1965. Allergic interstitial pancreatitis in rats injected with guinea pig anti-insulin serum. Diabetes 14:634–42 [Google Scholar]
  48. Renold AE, Soeldner S, Steinke J. 48.  1964. Immunologic studies with homologous and heterologous pancreatic insulin in the cow. Aetiology of Diabetes Mellitus and Its Complications MP Cameron, M O'Connor 122–39 Chichester, UK: Wiley [Google Scholar]
  49. Renold AE, Steinke J, Soeldner JS, Antoniades HN, Smith RE. 49.  1966. Immunological response to the prolonged administration of heterologous and homologous insulin in cattle. J. Clin. Investig. 45:702–13 [Google Scholar]
  50. Toreson WE, Lee JC, Grodsky GM. 50.  1968. The histopathology of immune diabetes in the rabbit. Am. J. Pathol. 52:1099–115 [Google Scholar]
  51. Lee JC, Grodsky GM, Caplan J, Craw L. 51.  1969. Experimental immune diabetes in the rabbit. Light, fluorescence, and electron microscopic studies. Am. J. Pathol. 57:597–616 [Google Scholar]
  52. Klöppel G, Altenähr E, Freytag G, Jansen FK. 52.  1974. Immune insulitis and manifest diabetes mellitus. Studies on the course of immune insulitis and the induction of diabetes mellitus in rabbits immunized with insulin. Virchows Arch. A 364:333–46 [Google Scholar]
  53. Wright PH, Gingerich RL, King S, Lacy PE. 53.  1976. Pancreatic lesions induced in rabbits and guinea-pigs with pancreatic antigens. Clin. Exp. Immunol. 25:328–37 [Google Scholar]
  54. Zhang L, Nakayama M, Eisenbarth GS. 54.  2008. Insulin as an autoantigen in NOD/human diabetes. Curr. Opin. Immunol. 20:111–18 [Google Scholar]
  55. Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M. 55.  et al. 1996. Prediction of type I diabetes mellitus in first degree relatives using a combination of insulin, glutamic acid decarboxylase and ICA512bdc/IA-2 autoantibodies. Diabetes 45:926–33 [Google Scholar]
  56. Pietropaolo M, Towns R, Eisenbarth GS. 56.  2012. Humoral autoimmunity in type 1 diabetes: prediction, significance, and detection of distinct disease subtypes. Cold Spring Harb. Perspect. Med. 2:1–18 [Google Scholar]
  57. Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J. 57.  et al. 2013. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. J. Am. Med. Assoc. 309:2473–79 [Google Scholar]
  58. Naquet P, Ellis J, Tibensky D, Kenshole A, Singh B. 58.  et al. 1988. T cell autoreactivity to insulin in diabetic and related non-diabetic individuals. J. Immunol. 140:2569–78 [Google Scholar]
  59. Alleva DG, Crowe PD, Jin L, Kwok WW, Ling N. 59.  et al. 2001. A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin. J. Clin. Investig. 107:173–80 [Google Scholar]
  60. Semana G, Gausling R, Jackson RA, Hafler DA. 60.  1999. T cell autoreactivity to proinsulin epitopes in diabetic patients and healthy subjects. J. Autoimmun. 12:259–67 [Google Scholar]
  61. Ellis T, Jodoin E, Ottendorfer E, Salisbury P, She JX. 61.  et al. 1999. Cellular immune responses against proinsulin. No evidence for enhanced reactivity in individuals with IDDM. Diabetes 48:299–303 [Google Scholar]
  62. Durinovic-Belló I, Boehm BO, Ziegler AG. 62.  2002. Predominantly recognized proinsulin T helper cell epitopes in individuals with and without islet cell autoimmunity. J. Autoimmun. 18:55–66 [Google Scholar]
  63. Brezar V, Carel JC, Boitard C, Mallone R. 63.  2011. Beyond the hormone: insulin as an autoimmune target in type 1 diabetes. Endocr. Rev. 32:623–69 [Google Scholar]
  64. Erlich H, Valdes AM, Noble J, Carlson JA, Varney M. 64.  et al. 2008. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the Type 1 Diabetes Genetics Consortium families. Diabetes 57:1084–92 [Google Scholar]
  65. Noble JA, Erlich HA. 65.  2012. Genetics of type 1 diabetes. Cold Spring Harb. Perspect. Med. 2:a007732 [Google Scholar]
  66. Julier C, Akolkar B, Concannon P, Morahan G, Nierras C, Pugliese A. 66.  2009. The Type I Diabetes Genetics Consortium ‘Rapid Response’ family-based candidate gene study: strategy, genes selection, and main outcome. Genes Immun. 10:Suppl. 1S121–27 [Google Scholar]
