Skip to main content

Molecular Mechanisms in Autoimmune Type 1 Diabetes: a Critical Review

An Erratum to this article was published on 30 May 2014

Abstract

Autoimmune type 1 diabetes is characterized by selective destruction of insulin-secreting beta cells in the pancreas of genetically susceptible individuals. The mechanisms underlying the development of type 1 diabetes are not fully understood. However, a widely accepted point is that type 1 diabetes is caused by a combination of genetic and environmental factors. Although most type 1 diabetes patients do not have a family history, genetic susceptibility does play a vital role in beta cell autoimmunity and destruction. Human leukocyte antigen (HLA) regions are the strongest genetic determinants, which can contribute 40–50 % of the genetic risk to type 1 diabetes. Other genes, including INS also contribute to disease risk. The mechanisms of the susceptible genes in type 1 diabetes may relate to their respective roles in antigen presentation, beta cell autoimmunity, immune tolerance, and autoreactive T cell response. Environmental susceptibility factors also contribute to the risk of developing type 1 diabetes. From an epigenetic standpoint, the pathologic mechanisms involved in the development of type 1 diabetes may include DNA methylation, histone modification, microRNA, and molecular mimicry. These mechanisms may act through regulating of gene expression, thereby affecting the immune system response toward islet beta cells. One of the characteristics of type 1 diabetes is the recognition of islet autoantigens by autoreactive CD4+ and CD8+ T cells and autoantibodies. Autoantibodies against islet autoantigens are involved in autoantigen processing and presentation by HLA molecules. This review will mainly focus on the molecular mechanism by which genetic, epigenetic, and environmental factors contribute to the risk of type 1 diabetes.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G, Group ES (2009) Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet 373:2027–2033

    PubMed  Google Scholar 

  2. 2.

    Ounissi-Benkalha H, Polychronakos C (2008) The molecular genetics of type 1 diabetes: new genes and emerging mechanisms. Trends Mol Med 14:268–275

    PubMed  CAS  Google Scholar 

  3. 3.

    Todd JA (2010) Etiology of type 1 diabetes. Immunity 32:457–467

    PubMed  CAS  Google Scholar 

  4. 4.

    Atkinson MA, Eisenbarth GS, Michels AW (2014) Type 1 diabetes. Lancet 383:69–82

    PubMed  Google Scholar 

  5. 5.

    Kelly MA, Rayner ML, Mijovic CH, Barnett AH (2003) Molecular aspects of type 1 diabetes. Mol Pathol: MP 56:1–10

    PubMed  CAS  PubMed Central  Google Scholar 

  6. 6.

    Dabelea D (2009) The accelerating epidemic of childhood diabetes. Lancet 373:1999–2000

    PubMed  Google Scholar 

  7. 7.

    Gale EA (2005) Type 1 diabetes in the young: the harvest of sorrow goes on. Diabetologia 48:1435–1438

    PubMed  CAS  Google Scholar 

  8. 8.

    Podar T, Solntsev A, Reunanen A, Urbonaite B, Zalinkevicius R, Karvonen M et al (2000) Mortality in patients with childhood-onset type 1 diabetes in Finland, Estonia, and Lithuania: follow-up of nationwide cohorts. Diabetes Care 23:290–294

    PubMed  CAS  Google Scholar 

  9. 9.

    Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J (2000) Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 23:1516–1526

    PubMed  CAS  Google Scholar 

  10. 10.

    Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ (2010) Epidemiology of type 1 diabetes. Endocrinol Metab Clin N Am 39:481–497

    Google Scholar 

  11. 11.

    Levy-Marchal C, Patterson CC, Green A, Europe EASG, Diabetes (2001) Geographical variation of presentation at diagnosis of type I diabetes in children: the EURODIAB study. European and Dibetes. Diabetologia 44(Suppl 3):B75–B80

    PubMed  Google Scholar 

  12. 12.

    Yang Z, Wang K, Li T, Sun W, Li Y, Chang YF et al (1998) Childhood diabetes in China. Enormous variation by place and ethnic group. Diabetes Care 21:525–529

    PubMed  CAS  Google Scholar 

  13. 13.

    Groop LC, Bottazzo GF, Doniach D (1986) Islet cell antibodies identify latent type I diabetes in patients aged 35–75 years at diagnosis. Diabetes 35:237–241

    PubMed  CAS  Google Scholar 

  14. 14.

    Zhou Z, Xiang Y, Ji L, Jia W, Ning G, Huang G et al (2013) Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a nationwide, multicenter, clinic-based cross-sectional study. Diabetes 62:543–550

    PubMed  CAS  PubMed Central  Google Scholar 

  15. 15.

    Brahmkshatriya PP, Mehta AA, Saboo BD, Goyal RK (2012) Characteristics and prevalence of latent autoimmune diabetes in adults (LADA). ISRN Pharmacol 2012:580202

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Fourlanos S, Dotta F, Greenbaum CJ, Palmer JP, Rolandsson O, Colman PG et al (2005) Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia 48:2206–2212

    PubMed  CAS  Google Scholar 

  17. 17.

    Redondo MJ (2013) LADA: time for a new definition. Diabetes 62:339–340

    PubMed  CAS  PubMed Central  Google Scholar 

  18. 18.

    Purushothaman R, Ramchandani N, Kazachkova I, Ten S (2007) Prevalence and clinical features of type 1.5 diabetes mellitus in children. J Pediatr Endocrinol Metab: JPEM 20:981–987

    PubMed  Google Scholar 

  19. 19.

    Lampasona V, Petrone A, Tiberti C, Capizzi M, Spoletini M, di Pietro S et al (2010) Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes: non insulin requiring autoimmune diabetes (NIRAD) 4. Diabetes Care 33:104–108

    PubMed  CAS  PubMed Central  Google Scholar 

  20. 20.

    Munakata Y, Yamada T, Takahashi K, Tsukita S, Takahashi K, Sawada S et al (2012) A case of slowly progressive type 1 diabetes with insulin independence maintained for 10years with alpha-glucosidase inhibitor monotherapy. Intern Med 51:3391–3394

    PubMed  Google Scholar 

  21. 21.

    Gale EA (2005) Latent autoimmune diabetes in adults: a guide for the perplexed. Diabetologia 48:2195–2199

    PubMed  CAS  Google Scholar 

  22. 22.

    Leslie RD, Williams R, Pozzilli P (2006) Clinical review: Type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow. J Clin Endocrinol Metab 91:1654–1659

    PubMed  Google Scholar 

  23. 23.

    Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A et al (1999) Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48:150–157

    PubMed  CAS  Google Scholar 

  24. 24.

    Stenstrom G, Berger B, Borg H, Fernlund P, Dorman JS, Sundkvist G (2002) HLA-DQ genotypes in classic type 1 diabetes and in latent autoimmune diabetes of the adult. Am J Epidemiol 156:787–796

    PubMed  Google Scholar 

  25. 25.

    Hosszufalusi N, Vatay A, Rajczy K, Prohaszka Z, Pozsonyi E, Horvath L et al (2003) Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes in adults (LADA) compared with adult-onset type 1 diabetes with rapid progression. Diabetes Care 26:452–457

    PubMed  Google Scholar 

  26. 26.

