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T Cell Epitopes and Post-Translationally Modified Epitopes in Type 1 Diabetes

  • Pathogenesis of Type 1 Diabetes (A Pugliese, Section Editor)
  • Published:
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Abstract

Type 1 diabetes (T1D) is an autoimmune disease in which progressive loss of self-tolerance, evidenced by accumulation of auto-antibodies and auto-reactive T cells that recognize diverse self-proteins, leads to immune-mediated destruction of pancreatic beta cells and loss of insulin secretion. In this review, we discuss antigens and epitopes in T1D and the role that post-translational modifications play in circumventing tolerance mechanisms and increasing antigenic diversity. Emerging data suggest that, analogous to other autoimmune diseases such as rheumatoid arthritis and celiac disease, enzymatically modified epitopes are preferentially recognized in T1D. Modifying enzymes such as peptidyl deiminases and tissue transglutaminase are activated in response to beta cell stress, providing a mechanistic link between post-translational modification and interactions with the environment. Although studies of such responses in the at-risk population have been limited, current data suggests that breakdown in tolerance through post-translational modification represents an important checkpoint in the development of T1D.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Eisenbarth GS. Type I, diabetes mellitus. A chronic autoimmune disease. N Engl J Med. 1986;314:1360–8.

    Article  CAS  PubMed  Google Scholar 

  2. Noble JA, Valdes AM. Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diab Rep. 2011;11:533–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Achenbach P, Bonifacio E, Koczwara K, Ziegler AG. Natural history of type 1 diabetes. Diabetes. 2005;54 Suppl 2:S25–31.

    Article  CAS  PubMed  Google Scholar 

  4. Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172:5967–72.

    Article  CAS  PubMed  Google Scholar 

  5. TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study. Ann N Y Acad Sci. 2008;1150:1–13.

    Article  PubMed Central  Google Scholar 

  6. Yu L, Rewers M, Gianani R, Kawasaki E, Zhang Y, Verge C, et al. Antiislet autoantibodies usually develop sequentially rather than simultaneously. J Clin Endocrinol Metab. 1996;81:4264–7.

    CAS  PubMed  Google Scholar 

  7. Orban T, Sosenko JM, Cuthbertson D, Krischer JP, Skyler JS, Jackson R, et al. Pancreatic islet autoantibodies as predictors of type 1 diabetes in the diabetes prevention trial-type 1. Diabetes Care. 2009;32:2269–74.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Arif S, Moore F, Marks K, Bouckenooghe T, Dayan CM, Planas R, et al. Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated β-cell death. Diabetes. 2011;60:2112–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Tree TI, Lawson J, Edwards H, Skowera A, Arif S, Roep BO, et al. Naturally arising human CD4 T-cells that recognize islet autoantigens and secrete interleukin-10 regulate proinflammatory T-cell responses via linked suppression. Diabetes. 2010;59:1451–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Schloot NC, Willemen S, Duinkerken G, de Vries RR, Roep BO. Cloned T cells from a recent onset IDDM patient reactive with insulin B-chain. J Autoimmun. 1998;11:169–75.

    Article  CAS  PubMed  Google Scholar 

  11. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature. 2005;435:220–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Yang J, Chow IT, Sosinowski T, Torres-Chinn N, Greenbaum CJ, James EA, et al. Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes. Proc Natl Acad Sci U S A. 2014;111:14840–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Durinovic-Belló I, Schlosser M, Riedl M, Maisel N, Rosinger S, Kalbacher H, et al. Pro- and anti-inflammatory cytokine production by autoimmune T cells against preproinsulin in HLA-DRB1*04, DQ8 type 1 diabetes. Diabetologia. 2004;47:439–50.

    Article  PubMed  Google Scholar 

  14. Yang J, Danke N, Roti M, Huston L, Greenbaum C, Pihoker C, et al. CD4+ T cells from type 1 diabetic and healthy subjects exhibit different thresholds of activation to a naturally processed proinsulin epitope. J Autoimmun. 2008;31:30–41.

    Article  PubMed  Google Scholar 

  15. Skowera A, Ellis RJ, Varela-Calviño R, Arif S, Huang GC, Van-Krinks C, et al. CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope. J Clin Invest. 2008;118:3390–402.