  67. Morahan G, Mehta M, James I, Chen WM, Akolkar B. 67.  et al. 2011. Tests for genetic interactions in type 1 diabetes: linkage and stratification analyses of 4,422 affected sib-pairs. Diabetes 60:1030–40 [Google Scholar]
  68. Polychronakos C, Li Q. 68.  2011. Understanding type 1 diabetes through genetics: advances and prospects. Nat. Rev. Genet. 12:781–92 [Google Scholar]
  69. Bell GI, Karam JH, Rutter WJ. 69.  1981. Polymorphic DNA region adjacent to the 5′ end of the human insulin gene. Proc. Natl. Acad. Sci. USA 78:5759–63 [Google Scholar]
  70. Bell GI, Horita S, Karam JH. 70.  1984. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176–83 [Google Scholar]
  71. Rotwein P, Yokoyama S, Didier DK, Chirgwin JM. 71.  1986. Genetic analysis of the hypervariable region flanking the human insulin gene. Am. J. Hum. Genet. 39:291–99 [Google Scholar]
  72. Lucassen AM, Julier C, Beressi JP, Boitard C, Froguel P. 72.  et al. 1993. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat. Genet. 4:305–10 [Google Scholar]
  73. Lucassen AM, Screaton GR, Julier C, Elliott TJ, Lathrop M, Bell JI. 73.  1995. Regulation of insulin gene expression by the IDDM associated, insulin locus haplotype. Hum. Mol. Genet. 4:501–6 [Google Scholar]
  74. Bennett ST, Lucassen AM, Gough SC, Powell EE, Undlien DE. 74.  et al. 1995. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat. Genet. 9:284–92 [Google Scholar]
  75. Barratt BJ, Payne F, Lowe CE, Hermann R, Healy BC. 75.  et al. 2004. Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53:1884–89 [Google Scholar]
  76. Pugliese A, Zeller M, Fernandez A Jr, Zalcberg LJ, Bartlet RJ. 76.  et al. 1997. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat. Genet. 15:293–97 [Google Scholar]
  77. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R. 77.  et al. 1997. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genet. 15:289–92 [Google Scholar]
  78. Husebye ES, Anderson MS. 78.  2010. Autoimmune polyendocrine syndromes: clues to type 1 diabetes pathogenesis. Immunity 32:479–87 [Google Scholar]
  79. Taubert R, Schwendemann J, Kyewski B. 79.  2007. Highly variable expression of tissue-restricted self-antigens in human thymus: implications for self-tolerance and autoimmunity. Eur. J. Immunol. 37:838–48 [Google Scholar]
  80. Klein L, Hinterberger M, Wirnsberger G, Kyewski B. 80.  2009. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat. Rev. Immunol. 9:833–44 [Google Scholar]
  81. Melanitou E, Devendra D, Liu E, Miao D, Eisenbarth GS. 81.  2004. Early and quantal (by litter) expression of insulin autoantibodies in the nonobese diabetic mice predict early diabetes onset. J. Immunol. 173:6603–10 [Google Scholar]
  82. Yu L, Robles DT, Abiru N, Kaur P, Rewers M. 82.  et al. 2000. Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes. Proc. Natl. Acad. Sci. USA 97:1701–6 [Google Scholar]
  83. Wentworth BM, Schaefer IM, Villa-Komaroff L, Chirgwin JM. 83.  1986. Characterization of the two nonallelic genes encoding mouse preproinsulin. J. Mol. Evol. 23:305–12 [Google Scholar]
  84. Heath VL, Moore NC, Parnell SM, Mason DW. 84.  1998. Intrathymic expression of genes involved in organic specific autoimmune disease. J. Autoimmun. 11:309–18 [Google Scholar]
  85. Chentoufi AA, Polychronakos C. 85.  2002. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance. Diabetes 51:1383–90 [Google Scholar]
  86. Thebault-Baumont K, Dubois-Laforgue D, Krief P, Briand J-P, Halbout P. 86.  et al. 2003. Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J. Clin. Investig. 111:851–57 [Google Scholar]
  87. Brimnes MK, Jensen T, Jørgensen TN, Michelsen BK, Troelsen J, Werdelin O. 87.  2002. Low expression of insulin in the thymus of non-obese diabetic mice. J. Autoimm. 19:203–13 [Google Scholar]