    Desai M, Zeggini E, Horton VA, Owen KR, Hattersley AT, Levy JC et al (2007) An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia 50:68–73

    PubMed  CAS  PubMed Central  Google Scholar 

  27. 27.

    Desai M, Zeggini E, Horton VA, Owen KR, Hattersley AT, Levy JC et al (2006) The variable number of tandem repeats upstream of the insulin gene is a susceptibility locus for latent autoimmune diabetes in adults. Diabetes 55:1890–1894

    PubMed  CAS  Google Scholar 

  28. 28.

    Petrone A, Suraci C, Capizzi M, Giaccari A, Bosi E, Tiberti C et al (2008) The protein tyrosine phosphatase nonreceptor 22 (PTPN22) is associated with high GAD antibody titer in latent autoimmune diabetes in adults: non insulin requiring autoimmune diabetes (NIRAD) study 3. Diabetes Care 31:534–538

    PubMed  Google Scholar 

  29. 29.

    Cervin C, Lyssenko V, Bakhtadze E, Lindholm E, Nilsson P, Tuomi T et al (2008) Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes 57:1433–1437

    PubMed  CAS  Google Scholar 

  30. 30.

    Lin J, Zhou ZG, Wang JP, Zhang C, Huang G (2008) From Type 1, through LADA, to type 2 diabetes: a continuous spectrum? Ann N Y Acad Sci 1150:99–102

    PubMed  CAS  Google Scholar 

  31. 31.

    Risch N (1987) Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet 40:1–14

    PubMed  CAS  PubMed Central  Google Scholar 

  32. 32.

    Olmos P, A’Hern R, Heaton DA, Millward BA, Risley D, Pyke DA et al (1988) The significance of the concordance rate for type 1 (insulin-dependent) diabetes in identical twins. Diabetologia 31:747–750

    PubMed  CAS  Google Scholar 

  33. 33.

    Redondo MJ, Yu L, Hawa M, Mackenzie T, Pyke DA, Eisenbarth GS et al (2001) Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 44:354–362

    PubMed  CAS  Google Scholar 

  34. 34.

    Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707

    PubMed  CAS  PubMed Central  Google Scholar 

  35. 35.

    Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH et al (2008) Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359:2767–2777

    PubMed  CAS  PubMed Central  Google Scholar 

  36. 36.

    Zoledziewska M, Perra C, Orru V, Moi L, Frongia P, Congia M et al (2008) Further evidence of a primary, causal association of the PTPN22 620W variant with type 1 diabetes. Diabetes 57:229–234

    PubMed  CAS  Google Scholar 

  37. 37.

    Bradfield JP, Qu HQ, Wang K, Zhang H, Sleiman PM, Kim CE et al (2011) A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet 7:e1002293

    PubMed  CAS  PubMed Central  Google Scholar 

  38. 38.

    Cooper JD, Howson JM, Smyth D, Walker NM, Stevens H, Yang JH et al (2012) Confirmation of novel type 1 diabetes risk loci in families. Diabetologia 55:996–1000

    PubMed  CAS  PubMed Central  Google Scholar 

  39. 39.

    Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V et al (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39:857–864

    PubMed  CAS  PubMed Central  Google Scholar 

  40. 40.

    Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ et al (2006) A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 38:617–619

    PubMed  CAS  Google Scholar 

  41. 41.

    Gestermann N, Mekinian A, Comets E, Loiseau P, Puechal X, Hachulla E et al (2010) STAT4 is a confirmed genetic risk factor for Sjogren’s syndrome and could be involved in type 1 interferon pathway signaling. Genes Immun 11:432–438

    PubMed  CAS  Google Scholar 

  42. 42.

    Nistico L, Buzzetti R, Pritchard LE, Van der Auwera B, Giovannini C, Bosi E et al (1996) The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet 5:1075–1080

    PubMed  CAS  Google Scholar 

  43. 43.

    Cooper JD, Smyth DJ, Smiles AM, Plagnol V, Walker NM, Allen JE et al (2008) Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 40:1399–1401

    PubMed  CAS  PubMed Central  Google Scholar 

  44. 44.

    Yang JH, Downes K, Howson JM, Nutland S, Stevens HE, Walker NM et al (2011) Evidence of association with type 1 diabetes in the SLC11A1 gene region. BMC Med Genet 12:59

    PubMed  CAS  PubMed Central  Google Scholar 

  45. 45.

    Baschal EE, Sarkar SA, Boyle TA, Siebert JC, Jasinski JM, Grabek KR et al (2011) Replication and further characterization of a Type 1 diabetes-associated locus at the telomeric end of the major histocompatibility complex. J Diabetes 3:238–247

    PubMed  CAS  PubMed Central  Google Scholar 

  46. 46.

    Cheung YH, Watkinson J, Anastassiou D (2011) Conditional meta-analysis stratifying on detailed HLA genotypes identifies a novel type 1 diabetes locus around TCF19 in the MHC. Hum Genet 129:161–176

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Howson JM, Walker NM, Clayton D, Todd JA, Type 1 Diabetes Genetics C (2009) Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A. Diabetes Obes Metab 11(Suppl 1):31–45

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE et al (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450:887–892

    PubMed  CAS  PubMed Central  Google Scholar 

  49. 49.

    Fung EY, Smyth DJ, Howson JM, Cooper JD, Walker NM, Stevens H et al (2009) Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun 10:188–191

    PubMed  CAS  Google Scholar 

  50. 50.

    Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D et al (2004) A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet 36:837–841

    PubMed  CAS  Google Scholar 

  51. 51.

    Swafford AD, Howson JM, Davison LJ, Wallace C, Smyth DJ, Schuilenburg H et al (2011) An allele of IKZF1 (Ikaros) conferring susceptibility to childhood acute lymphoblastic leukemia protects against type 1 diabetes. Diabetes 60:1041–1044

    PubMed  CAS  PubMed Central  Google Scholar 

  52. 52.

    Reddy MV, Wang H, Liu S, Bode B, Reed JC, Steed RD et al (2011) Association between type 1 diabetes and GWAS SNPs in the southeast US Caucasian population. Genes Immun 12:208–212

    PubMed  CAS  PubMed Central  Google Scholar 

  53. 53.

    Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R et al (2007) Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 39:1074–1082

    PubMed  CAS  Google Scholar 

  54. 54.

    Bell GI, Horita S, Karam JH (1984) A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176–183

    PubMed  CAS  Google Scholar 

  55. 55.

    Barratt BJ, Payne F, Lowe CE, Hermann R, Healy BC, Harold D et al (2004) Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53:1884–1889

    PubMed  CAS  Google Scholar 

  56. 56.

    Hakonarson H, Qu HQ, Bradfield JP, Marchand L, Kim CE, Glessner JT et al (2008) A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study. Diabetes 57:1143–1146

    PubMed  CAS  Google Scholar 

  57. 57.

    Keene KL, Quinlan AR, Hou X, Hall IM, Mychaleckyj JC, Onengut-Gumuscu S et al (2012) Evidence for two independent associations with type 1 diabetes at the 12q13 locus. Genes Immun 13:66–70

    PubMed  CAS  PubMed Central  Google Scholar 

  58. 58.