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Mannering SI, Harrison LC, Williamson NA, Morris JS, Thearle DJ, Jensen KP, et al. The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J Exp Med. 2005;202:1191–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Lohmann T, Leslie RD, Hawa M, Geysen M, Rodda S, Londei M. Immunodominant epitopes of glutamic acid decarboxylase 65 and 67 in insulin-dependent diabetes mellitus. Lancet. 1994;343:1607–8.

    Article  CAS  PubMed  Google Scholar 

  18. Reijonen H, Mallone R, Heninger AK, Laughlin EM, Kochik SA, Falk B, et al. GAD65-specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes. Diabetes. 2004;53:1987–94.

    Article  CAS  PubMed  Google Scholar 

  19. Yang J, James EA, Sanda S, Greenbaum C, Kwok WW. CD4+ T cells recognize diverse epitopes within GAD65: implications for repertoire development and diabetes monitoring. Immunology. 2013;138:269–79.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. McGinty JW, Chow IT, Greenbaum C, Odegard J, Kwok WW, James EA. Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes. Diabetes. 2014;63:3033–40. Demonstrates by direct ex vivo tetramer analysis and T cell cloning that citrullinated and deamidated self-epitopes are preferentially recognized by T cells from subjects with type 1 diabetes. Documents elevated frequencies and a Th1-like phenotype for T cells that recognize modified epitopes.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Herzog BA, Ott PA, Dittrich MT, Quast S, Karulin AY, Kalbacher H, et al. Increased in vivo frequency of IA-2 peptide-reactive IFNgamma+/IL-4-T cells in type 1 diabetic subjects. J Autoimmun. 2004;23:45–54.

    Article  CAS  PubMed  Google Scholar 

  22. Peakman M, Stevens EJ, Lohmann T, Narendran P, Dromey J, Alexander A, et al. Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4. J Clin Invest. 1999;104:1449–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Scotto M, Afonso G, Larger E, Raverdy C, Lemonnier FA, Carel JC, et al. Zinc transporter (ZnT)8(186–194) is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients. Diabetologia. 2012;55:2026–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Dang M, Rockell J, Wagner R, Wenzlau JM, Yu L, Hutton JC, et al. Human type 1 diabetes is associated with T cell autoimmunity to zinc transporter 8. J Immunol. 2011;186:6056–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Lieberman SM, Evans AM, Han B, Takaki T, Vinnitskaya Y, Caldwell JA, et al. Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci U S A. 2003;100:8384–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Mukherjee R, Wagar D, Stephens TA, Lee-Chan E, Singh B. Identification of CD4+ T cell-specific epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein: a novel beta cell autoantigen in type 1 diabetes. J Immunol. 2005;174:5306–15.

    Article  CAS  PubMed  Google Scholar 

  27. Yang J, Danke NA, Berger D, Reichstetter S, Reijonen H, Greenbaum C, et al. Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects. J Immunol. 2006;176:2781–9.

    Article  CAS  PubMed  Google Scholar 

  28. Stadinski BD, Delong T, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, et al. Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol. 2010;11:225–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Li Y, Zhou L, Li Y, Zhang J, Guo B, Meng G, et al. Identification of autoreactive CD8(+) T cell responses targeting chromogranin A in humanized NOD mice and type 1 diabetes patients. Clin Immunol. 2015;159:63–71.