  88. Nakayama M, Babaya N, Miao D, Sikora K, Elliott JF, Eisenbarth GS. 88.  2005. Thymic expression of mutated B16: A preproinsulin messenger RNA does not reverse acceleration of NOD diabetes associated with insulin 2 (thymic expression insulin) knockout. J. Autoimmun. 25:193–98 [Google Scholar]
  89. Moriyama H, Abiru N, Paronen J, Sikora K, Liu E. 89.  et al. 2003. Evidence for a primary islet autoantigen (preproinsulin1) for insulitis and diabetes in the nonobese diabetic mouse. Proc. Natl. Acad. Sci. USA 100:10376–81 [Google Scholar]
  90. Babaya N, Nakayama M, Moriyama H, Gianani R, Still T. 90.  et al. 2006. A new model of insulin-deficient diabetes: male NOD mice with a single copy of Ins1 and no Ins2. Diabetologia 49:1222–28 [Google Scholar]
  91. Byersdorfer CA, Schweitzer GG, Unanue ER. 91.  2005. Diabetes is predicted by the beta cell level of autoantigen. J. Immunol. 175:4347–54 [Google Scholar]
  92. Faideau B, Briand JP, Lotton C, Tardivel I, Halbout P. 92.  et al. 2004. Expression of preproinsulin-2 gene shapes the immune response to preproinsulin normal mice. J. Immunol. 172:25–33 [Google Scholar]
  93. Fan Y, Rudert WA, Grupillo M, He J, Sisino G, Trucco M. 93.  2009. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28:2812–24 [Google Scholar]
  94. Smith KM, Olson DC, Hirose R, Hanahan D. 94.  1997. Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance. Int. Immunol. 9:1355–65 [Google Scholar]
  95. Derbinski J, Schulte A, Kyewski B, Klein L. 95.  2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2:1032–39 [Google Scholar]
  96. Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S. 96.  2005. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202:33–45 [Google Scholar]
  97. Pinto S, Michel C, Schmidt-Glenewinkel H, Harder N, Rohr K. 97.  et al. 2013. Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity. Proc. Natl. Acad. Sci. USA 110:E3497–505 [Google Scholar]
  98. French MB, Allison J, Cram DS, Thomas HE, Dempsey-Collier M. 98.  et al. 1997. Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes 46:34–39 [Google Scholar]
  99. Jaeckel E, Lipes MA, von Boehmer H. 99.  2004. Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nat. Immunol. 5:1028–35 [Google Scholar]
  100. Muir A, Peck A, Clare-Salzler M, Song YH, Cornelius J. 100.  et al. 1995. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-γ transcriptor. J. Clin. Investig. 95:628–34 [Google Scholar]
  101. Coon B, An LL, Whitton JL, von Herrath MG. 101.  1999. DNA immunization to prevent autoimmune diabetes. J. Clin. Investig. 104:189–94 [Google Scholar]
  102. Homann D, Dyrberg T, Petersen J, Oldstone MB, von Herrath MG. 102.  1999. Insulin in oral immune “tolerance”: a one-amino acid change in the B chain makes the difference. J. Immunol. 163:1833–38 [Google Scholar]
  103. Bot A, Smith D, Bot S, Hughes A, Wolfe T. 103.  et al. 2001. Plasmid vaccination with insulin B chain prevents autoimmune diabetes in nonobese diabetic mice. J. Immunol. 167:2950–55 [Google Scholar]
  104. Abiru N, Maniatis AK, Yu L, Miao D, Moriyama H. 104.  et al. 2001. Peptide and major histocompatibility complex-specific breaking of humoral tolerance to native insulin with the B9-23 peptide in diabetes-prone and normal mice. Diabetes 50:1274–81 [Google Scholar]
  105. Alleva DG, Gaur A, Jin L, Wegmann D, Gottlieb PA. 105.  et al. 2002. Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9–23) peptide. Diabetes 51:2126–34 [Google Scholar]
  106. Aspord C, Thivolet C. 106.  2002. Nasal administration of CTB-insulin induces active tolerance against autoimmune diabetes in non-obese diabetic (NOD) mice. Clin. Exp. Immunol. 130:204–11 [Google Scholar]
  107. Steptoe RJ, Ritchie JM, Harrison LC. 107.  2003. Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes. J. Clin. Investig. 111:1357–63 [Google Scholar]