    Espino-Paisan L, de la Calle H, Fernandez-Arquero M, Figueredo MA, de la Concha EG, Urcelay E et al (2011) Polymorphisms in chromosome region 12q13 and their influence on age at onset of type 1 diabetes. Diabetologia 54:2033–2037

    PubMed  CAS  Google Scholar 

  59. 59.

    Lavrikova EY, Nikitin AG, Kuraeva TL, Peterkova VA, Tsitlidze NM, Chistiakov DA et al (2011) The carriage of the type 1 diabetes-associated R262W variant of human LNK correlates with increased proliferation of peripheral blood monocytes in diabetic patients. Pediatr Diabetes 12:127–132

    PubMed  CAS  Google Scholar 

  60. 60.

    Heinig M, Petretto E, Wallace C, Bottolo L, Rotival M, Lu H et al (2010) A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467:460–464

    PubMed  CAS  PubMed Central  Google Scholar 

  61. 61.

    Wallace C, Smyth DJ, Maisuria-Armer M, Walker NM, Todd JA, Clayton DG (2010) The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet 42:68–71

    PubMed  CAS  PubMed Central  Google Scholar 

  62. 62.

    Qu HQ, Grant SF, Bradfield JP, Kim C, Frackelton E, Hakonarson H et al (2009) Association of RASGRP1 with type 1 diabetes is revealed by combined follow-up of two genome-wide studies. J Med Genet 46:553–554

    PubMed  CAS  PubMed Central  Google Scholar 

  63. 63.

    Wang K, Baldassano R, Zhang H, Qu HQ, Imielinski M, Kugathasan S et al (2010) Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects. Hum Mol Genet 19:2059–2067

    PubMed  CAS  PubMed Central  Google Scholar 

  64. 64.

    Smyth DJ, Cooper JD, Howson JM, Clarke P, Downes K, Mistry T et al (2011) FUT2 nonsecretor status links type 1 diabetes susceptibility and resistance to infection. Diabetes 60:3081–3084

    PubMed  CAS  PubMed Central  Google Scholar 

  65. 65.

    Concannon P, Onengut-Gumuscu S, Todd JA, Smyth DJ, Pociot F, Bergholdt R et al (2008) A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Diabetes 57:2858–2861

    PubMed  CAS  PubMed Central  Google Scholar 

  66. 66.

    Turunen JA, Wessman M, Forsblom C, Kilpikari R, Parkkonen M, Pontynen N et al (2006) Association analysis of the AIRE and insulin genes in Finnish type 1 diabetic patients. Immunogenetics 58:331–338

    PubMed  CAS  Google Scholar 

  67. 67.

    Cooper JD, Walker NM, Smyth DJ, Downes K, Healy BC, Todd JA et al (2009) Follow-up of 1715 SNPs from the Wellcome Trust Case Control Consortium genome-wide association study in type I diabetes families. Genes Immun 10(Suppl 1):S85–S94

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Pociot F, Akolkar B, Concannon P, Erlich HA, Julier C, Morahan G et al (2010) Genetics of type 1 diabetes: what’s next? Diabetes 59:1561–1571

    PubMed  CAS  PubMed Central  Google Scholar 

  69. 69.

    Morahan G (2012) Insights into type 1 diabetes provided by genetic analyses. Curr Opin Endocrinol Diabetes Obes 19:263–270

    PubMed  CAS  Google Scholar 

  70. 70.

    Singal DP, Blajchman MA (1973) Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes 22:429–432

    PubMed  CAS  Google Scholar 

  71. 71.

    Mehers KL, Gillespie KM (2008) The genetic basis for type 1 diabetes. Br Med Bull 88:115–129

    PubMed  CAS  Google Scholar 

  72. 72.

    Horton R, Wilming L, Rand V, Lovering RC, Bruford EA, Khodiyar VK et al (2004) Gene map of the extended human MHC. Nat Rev Genet 5:889–899

    PubMed  CAS  Google Scholar 

  73. 73.

    Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. Nature. 1999;401:921-3

  74. 74.

    Noble JA, Erlich HA (2012) Genetics of type 1 diabetes. Cold Spring Harb Perspect Med 2:a007732

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    van Belle TL, Coppieters KT, von Herrath MG (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79–118

    PubMed  Google Scholar 

  76. 76.

    Thomson G, Valdes AM, Noble JA, Kockum I, Grote MN, Najman J et al (2007) Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Tissue Antigens 70:110–127

    PubMed  CAS  Google Scholar 

  77. 77.

    Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P et al (2008) HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 57:1084–1092

    PubMed  CAS  PubMed Central  Google Scholar 

  78. 78.

    Mimbacas A, Perez-Bravo F, Santos JL, Pisciottano C, Grignola R, Javiel G et al (2004) The association between HLA DQ genetic polymorphism and type 1 diabetes in a case-parent study conducted in an admixed population. Eur J Epidemiol 19:931–934

    PubMed  CAS  Google Scholar 

  79. 79.

    She JX (1996) Susceptibility to type I diabetes: HLA-DQ and DR revisited. Immunol Today 17:323–329

    PubMed  CAS  Google Scholar 

  80. 80.

    Undlien DE, Friede T, Rammensee HG, Joner G, Dahl-Jorgensen K, Sovik O et al (1997) HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection. Diabetes 46:143–149

    PubMed  CAS  Google Scholar 

  81. 81.

    Kawabata Y, Ikegami H, Kawaguchi Y, Fujisawa T, Shintani M, Ono M et al (2002) Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes. Diabetes 51:545–551

    PubMed  CAS  Google Scholar 

  82. 82.

    Katahira M, Ishiguro T, Segawa S, Kuzuya-Nagao K, Hara I, Nishisaki T (2008) Reevaluation of human leukocyte antigen DR-DQ haplotype and genotype in type 1 diabetes in the Japanese population. Horm Res 69:284–289

    PubMed  CAS  Google Scholar 

  83. 83.

    Park YS, Wang CY, Ko KW, Yang SW, Park M, Yang MC et al (1998) Combinations of HLA DR and DQ molecules determine the susceptibility to insulin-dependent diabetes mellitus in Koreans. Hum Immunol 59:794–801

    PubMed  CAS  Google Scholar 

  84. 84.

    Park Y, She JX, Wang CY, Lee H, Babu S, Erlich HA et al (2000) Common susceptibility and transmission pattern of human leukocyte antigen DRB1-DQB1 haplotypes to Korean and Caucasian patients with type 1 diabetes. J Clin Endocrinol Metab 85:4538–4542

    PubMed  CAS  Google Scholar 

  85. 85.

    Zhang XM, Wang HY, Luo YY, Ji LN (2009) HLA-DQ, DR allele polymorphism of type 1 diabetes in the Chinese population: a meta-analysis. Chin Med J 122:980–986

    PubMed  Google Scholar 

  86. 86.

    Huang HS, Peng JT, She JY, Zhang LP, Chao CC, Liu KH et al (1995) HLA-encoded susceptibility to insulin-dependent diabetes mellitus is determined by DR and DQ genes as well as their linkage disequilibria in a Chinese population. Hum Immunol 44:210–219

    PubMed  CAS  Google Scholar 

  87. 87.

    Noble JA, Valdes AM, Cook M, Klitz W, Thomson G, Erlich HA (1996) The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Hum Genet 59:1134–1148

    PubMed  CAS  PubMed Central  Google Scholar 

  88. 88.