    Article  CAS  PubMed  Google Scholar 

  30. Delong T, Baker RL, He J, Barbour G, Bradley B, Haskins K. Diabetogenic T-cell clones recognize an altered peptide of chromogranin A. Diabetes. 2012;61:3239–46. Provides the first evidence that antigen cross linking alters the antigenicity of self-peptides.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Gottlieb PA, Delong T, Baker RL, Fitzgerald-Miller L, Wagner R, Cook G, et al. Chromogranin A is a T cell antigen in human type 1 diabetes. J Autoimmun. 2014;50:38–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Delong T, Baker RL, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, et al. Islet amyloid polypeptide is a target antigen for diabetogenic CD4+ T cells. Diabetes. 2011;60:2325–30. Presents the first direct evidence that IAPP is targeted by CD4+ T cells in autoimmune diabetes.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Wicker LS, Chen SL, Nepom GT, Elliott JF, Freed DC, Bansal A, et al. Naturally processed T cell epitopes from human glutamic acid decarboxylase identified using mice transgenic for the type 1 diabetes-associated human MHC class II allele, DRB1*0401. J Clin Invest. 1996;98:2597–603.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Yu L, Dong F, Miao D, Fouts AR, Wenzlau JM, Steck AK. Proinsulin/Insulin autoantibodies measured with electrochemiluminescent assay are the earliest indicator of prediabetic islet autoimmunity. Diabetes Care. 2013;36:2266–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Sabbah E, Savola K, Kulmala P, Veijola R, Vähäsalo P, Karjalainen J, et al. Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The childhood diabetes in Finland study group. J Clin Endocrinol Metab. 1999;84:1534–9.

    CAS  PubMed  Google Scholar 

  36. Hinman RM, Cambier JC. Role of B lymphocytes in the pathogenesis of type 1 diabetes. Curr Diab Rep. 2014;14:543–8. Useful review discussing potential roles for B cells in the initiation of autoimmune diabetes.

    Article  PubMed  Google Scholar 

  37. Sette A, Moutaftsi M, Moyron-Quiroz J, McCausland MM, Davies DH, Johnston RJ, et al. Selective CD4+ T cell help for antibody responses to a large viral pathogen: deterministic linkage of specificities. Immunity. 2008;28:847–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TW, Atkinson MA, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med. 2012;209:51–60. Presents direct visual evidence that autoreactive T cells infiltrate the pancreatic islets of patients with type 1 diabetes.

  39. Noble JA, Valdes AM, Varney MD, Carlson JA, Moonsamy P, Fear AL, et al. Type 1 diabetes genetics consortium. HLA class I and genetic susceptibility to type 1 diabetes: results from the type 1 diabetes genetics consortium. Diabetes. 2010;59:2972–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Rammensee H, Bachmann J, Emmerich NP, Bachor OA, Stevanović S. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics. 1999;50:213–9.

    Article  CAS  PubMed  Google Scholar 

  41. Peters B, Tong W, Sidney J, Sette A, Weng Z. Examining the independent binding assumption for binding of peptide epitopes to MHC-I molecules. Bioinformatics. 2003;19:1765–72.

    Article  CAS  PubMed  Google Scholar 

  42. Knight RR, Dolton G, Kronenberg-Versteeg D, Eichmann M, Zhao M, Huang GC, et al. A distinct immunogenic region of glutamic acid decarboxylase 65 is naturally processed and presented by human islet cells to cytotoxic CD8 T cells. Clin Exp Immunol. 2015;179:100–7.

    Article  CAS  PubMed  Google Scholar 

  43. Velthuis JH, Unger WW, Abreu JR, Duinkerken G, Franken K, Peakman M, et al. Simultaneous detection of circulating autoreactive CD8+ T-cells specific for different islet cell-associated epitopes using combinatorial MHC multimers. Diabetes. 2010;59:1721–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Skowera A, Ladell K, McLaren JE, Dolton G, Matthews KK, Gostick E, et al. β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure. Diabetes. 2015;64:916–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Trudeau JD, Kelly-Smith C, Verchere CB, Elliott JF, Dutz JP, Finegood DT, et al. Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood. J Clin Invest. 2003;111:217–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Doyle HA, Mamula MJ. Autoantigenesis: the evolution of protein modifications in autoimmune disease. Curr Opin Immunol. 2012;24:112–8. Useful review summarizing current knowledge about a variety of post-translational modifications that modulate immune recognition of self-proteins.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. van de Wal Y, Kooy Y, Van Veelen VP, Pena S, Mearin L, Papadopoulos G, et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol. 1998;161:1585–8.

    PubMed  Google Scholar 

  48. Hovhannisyan Z, Weiss A, Martin A, Wiesner M, Tollefsen S, Yoshida K, et al. The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature. 2008;56:534–8.

    Article  Google Scholar 

  49. Snir O, Widhe M, von Spee C, Lindberg J, Padyukov L, Lundberg K, et al. Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles. Ann Rheum Dis. 2009;68:736–43.