  108. Every AL, Kramer DR, Mannering SI, Lew AM, Harrison LC. 108.  2006. Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes. J. Immunol. 176:4608–15 [Google Scholar]
  109. Gong Z, Jin Y, Zhang Y. 109.  2007. Suppression of diabetes in non-obese diabetic (NOD) mice by oral administration of a cholera toxin B subunit-insulin B chain fusion protein vaccine produced in silkworm. Vaccine 25:1444–51 [Google Scholar]
  110. Kobayashi M, Abiru N, Arakawa T, Fukushima K, Zhou H. 110.  2007. Altered B:9–23 insulin, when administered intranasally with cholera toxin adjuvant, suppresses the expression of insulin autoantibodies and prevents diabetes. J. Immunol. 179:2082–88 [Google Scholar]
  111. Daniel C, Weigmann B, Bronson R, von Boehmer H. 111.  2011. Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope. J. Exp. Med. 208:2501–10 [Google Scholar]
  112. Suri A, Shimizu J, Katz JD, Sakaguchi S, Unanue ER, Kanagawa O. 112.  2004. Regulation of autoimmune diabetes by non-islet-specific T cells—a role for the glucocorticoid-induced TNF receptor. Eur. J. Immunol. 34:447–54 [Google Scholar]
  113. Wegmann DR, Norbury-Glaser M, Daniel D. 113.  1994. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur. J. Immunol. 24:1853–57 [Google Scholar]
  114. Wegmann DR, Gill RG, Norbury-Glaser M, Schloot N, Daniel D. 114.  1994. Analysis of the spontaneous T cell response to insulin in NOD mice. J. Autoimmun. 7:833–43 [Google Scholar]
  115. Daniel D, Gill RG, Schloot N, Wegmann D. 115.  1995. Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur. J. Immunol. 25:1056–62 [Google Scholar]
  116. Chen W, Bergerot I, Elliott JF, Harrison LC, Abiru N. 116.  et al. 2001. Evidence that a peptide spanning the B-C junction of proinsulin is an early autoantigen epitope in the pathogenesis of type 1 diabetes. J. Immunol. 167:4926–35 [Google Scholar]
  117. Crawford M, Daniel D, Wegmann D, Yang H, Gill RG. 117.  1997. Autoimmune islet damage mediated by insulin-specific T cells. Transplant. Proc. 29:758–59 [Google Scholar]
  118. Abiru N, Wegmann D, Kawasaki E, Gottlieb P, Simone E, Eisenbarth GS. 118.  2000. Dual overlapping peptides recognized by insulin peptide B:9–23 T cell receptor AV13S3 T cell clones of the NOD mouse. J. Autoimmun. 14:231–37 [Google Scholar]
  119. Halbout P, Briand J-P, Becourt C, Muller S, Boitard C. 119.  2002. T cell response to preproinsulin I and II in the nonobese diabetic mouse. J. Immunol. 169:2436–43 [Google Scholar]
  120. Levisetti MG, Suri A, Petzold SJ, Unanue ER. 120.  2007. The insulin-specific T cells of NOD mice recognize a weak MHC-binding segment in more than one register. J. Immunol. 178:6051–57 [Google Scholar]
  121. Crawford F, Stadinski B, Jin N, Michels A, Nakayama M. 121.  et al. 2011. Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse. Proc. Natl. Acad. Sci. USA 108:16729–34 [Google Scholar]
  122. Mohan JF, Petzold SJ, Unanue ER. 122.  2011. Register shifting of an autoimmune insulin peptide-MHC II complex allows for the escape of diabetogenic T cells from negative selection. J. Exp. Med. 208:2375–83 [Google Scholar]
  123. Heath VL, Hutchings P, Fowell DJ, Cooke A, Mason DW. 123.  1999. Peptides derived from murine insulin are diabetogenic in both rats and mice, but the disease-inducing epitopes are different: evidence against a common environmental cross-reactivity in the pathogenicity of type 1 diabetes. Diabetes 48:2157–65 [Google Scholar]
  124. Stadinski BD, Zhang L, Crawford F, Marrack P, Eisenbarth GS, Kappler JW. 124.  2010. Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. Proc. Natl. Acad. Sci. USA 107:10978–83 [Google Scholar]
  125. Wong FS, Karttunen J, Dumont C, Wen L, Visintin I. 125.  et al. 1999. Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat. Med. 5:1026–31 [Google Scholar]
/content/journals/10.1146/annurev-immunol-032712-095941
Loading
/content/journals/10.1146/annurev-immunol-032712-095941
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error