    Ikegami H, Kawabata Y, Noso S, Fujisawa T, Ogihara T (2007) Genetics of type 1 diabetes in Asian and Caucasian populations. Diabetes Res Clin Pract 77(Suppl 1):S116–S121

    PubMed  CAS  Google Scholar 

  89. 89.

    Undlien DE, Kockum I, Ronningen KS, Lowe R, Saanjeevi CB, Graham J et al (1999) HLA associations in type 1 diabetes among patients not carrying high-risk DR3-DQ2 or DR4-DQ8 haplotypes. Tissue Antigens 54:543–551

    PubMed  CAS  Google Scholar 

  90. 90.

    Kawasaki E, Noble J, Erlich H, Mulgrew CL, Fain PR, Eisenbarth GS (1998) Transmission of DQ haplotypes to patients with type 1 diabetes. Diabetes 47:1971–1973

    PubMed  CAS  Google Scholar 

  91. 91.

    Awata T, Kuzuya T, Matsuda A, Iwamoto Y, Kanazawa Y (1992) Genetic analysis of HLA class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 35:419–424

    PubMed  CAS  Google Scholar 

  92. 92.

    Karjalainen J, Salmela P, Ilonen J, Surcel HM, Knip M (1989) A comparison of childhood and adult type I diabetes mellitus. N Engl J Med 320:881–886

    PubMed  CAS  Google Scholar 

  93. 93.

    Cerna M, Novota P, Kolostova K, Cejkova P, Zdarsky E, Novakova D et al (2003) HLA in Czech adult patients with autoimmune diabetes mellitus: comparison with Czech children with type 1 diabetes and patients with type 2 diabetes. Eur J immunogenet 30:401–407

    Google Scholar 

  94. 94.

    Fukui M, Kitagawa Y, Nakamura N, Yoshikawa T (2003) Clinical and genetic heterogeneity of latent autoimmune diabetes in adults. Diabetes Care 26:2223, author reply 4

    PubMed  Google Scholar 

  95. 95.

    Andersen MK, Lundgren V, Turunen JA, Forsblom C, Isomaa B, Groop PH et al (2010) Latent autoimmune diabetes in adults differs genetically from classical type 1 diabetes diagnosed after the age of 35years. Diabetes Care 33:2062–2064

    PubMed  CAS  PubMed Central  Google Scholar 

  96. 96.

    Weber P, Meluzinova H, Kubesova H, Ambrosova P, Polcarova V, Cejkova P et al (2010) Type 1 diabetes and LADA–occurrence of HLA-DRB1 *03 and DRB1 *04 alleles in two age different groups of diabetics. Adv Gerontol Usp Gerontol Ross Akad Nauk Gerontol Obshch 23:243–248

    CAS  Google Scholar 

  97. 97.

    Bennett ST, Lucassen AM, Gough SC, Powell EE, Undlien DE, Pritchard LE 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 9:284–292

    PubMed  CAS  Google Scholar 

  98. 98.

    Durinovic-Bello I, Wu RP, Gersuk VH, Sanda S, Shilling HG, Nepom GT (2010) Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin. Genes Immun 11:188–193

    PubMed  CAS  PubMed Central  Google Scholar 

  99. 99.

    Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG et al (1997) Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15:289–292

    PubMed  CAS  Google Scholar 

  100. 100.

    Pugliese A, Zeller M, Fernandez A Jr, Zalcberg LJ, Bartlett RJ, Ricordi C et al (1997) The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15:293–297

    PubMed  CAS  Google Scholar 

  101. 101.

    Vafiadis P, Ounissi-Benkalha H, Palumbo M, Grabs R, Rousseau M, Goodyer CG et al (2001) Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes. J Clin Endocrinol Metab 86:3705–3710

    PubMed  CAS  Google Scholar 

  102. 102.

    Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511

    PubMed  CAS  Google Scholar 

  103. 103.

    Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z et al (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:271–275

    PubMed  CAS  Google Scholar 

  104. 104.

    Atabani SF, Thio CL, Divanovic S, Trompette A, Belkaid Y, Thomas DL et al (2005) Association of CTLA4 polymorphism with regulatory T cell frequency. Eur J Immunol 35:2157–2162

    PubMed  CAS  Google Scholar 

  105. 105.

    Korolija M, Renar IP, Hadzija M, Medvidovic EP, Pavkovic P, Jokic M et al (2009) Association of PTPN22 C1858T and CTLA-4 A49G polymorphisms with type 1 diabetes in Croatians. Diabetes Res Clin Pract 86:e54–e57

    PubMed  CAS  Google Scholar 

  106. 106.

    Cutolo M, Nadler SG (2013) Advances in CTLA-4-Ig-mediated modulation of inflammatory cell and immune response activation in rheumatoid arthritis. Autoimmun Rev 12:758–767

    PubMed  CAS  Google Scholar 

  107. 107.

    Romo-Tena J, Gomez-Martin D, Alcocer-Varela J (2013) CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance. Autoimmun Rev 12:1171–1176

    PubMed  CAS  Google Scholar 

  108. 108.

    Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JM et al (2004) Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53:3020–3023

    PubMed  CAS  Google Scholar 

  109. 109.

    Gregersen PK, Behrens TW (2006) Genetics of autoimmune diseases—disorders of immune homeostasis. Nat Rev Genet 7:917–928

    PubMed  CAS  Google Scholar 

  110. 110.

    Vang T, Congia M, Macis MD, Musumeci L, Orru V, Zavattari P et al (2005) Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 37:1317–1319

    PubMed  CAS  Google Scholar 

  111. 111.

    Gregersen PK (2005) Gaining insight into PTPN22 and autoimmunity. Nat Genet 37:1300–1302

    PubMed  CAS  Google Scholar 

  112. 112.

    Chung SA, Criswell LA (2007) PTPN22: its role in SLE and autoimmunity. Autoimmunity 40:582–590

    PubMed  CAS  PubMed Central  Google Scholar 

  113. 113.

    Gianchecchi E, Palombi M, Fierabracci A (2013) The putative role of the C1858T polymorphism of protein tyrosine phosphatase PTPN22 gene in autoimmunity. Autoimmun Rev 12:717–725

    PubMed  CAS  Google Scholar 

  114. 114.

    Zheng J, Petersen F, Yu X (2014) The role of PTPN22 in autoimmunity: learning from mice. Autoimmun Rev 13:266–271

    PubMed  CAS  Google Scholar 

  115. 115.

    Corthay A (2009) How do regulatory T cells work? Scand J Immunol 70:326–336

    PubMed  CAS  PubMed Central  Google Scholar 

  116. 116.

    Askenasy N (2013) Enhanced killing activity of regulatory T cells ameliorates inflammation and autoimmunity. Autoimmun Rev 12:972–975

    PubMed  CAS  Google Scholar 

  117. 117.

    Smyth DJ, Howson JM, Lowe CE, Walker NM, Lam AC, Nutland S et al (2005) Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes. Nat Genet 37:110–111, author reply 2-3

    PubMed  CAS  Google Scholar 

  118. 118.

    Guo D, Han J, Adam BL, Colburn NH, Wang MH, Dong Z et al (2005) Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. Biochem Biophys Res Commun 337:1308–1318

    PubMed  CAS  Google Scholar 

  119. 119.