    Article  CAS  PubMed  Google Scholar 

  50. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48:2741–9.

    Article  PubMed  Google Scholar 

  51. Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 2013;210:2569–82. Presents a crystal structure that depicts the altered presentation of citrullinated peptides by HLA-DR4 proteins.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol. 2003;171:538–41.

    Article  CAS  PubMed  Google Scholar 

  53. James EA, Moustakas AK, Bui J, Papadopoulos GK, Bondinas G, Buckner JH, et al. HLA-DR1001 presents “altered-self” peptides derived from joint-associated proteins by accepting citrulline in three of its binding pockets. Arthritis Rheum. 2010;62:2909–18.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. James EA, Rieck M, Pieper J, Gebe JA, Yue BB, Tatum M, et al. Arthritis Rheum. 2014;66:1712–22. Presents the first direct ex vivo analysis of citrulline specific T cells in arthritis. Documents a Th1 memory phenotype for these T cells and presents cross-sectional data indicating that the frequency of citrulline-specific T cells varies with disease duration and treatment.

    Article  CAS  Google Scholar 

  55. Gyorgy B, Toth E, Tarcsa E, Falus A, Buzas EI. Citrullination: a posttranslational modification in health and disease. Int J Biochem Cell Biol. 2006;38:1662–77.

    Article  PubMed  Google Scholar 

  56. van Lummel M, Duinkerken G, van Veelen PA, de Ru A, Cordfunke R, Zaldumbide A, et al. Posttranslational modification of HLA-DQ binding islet autoantigens in type 1 diabetes. Diabetes. 2014;63:237–47. Provides mass spectrometry data verifying that deamidated peptides can be eluted from human antigen presenting cells. Further demonstrates that such peptides are recognized by T cells in the context of DQ8 and the DQ2/8 transdimer.

    Article  PubMed  Google Scholar 

  57. Rondas D, Crèvecoeur I, D’Hertog W, Ferreira GB, Staes A, Garg AD, et al. Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes. Diabetes. 2015;64:573–86. Demonstrates selective recognition of citrullinated GRP78 by antibodies and autoreactive T cells in NOD mice.

    Article  CAS  PubMed  Google Scholar 

  58. Patel SD, Cope AP, Congia M, Chen TT, Kim E, Fugger L, et al. Identification of immunodominant T cell epitopes of human glutamic acid decarboxylase 65 by using HLA-DR(alpha1*0101, beta1*0401) transgenic mice. Proc Natl Acad Sci U S A. 1997;94:8082–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Gianfrani C, Troncone R, Mugione P, Cosentini E, De Pascale M, Faruolo C, et al. Celiac disease association with CD8+ T cell responses: identification of a novel gliadin-derived HLA-A2-restricted epitope. J Immunol. 2003;170:2719–26.

    Article  CAS  PubMed  Google Scholar 

  60. Lesort M, Attanavanich K, Zhang J, Johnson GV. Distinct nuclear localization and activity of tissue transglutaminase. J Biol Chem. 1998;273:11991–4.

    Article  CAS  PubMed  Google Scholar 

  61. Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. BioEssays. 2003;25:1106–18.

    Article  CAS  PubMed  Google Scholar 

  62. Lentile R, Caccamo D, Griffin M. Tissue transglutaminase and the stress response. Amino Acids. 2007;33:385–94.

    Article  Google Scholar 

  63. Kojima S, Kuo TF, Tatsukawa H, Hirose S. Induction of cross-linking and silencing of Sp1 by transglutaminase during liver injury in ASH and NASH Via different ER stress pathways. Dig Dis. 2010;28:715–21.

    Article  PubMed  Google Scholar 

  64. Kuo TF, Tatsukawa H, Matsuura T, Nagatsuma K, Hirose S, Kojima S. Free fatty acids induce transglutaminase 2-dependent apoptosis in hepatocytes via ER stress-stimulated PERK pathways. J Cell Physiol. 2012;227:1130–7.

    Article  CAS  PubMed  Google Scholar 

  65. Takahara H, Okamoto H, Sugawara K. Calcium-dependent properties of peptidylarginine deiminase from rabbit skeletal muscle. Agric Biol Chem. 1986;50:2899–904.