    Caamano J, Hunter CA (2002) NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions. Clin Microbiol Rev 15:414–429

    PubMed  CAS  PubMed Central  Google Scholar 

  120. 120.

    Lee HS, Park H, Yang S, Kim D, Park Y (2008) STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes. Ann N Y Acad Sci 1150:93–98

    PubMed  CAS  Google Scholar 

  121. 121.

    Frucht DM, Aringer M, Galon J, Danning C, Brown M, Fan S et al (2000) Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J Immunol 164:4659–4664

    PubMed  CAS  Google Scholar 

  122. 122.

    Yang Z, Chen M, Ellett JD, Fialkow LB, Carter JD, McDuffie M et al (2004) Autoimmune diabetes is blocked in Stat4-deficient mice. J Autoimmun 22:191–200

    PubMed  CAS  Google Scholar 

  123. 123.

    Trinchieri G (1994) Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 84:4008–4027

    PubMed  CAS  Google Scholar 

  124. 124.

    Pettersen E, Skorpen F, Kvaloy K, Midthjell K, Grill V (2010) Genetic heterogeneity in latent autoimmune diabetes is linked to various degrees of autoimmune activity: results from the Nord-Trondelag Health Study. Diabetes 59:302–310

    PubMed  CAS  PubMed Central  Google Scholar 

  125. 125.

    Howson JM, Rosinger S, Smyth DJ, Boehm BO, Group A-ES, Todd JA (2011) Genetic analysis of adult-onset autoimmune diabetes. Diabetes 60:2645–2653

    PubMed  CAS  PubMed Central  Google Scholar 

  126. 126.

    Okruszko A, Szepietowska B, Wawrusiewicz-Kurylonek N, Gorska M, Kretowski A, Szelachowska M (2012) HLA-DR, HLA-DQB1 and PTPN22 gene polymorphism: association with age at onset for autoimmune diabetes. Arch Med Sci AMS 8:874–878

    CAS  Google Scholar 

  127. 127.

    Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Eriksson J et al (1992) Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 35:1060–1067

    PubMed  CAS  Google Scholar 

  128. 128.

    Dang MN, Buzzetti R, Pozzilli P (2013) Epigenetics in autoimmune diseases with focus on type 1 diabetes. Diabetes Metab Res Rev 29:8–18

    PubMed  CAS  Google Scholar 

  129. 129.

    Knip M, Veijola R, Virtanen SM, Hyoty H, Vaarala O, Akerblom HK (2005) Environmental triggers and determinants of type 1 diabetes. Diabetes 54(Suppl 2):S125–S136

    PubMed  CAS  Google Scholar 

  130. 130.

    Akerblom HK, Knip M (1998) Putative environmental factors in Type 1 diabetes. Diabetes Metab Rev 14:31–67

    PubMed  CAS  Google Scholar 

  131. 131.

    Hermann R, Knip M, Veijola R, Simell O, Laine AP, Akerblom HK et al (2003) Temporal changes in the frequencies of HLA genotypes in patients with type 1 diabetes—indication of an increased environmental pressure? Diabetologia 46:420–425

    PubMed  CAS  Google Scholar 

  132. 132.

    Gillespie KM, Bain SC, Barnett AH, Bingley PJ, Christie MR, Gill GV et al (2004) The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet 364:1699–1700

    PubMed  Google Scholar 

  133. 133.

    EURODIAB ACE Study Group (2000) Variation and trends in incidence of childhood diabetes in Europe. Lancet 355:873–876

    Google Scholar 

  134. 134.

    Karagkouni A, Alevizos M, Theoharides TC (2013) Effect of stress on brain inflammation and multiple sclerosis. Autoimmun Rev 12:947–953

    PubMed  CAS  Google Scholar 

  135. 135.

    Selmi C (2013) Autoimmunity in 2012. Clin Rev Allergy Immunol 45:290–301

    PubMed  CAS  Google Scholar 

  136. 136.

    Selmi C, Crotti C, Meroni PL (2013) Less travelled roads in clinical immunology and allergy: drug reactions and the environmental influence. Clin Rev Allergy Immunol 45:1–5

    PubMed  CAS  Google Scholar 

  137. 137.

    Brooks WH (2012) Autoimmune diseases and polyamines. Clin Rev Allergy Immunol 42:58–70

    PubMed  CAS  Google Scholar 

  138. 138.

    Rook GA (2012) Hygiene hypothesis and autoimmune diseases. Clin Rev Allergy Immunol 42:5–15

    PubMed  CAS  Google Scholar 

  139. 139.

    Longnecker MP, Daniels JL (2001) Environmental contaminants as etiologic factors for diabetes. Environ Health Perspect 109(Suppl 6):871–876

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Virtanen SM, Knip M (2003) Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age. Am J Clin Nutr 78:1053–1067

    PubMed  CAS  Google Scholar 

  141. 141.

    Howard SG, Lee DH (2012) What is the role of human contamination by environmental chemicals in the development of type 1 diabetes? J Epidemiol Community Health 66:479–481

    PubMed  Google Scholar 

  142. 142.

    Atkinson M, Gale EA (2003) Infant diets and type 1 diabetes: too early, too late, or just too complicated? JAMA J Am Med Assoc 290:1771–1772

    CAS  Google Scholar 

  143. 143.

    Knip M, Virtanen SM, Akerblom HK (2010) Infant feeding and the risk of type 1 diabetes. Am J Clin Nutr 91:1506S–1513S

    PubMed  Google Scholar 

  144. 144.

    Vaarala O (2002) The gut immune system and type 1 diabetes. Ann N Y Acad Sci 958:39–46

    PubMed  CAS  Google Scholar 

  145. 145.

    Sepa A, Ludvigsson J (2006) Psychological stress and the risk of diabetes-related autoimmunity: a review article. Neuroimmunomodulation 13:301–308

    PubMed  CAS  Google Scholar 

  146. 146.

    Harder T, Roepke K, Diller N, Stechling Y, Dudenhausen JW, Plagemann A (2009) Birth weight, early weight gain, and subsequent risk of type 1 diabetes: systematic review and meta-analysis. Am J Epidemiol 169:1428–1436

    PubMed  Google Scholar 

  147. 147.

    Yeung WC, Rawlinson WD, Craig ME (2011) Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ 342:d35

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    Oikarinen S, Martiskainen M, Tauriainen S, Huhtala H, Ilonen J, Veijola R et al (2011) Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes 60:276–279

    PubMed  CAS  PubMed Central  Google Scholar 

  149. 149.

    Stene LC, Oikarinen S, Hyoty H, Barriga KJ, Norris JM, Klingensmith G et al (2010) Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the Diabetes and Autoimmunity Study in the Young (DAISY). Diabetes 59:3174–3180

    PubMed  CAS  PubMed Central  Google Scholar 

  150. 150.

    Javierre BM, Hernando H, Ballestar E (2011) Environmental triggers and epigenetic deregulation in autoimmune disease. Discov Med 12:535–545

    PubMed  Google Scholar 

  151. 151.

    Lu Q (2013) The critical importance of epigenetics in autoimmunity. J Autoimmun 41:1–5

    PubMed  Google Scholar 

  152. 152.

    Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057–1068

    PubMed  CAS  Google Scholar 

  153. 153.