    Article  CAS  Google Scholar 

  66. Verhaar R, Drukarch B, Bol JG, Jongenelen CA, Musters RJ, Wilhelmus MM. Increase in endoplasmic reticulum-associated tissue transglutaminase and enzymatic activation in a cellular model of Parkinson’s disease. Neurobiol Dis. 2012;45:839–50.

    Article  CAS  PubMed  Google Scholar 

  67. Wilhelmus MM, Verhaar R, Andringa G, Bol JG, Cras P, Shan L, et al. Presence of tissue transglutaminase in granular endoplasmic reticulum is characteristic of melanized neurons in Parkinson’s disease brain. Brain Pathol. 2011;21:130–9.

    Article  CAS  PubMed  Google Scholar 

  68. Araki E, Oyadomari S, Mori M. Endoplasmic reticulum stress and diabetes mellitus. Intern Med. 2003;42:7–14.

    Article  PubMed  Google Scholar 

  69. Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008;29:42–61.

    Article  CAS  PubMed  Google Scholar 

  70. Fonseca SG, Lipson KL, Urano F. Endoplasmic reticulum stress signaling in pancreatic beta-cells. Antioxid Redox Signal. 2007;9:2335–44.

    Article  CAS  PubMed  Google Scholar 

  71. Kim MK, Kim HS, Lee IK, Park KG. Endoplasmic reticulum stress and insulin biosynthesis: a review. Exp Diabetes Res. 2012;509437.

  72. Lipson KL, Fonseca SG, Ishigaki S, Nguyen LX, Foss E, Bortell R, et al. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 2006;4:245–54.

    Article  CAS  PubMed  Google Scholar 

  73. Lipson KL, Fonseca SG, Urano F. Endoplasmic reticulum stress-induced apoptosis and auto-immunity in diabetes. Curr Mol Med. 2006;6:71–7.

    Article  CAS  PubMed  Google Scholar 

  74. Ortsater H, Sjoholm A. A busy cell—endoplasmic reticulum stress in the pancreatic beta-cell. Mol Cell Endocrinol. 2007;277:1–5.

    Article  PubMed  Google Scholar 

  75. Teodoro T, Odisho T, Sidorova E, Volchuk A. Pancreatic beta-cells depend on basal expression of active ATF6alpha-p50 for cell survival even under nonstress conditions. Am J Physiol Cell Physiol. 2012;302:C992–1003.

    Article  CAS  PubMed  Google Scholar 

  76. Volchuk A, Ron D. The endoplasmic reticulum stress response in the pancreatic beta-cell. Diabetes Obes Metab. 2010;12:48–57.

    Article  CAS  PubMed  Google Scholar 

  77. Wu J, Kaufman RJ. From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ. 2006;13:374–84.

    Article  CAS  PubMed  Google Scholar 

  78. Scheuner D, Kaufman RJ. The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev. 2008;29:317–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Iwawaki T, Akai R, Kohno K, Miura M. A transgenic mouse model for monitoring endoplasmic reticulum stress. Nat Med. 2004;10:98–102.

    Article  CAS  PubMed  Google Scholar 

  80. van Kuppeveld FJ, de Jong AS, Melchers WJ, Willems PH. Enterovirus protein 2B Po(U)Res out the calcium: a viral strategy to survive? Trends Microbiol. 2005;13:41–4.

    Article  PubMed  Google Scholar 

  81. van Kuppeveld FJ, Hoenderop JG, Smeets RL, Willems PH, Dijkman HB, Galama JM, et al. Coxsackievirus protein 2B modifies endoplasmic reticulum membrane and plasma membrane permeability and facilitates virus release. EMBO J. 1997;16:3519–32.

    Article  PubMed Central  PubMed  Google Scholar 

  82. van Kuppeveld FJ, Melchers WJ, Willems PH, Gadella Jr TW. Homomultimerization of the coxsackievirus 2B protein in living cells visualized by fluorescence resonance energy transfer microscopy. J Virol. 2002;76:9446–56.

    Article  PubMed Central  PubMed  Google Scholar 

  83. Sandler S, Swenne I. Streptozotocin, but not alloxan, induces DNA repair synthesis in mouse pancreatic islets in vitro. Diabetologia. 1983;25:444–7.