    He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q et al (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333:1303–1307

    PubMed  CAS  PubMed Central  Google Scholar 

  154. 154.

    Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21

    PubMed  CAS  Google Scholar 

  155. 155.

    Wu SC, Zhang Y (2010) Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol 11:607–620

    PubMed  CAS  PubMed Central  Google Scholar 

  156. 156.

    Sananbenesi F, Fischer A (2009) The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Biol Chem 390:1145–1153

    PubMed  CAS  Google Scholar 

  157. 157.

    Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610

    PubMed  CAS  Google Scholar 

  158. 158.

    Bell CG, Teschendorff AE, Rakyan VK, Maxwell AP, Beck S, Savage DA (2010) Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus. BMC Med Genet 3:33

    Google Scholar 

  159. 159.

    Rakyan VK, Beyan H, Down TA, Hawa MI, Maslau S, Aden D et al (2011) Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet 7:e1002300

    PubMed  CAS  PubMed Central  Google Scholar 

  160. 160.

    Wang Z, Zheng Y, Hou C, Yang L, Li X, Lin J et al (2013) DNA methylation impairs TLR9 induced Foxp3 expression by attenuating IRF-7 binding activity in fulminant type 1 diabetes. J Autoimmun 41:50–59

    PubMed  Google Scholar 

  161. 161.

    Fradin D, Le Fur S, Mille C, Naoui N, Groves C, Zelenika D et al (2012) Association of the CpG methylation pattern of the proximal insulin gene promoter with type 1 diabetes. PLoS One 7:e36278

    PubMed  CAS  PubMed Central  Google Scholar 

  162. 162.

    Akirav EM, Lebastchi J, Galvan EM, Henegariu O, Akirav M, Ablamunits V et al (2011) Detection of beta cell death in diabetes using differentially methylated circulating DNA. Proc Natl Acad Sci U S A 108:19018–19023

    PubMed  CAS  PubMed Central  Google Scholar 

  163. 163.

    Fisher MM, Perez Chumbiauca CN, Mather KJ, Mirmira RG, Tersey SA (2013) Detection of islet beta-cell death in vivo by multiplex PCR analysis of differentially methylated DNA. Endocrinology 154:3476–3481

    PubMed  CAS  PubMed Central  Google Scholar 

  164. 164.

    Stefan M, Zhang W, Concepcion E, Yi Z, Tomer Y (2013) DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J Autoimmun. doi:10.1016/j.jaut.2013.10.001

    PubMed Central  Google Scholar 

  165. 165.

    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45

    PubMed  CAS  Google Scholar 

  166. 166.

    Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102:10604–10609

    PubMed  CAS  PubMed Central  Google Scholar 

  167. 167.

    Menegatti E, Berardi D, Messina M, Ferrante I, Giachino O, Spagnolo B et al (2013) Lab-on-a-chip: emerging analytical platforms for immune-mediated diseases. Autoimmun Rev 12:814–820

    PubMed  CAS  Google Scholar 

  168. 168.

    Miao F, Smith DD, Zhang L, Min A, Feng W, Natarajan R (2008) Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation: an epigenetic study in diabetes. Diabetes 57:3189–3198

    PubMed  CAS  PubMed Central  Google Scholar 

  169. 169.

    Orban T, Kis J, Szereday L, Engelmann P, Farkas K, Jalahej H et al (2007) Reduced CD4+ T-cell-specific gene expression in human type 1 diabetes mellitus. J Autoimmun 28:177–187

    PubMed  CAS  Google Scholar 

  170. 170.

    Miao F, Chen Z, Zhang L, Liu Z, Wu X, Yuan YC et al (2012) Profiles of epigenetic histone post-translational modifications at type 1 diabetes susceptible genes. J Biol Chem 287:16335–16345

    PubMed  CAS  PubMed Central  Google Scholar 

  171. 171.

    Chen K, Rajewsky N (2007) The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet 8:93–103

    PubMed  CAS  Google Scholar 

  172. 172.

    Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    PubMed  CAS  Google Scholar 

  173. 173.

    Singh RP, Massachi I, Manickavel S, Singh S, Rao NP, Hasan S et al (2013) The role of miRNA in inflammation and autoimmunity. Autoimmun Rev 12:1160–1165

    PubMed  CAS  Google Scholar 

  174. 174.

    Saito Y, Saito H, Liang G, Friedman JM (2013) Epigenetic alterations and microRNA misexpression in cancer and autoimmune diseases: a critical review. Clin Revi Allergy Immunol. [E-pub ahead of print]

  175. 175.

    Iborra M, Bernuzzi F, Invernizzi P, Danese S (2012) MicroRNAs in autoimmunity and inflammatory bowel disease: crucial regulators in immune response. Autoimmun Rev 11:305–314

    PubMed  CAS  Google Scholar 

  176. 176.

    Fernandez-Valverde SL, Taft RJ, Mattick JS (2011) MicroRNAs in beta-cell biology, insulin resistance, diabetes and its complications. Diabetes 60:1825–1831

    PubMed  CAS  PubMed Central  Google Scholar 

  177. 177.

    Sebastiani G, Grieco FA, Spagnuolo I, Galleri L, Cataldo D, Dotta F (2011) Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity. Diabetes Metab Res Rev 27:862–866

    PubMed  CAS  Google Scholar 

  178. 178.

    Hezova R, Slaby O, Faltejskova P, Mikulkova Z, Buresova I, Raja KR et al (2010) microRNA-342, microRNA-191 and microRNA-510 are differentially expressed in T regulatory cells of type 1 diabetic patients. Cell Immunol 260:70–74

    PubMed  CAS  Google Scholar 

  179. 179.

    Salas-Perez F, Codner E, Valencia E, Pizarro C, Carrasco E, Perez-Bravo F (2013) MicroRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology 218:733–737

    PubMed  CAS  Google Scholar 

  180. 180.

    Nielsen LB, Wang C, Sorensen K, Bang-Berthelsen CH, Hansen L, Andersen ML et al (2012) Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual beta-cell function and glycaemic control during disease progression. Exp Diabetes Res 2012:896362

    PubMed  PubMed Central  Google Scholar 

  181. 181.

    Sebastiani G, Spagnuolo I, Patti A, Grieco FA, Cataldo D, Ferretti E et al (2012) MicroRNA expression fingerprint in serum of type 1 diabetic patients. Diabetologia 55:S48

    Google Scholar 

  182. 182.

    Ruan Q, Wang T, Kameswaran V, Wei Q, Johnson DS, Matschinsky F et al (2011) The microRNA-21-PDCD4 axis prevents type 1 diabetes by blocking pancreatic beta cell death. Proc Natl Acad Sci U S A 108:12030–12035

    PubMed  CAS  PubMed Central  Google Scholar 

  183. 183.

    Jimenez SA, Piera-Velazquez S (2013) Potential role of human-specific genes, human-specific microRNAs and human-specific non-coding regulatory RNAs in the pathogenesis of systemic sclerosis and Sjogren’s syndrome. Autoimmun Rev 12:1046–1051

    PubMed  CAS  PubMed Central  Google Scholar 

  184. 184.

    De Santis M, Selmi C (2012) The therapeutic potential of epigenetics in autoimmune diseases. Clin Rev Allergy Immunol 42:92–101

    PubMed  CAS  Google Scholar 

  185. 185.

    Hyoty H, Taylor KW (2002) The role of viruses in human diabetes. Diabetologia 45:1353–1361

    PubMed  CAS  Google Scholar 

  186. 186.

    Honeyman MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE et al (2000) Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 49:1319–1324

    PubMed  CAS  Google Scholar 

  187. 187.

    Ramondetti F, Sacco S, Comelli M, Bruno G, Falorni A, Iannilli A et al (2012) Type 1 diabetes and measles, mumps and rubella childhood infections within the Italian Insulin-dependent Diabetes Registry. Diabet Med J Br Diabet Assoc 29:761–766

    CAS  Google Scholar 

  188. 188.

    Aarnisalo J, Veijola R, Vainionpaa R, Simell O, Knip M, Ilonen J (2008) Cytomegalovirus infection in early infancy: risk of induction and progression of autoimmunity associated with type 1 diabetes. Diabetologia 51:769–772

    PubMed  CAS  Google Scholar 

  189. 189.

    Coppieters KT, Wiberg A, von Herrath MG (2012) Viral infections and molecular mimicry in type 1 diabetes. APMIS 120:941–949

    PubMed  CAS  Google Scholar 

  190. 190.

    Blank M, Barzilai O, Shoenfeld Y (2007) Molecular mimicry and auto-immunity. Clin Rev Allergy Imunol 32:111–118

    Google Scholar 

  191. 191.

    Atkinson MA, Bowman MA, Campbell L, Darrow BL, Kaufman DL, Maclaren NK (1994) Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J Clin Invest 94:2125–2129

    PubMed  CAS  PubMed Central  Google Scholar 

  192. 192.

    Cusick MF, Libbey JE, Fujinami RS (2012) Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Imunol 42:102–111

    CAS  Google Scholar 

  193. 193.

    Harkonen T, Lankinen H, Davydova B, Hovi T, Roivainen M (2002) Enterovirus infection can induce immune responses that cross-react with beta-cell autoantigen tyrosine phosphatase IA-2/IAR. J Med Virol 66:340–350

    PubMed  CAS  Google Scholar 

  194. 194.

    Hiemstra HS, Schloot NC, van Veelen PA, Willemen SJ, Franken KL, van Rood JJ et al (2001) Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase. Proc Natl Acad Sci U S A 98:3988–3991

    PubMed  CAS  PubMed Central  Google Scholar 

  195. 195.

    Singh B, Delovitch TL (2000) Immune mechanisms that regulate susceptibility to autoimmune type I diabetes. Clin Rev Allergy Imunol 19:247–264

    CAS  Google Scholar 

  196. 196.

    Han S, Donelan W, Wang H, Reeves W, Yang LJ (2013) Novel autoantigens in type 1 diabetes. Am J Transl Res 5:379–392

    PubMed  CAS  PubMed Central  Google Scholar 

  197. 197.

    Roep BO, Peakman M (2012) Antigen targets of type 1 diabetes autoimmunity. Cold Spring Harb Perspect Med 2:a007781

    PubMed  PubMed Central  Google Scholar 

  198. 198.

    Delong T, Baker RL, He J, Haskins K (2013) Novel autoantigens for diabetogenic CD4 T cells in autoimmune diabetes. Immunol Res 55:167–172

    PubMed  CAS  PubMed Central  Google Scholar 

  199. 199.

    Brooks-Worrell B, Warsen A, Palmer JP (2009) Improved T cell assay for identification of type 1 diabetes patients. J Immunol Methods 344:79–83

    PubMed  CAS  Google Scholar 

  200. 200.

    Knip M, Siljander H (2008) Autoimmune mechanisms in type 1 diabetes. Autoimmun Rev 7:550–557

    PubMed  CAS  Google Scholar 

  201. 201.

    Wildner G, Kaufmann U (2013) What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells. Autoimmun Rev 12:1070–1075

    PubMed  CAS  Google Scholar 

  202. 202.

    Sarikonda G, Pettus J, Phatak S, Sachithanantham S, Miller JF, Wesley JD et al (2013) CD8 T-cell reactivity to islet antigens is unique to type 1 while CD4 T-cell reactivity exists in both type 1 and type 2 diabetes. J Autoimmun. doi:10.1016/j.jaut.2013.12.003

    PubMed  Google Scholar 

  203. 203.

    Stadinski B, Kappler J, Eisenbarth GS (2010) Molecular targeting of islet autoantigens. Immunity 32:446–456

    PubMed  CAS  Google Scholar 

  204. 204.

    Askenasy EM, Askenasy N (2013) Is autoimmune diabetes caused by aberrant immune activity or defective suppression of physiological self-reactivity? Autoimmun Rev 12:633–637

    PubMed  CAS  Google Scholar 

  205. 205.

    Schloot NC, Willemen SJ, Duinkerken G, Drijfhout JW, de Vries RR, Roep BO (2001) Molecular mimicry in type 1 diabetes mellitus revisited: T-cell clones to GAD65 peptides with sequence homology to Coxsackie or proinsulin peptides do not crossreact with homologous counterpart. Hum Immunol 62:299–309

    PubMed  CAS  Google Scholar 

  206. 206.

    Boettler T, Pagni PP, Jaffe R, Cheng Y, Zerhouni P, von Herrath M (2013) The clinical and immunological significance of GAD-specific autoantibody and T-cell responses in type 1 diabetes. J Autoimmun 44:40–48

    PubMed  CAS  Google Scholar 

  207. 207.

    Leslie RD, Atkinson MA, Notkins AL (1999) Autoantigens IA-2 and GAD in type I (insulin-dependent) diabetes. Diabetologia 42:3–14

    PubMed  CAS  Google Scholar 

  208. 208.

    Palmer JP, Asplin CM, Clemons P, Lyen K, Tatpati O, Raghu PK et al (1983) Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 222:1337–1339

    PubMed  CAS  Google Scholar 

  209. 209.

    Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P et al (2007) The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 104:17040–17045

    PubMed  CAS  PubMed Central  Google Scholar 

  210. 210.

    Bottazzo GF, Florin-Christensen A, Doniach D (1974) Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2:1279–1283

    PubMed  CAS  Google Scholar 

  211. 211.

    Taplin CE, Barker JM (2008) Autoantibodies in type 1 diabetes. Autoimmunity 41:11–18

    PubMed  CAS  Google Scholar 

  212. 212.

    Yang L, Luo S, Huang G, Peng J, Li X, Yan X et al (2010) The diagnostic value of zinc transporter 8 autoantibody (ZnT8A) for type 1 diabetes in Chinese. Diabetes Metab Res Rev 26:579–584

    PubMed  CAS  PubMed Central  Google Scholar 

  213. 213.

    Pihoker C, Gilliam LK, Hampe CS, Lernmark A (2005) Autoantibodies in diabetes. Diabetes 54(Suppl 2):S52–S61

    PubMed  CAS  Google Scholar 

  214. 214.

    Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Chase HP et al (1996) Number of autoantibodies (against insulin, GAD or ICA512/IA2) rather than particular autoantibody specificities determines risk of type I diabetes. J Autoimmun 9:379–383

    PubMed  CAS  Google Scholar 

  215. 215.