    Article  CAS  PubMed  Google Scholar 

  84. Bedoya FJ, Solano F, Lucas M. N-monomethyl-arginine and nicotinamide prevent streptozotocin-induced double strand DNA break formation in pancreatic rat islets. Experientia. 1996;52:344–7.

    Article  CAS  PubMed  Google Scholar 

  85. Heikkila RE, Winston B, Cohen G. Alloxan-induced diabetes-evidence for hydroxyl radical as a cytotoxic intermediate. Biochem Pharmacol. 1976;25:1085–92.

    Article  CAS  PubMed  Google Scholar 

  86. Takasu N, Komiya I, Asawa T, Nagasawa Y, Yamada T. Streptozocin- and alloxan-induced H2O2 generation and DNA fragmentation in pancreatic islets. H2O2 as mediator for DNA fragmentation. Diabetes. 1991;40:1141–5.

    Article  CAS  PubMed  Google Scholar 

  87. Kim HR, Rho HW, Park BH, Park JW, Kim JS, Kim UH, et al. Role of Ca2+ in alloxan-induced pancreatic beta-cell damage. Biochim Biophys Acta. 1994;1227:87–91.

    Article  CAS  PubMed  Google Scholar 

  88. Park BH, Rho HW, Park JW, Cho CG, Kim JS, Chung HT, et al. Protective mechanism of glucose against alloxan-induced pancreatic beta-cell damage. Biochem Biophys Res Commun. 1995;210:1–6.

    Article  CAS  PubMed  Google Scholar 

  89. Favero TG, Zable AC, Abramson JJ. Hydrogen peroxide stimulates the Ca2+ release channel from skeletal muscle sarcoplasmic reticulum. J Biol Chem. 1995;270:25557–63.

    Article  CAS  PubMed  Google Scholar 

  90. Gorlach A, Klappa P, Kietzmann T. The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal. 2006;8:1391–418.

    Article  PubMed  Google Scholar 

  91. Xu L, Eu JP, Meissner G, Stamler JS. Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science. 1998;279:234–7.

    Article  CAS  PubMed  Google Scholar 

  92. Lee H, Park MT, Choi BH, Oh ET, Song MJ, Lee J, et al. Endoplasmic reticulum stress-induced JNK activation is a critical event leading to mitochondria-mediated cell death caused by beta-lapachone treatment. PLoS One. 2011;6:e21533.

    Article  PubMed Central  PubMed  Google Scholar 

  93. Wang Q, Zhang H, Zhao B, Fei H. IL-1beta caused pancreatic beta-cells apoptosis is mediated in part by endoplasmic reticulum stress via the induction of endoplasmic reticulum Ca2+ release through the C-Jun N-terminal kinase pathway. Mol Cell Biochem. 2009;324:183–90.

    Article  CAS  PubMed  Google Scholar 

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Conflict of Interest

John W. McGinty, Meghan L. Marré, and Veronique Bajzik declare that they have no conflict of interest.

Eddie A. James and Jon D. Piganelli report grants from the Juvenile Diabetes Research Foundation.

Human and Animal Rights and Informed Consent

Informed consent was obtained from all individual participants included in the study.

This article does not contain any studies with animals performed by any of the authors.

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Authors and Affiliations

  1. Benaroya Research Institute at Virginia Mason, 1201 9th Ave, Seattle, WA, USA

    John W. McGinty, Veronique Bajzik & Eddie A. James

  2. Children’s Hospital of Pittsburgh, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, USA

    Meghan L. Marré & Jon D. Piganelli

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  1. John W. McGinty
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  2. Meghan L. Marré
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Correspondence to Eddie A. James.

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This article is part of the Topical Collection on Pathogenesis of Type 1 Diabetes

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McGinty, J.W., Marré, M.L., Bajzik, V. et al. T Cell Epitopes and Post-Translationally Modified Epitopes in Type 1 Diabetes. Curr Diab Rep 15, 90 (2015). https://doi.org/10.1007/s11892-015-0657-7

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  • DOI: https://doi.org/10.1007/s11892-015-0657-7

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