    Huang G, Wang X, Li Z, Li H, Li X, Zhou Z (2012) Insulin autoantibody could help to screen latent autoimmune diabetes in adults in phenotypic type 2 diabetes mellitus in Chinese. Acta Diabetol 49:327–331

    PubMed  CAS  Google Scholar 

  216. 216.

    Graham J, Hagopian WA, Kockum I, Li LS, Sanjeevi CB, Lowe RM et al (2002) Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 51:1346–1355

    PubMed  CAS  Google Scholar 

  217. 217.

    Miao D, Yu L, Eisenbarth GS (2007) Role of autoantibodies in type 1 diabetes. Front Biosci J Virtual Libr 12:1889–1898

    CAS  Google Scholar 

  218. 218.

    Noble JA, Valdes AM, Bugawan TL, Apple RJ, Thomson G, Erlich HA (2002) The HLA class I A locus affects susceptibility to type 1 diabetes. Hum Immunol 63:657–664

    PubMed  CAS  PubMed Central  Google Scholar 

  219. 219.

    Noble JA, Valdes AM, Varney MD, Carlson JA, Moonsamy P, Fear AL et al (2010) HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes 59:2972–2979

    PubMed  CAS  PubMed Central  Google Scholar 

  220. 220.

    Coit P, Jeffries M, Altorok N, Dozmorov MG, Koelsch KA, Wren JD et al (2013) Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naive CD4+ T cells from lupus patients. J Autoimmun 43:78–84

    PubMed  CAS  PubMed Central  Google Scholar 

  221. 221.

    Cui Y, Sheng Y, Zhang X (2013) Genetic susceptibility to SLE: recent progress from GWAS. J Autoimmun 41:25–33

    PubMed  CAS  Google Scholar 

  222. 222.

    Qu HQ, Bradfield JP, Li Q, Kim C, Frackelton E, Grant SF et al (2010) In silico replication of the genome-wide association results of the Type 1 Diabetes Genetics Consortium. Hum Mol Genet 19:2534–2538

    PubMed  CAS  Google Scholar 

  223. 223.

    Schaschl H, Aitman TJ, Vyse TJ (2009) Copy number variation in the human genome and its implication in autoimmunity. Clin Exp Immunol 156:12–16

    PubMed  CAS  PubMed Central  Google Scholar 

  224. 224.

    Grayson BL, Smith ME, Thomas JW, Wang L, Dexheimer P, Jeffrey J et al (2010) Genome-wide analysis of copy number variation in type 1 diabetes. PLoS One 5:e15393

    PubMed  PubMed Central  Google Scholar 

  225. 225.

    Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD (2008) MicroRNAs: new regulators of immune cell development and function. Nat Immunol 9:839–845

    PubMed  CAS  Google Scholar 

  226. 226.

    Pauley KM, Cha S, Chan EK (2009) MicroRNA in autoimmunity and autoimmune diseases. J Autoimmun 32:189–194

    PubMed  CAS  PubMed Central  Google Scholar 

  227. 227.

    Dai R, Ahmed SA (2011) MicroRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases. Transl Res J Lab Clin Med 157:163–179

    CAS  Google Scholar 

  228. 228.

    Dahan R, Gebe JA, Preisinger A, James EA, Tendler M, Nepom GT et al (2013) Antigen-specific immunomodulation for type 1 diabetes by novel recombinant antibodies directed against diabetes-associates auto-reactive T cell epitope. J Autoimmun 47:83–93

    PubMed  CAS  Google Scholar 

  229. 229.

    Dunne JL, Overbergh L, Purcell AW, Mathieu C (2012) Posttranslational modifications of proteins in type 1 diabetes: the next step in finding the cure? Diabetes 61:1907–1914

    PubMed  PubMed Central  Google Scholar 

  230. 230.

    van Lummel M, Zaldumbide A, Roep BO (2013) Changing faces, unmasking the beta-cell: post-translational modification of antigens in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 20:299–306

    PubMed  Google Scholar 

  231. 231.

    Mannering SI, Harrison LC, Williamson NA, Morris JS, Thearle DJ, Jensen KP et al (2005) The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J Exp Med 202:1191–1197

    PubMed  CAS  PubMed Central  Google Scholar 

  232. 232.

    Storling J, Overgaard AJ, Brorsson CA, Piva F, Bang-Berthelsen CH, Haase C et al (2013) Do post-translational beta cell protein modifications trigger type 1 diabetes? Diabetologia 56:2347–2354

    PubMed  Google Scholar 

  233. 233.

    Lernmark A (2013) Is there evidence for post-translational modification of beta cell autoantigens in the aetiology and pathogenesis of type 1 diabetes? Diabetologia [E-pub ahead of print].

  234. 234.

    Edwards LJ, Evavold BD (2013) Destabilization of peptide:MHC interaction induces IL-2 resistant anergy in diabetogenic T cells. J Autoimmun 44:82–90

    PubMed  CAS  Google Scholar 

  235. 235.

    Gravano DM, Hoyer KK (2013) Promotion and prevention of autoimmune disease by CD8+ T cells. J Autoimmun 45:68–79

    PubMed  CAS  Google Scholar 

  236. 236.

    Vaarala O (2012) Is the origin of type 1 diabetes in the gut? Immunol Cell Biol 90:271–276

    PubMed  CAS  Google Scholar 

  237. 237.

    Kosiewicz MM, Zirnheld AL, Alard P (2011) Gut microbiota, immunity, and disease: a complex relationship. Front Microbiol 2:180

    PubMed  PubMed Central  Google Scholar 

  238. 238.

    Pillai S (2013) Rethinking mechanisms of autoimmune pathogenesis. J Autoimmun 45:97–103

    PubMed  CAS  Google Scholar 

  239. 239.

    Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F et al (2013) Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med 11:46

    PubMed  PubMed Central  Google Scholar 

  240. 240.

    Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U et al (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–498

    PubMed  CAS  PubMed Central  Google Scholar 

  241. 241.

    Romano-Keeler J, Weitkamp JH, Moore DJ (2012) Regulatory properties of the intestinal microbiome effecting the development and treatment of diabetes. Curr Opin Endocrinol Diabetes Obes 19:73–80

    PubMed  CAS  PubMed Central  Google Scholar 

  242. 242.

    Vaarala O (2013) Human intestinal microbiota and type 1 diabetes. Curr Diabetes Rep 13:601–607

    CAS  Google Scholar 

  243. 243.

    Brooks WH (2012) Mechanisms and pathophysiology of autoimmune disease. Clin Rev Allergy Immunol 42:1–4

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Dr. Eric Gershwin and Qianjin Lu for their advice and proofreading of the manuscript. This work was supported by the National Natural Science Foundation of China (Grant No. 81170725), the European Foundation for the Study of Diabetes (Grant No. EFSD/CDS/Lilly-2010), Hunan Provincial Natural Science Foundation of China (11JJ7005), Program for Changjiang Scholars and Innovative Research Team in University (IRT1195) and the National Key Technology R&D program (2012BAI02B04).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Christopher Chang.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xie, Z., Chang, C. & Zhou, Z. Molecular Mechanisms in Autoimmune Type 1 Diabetes: a Critical Review. Clinic Rev Allerg Immunol 47, 174–192 (2014). https://doi.org/10.1007/s12016-014-8422-2

Download citation

Keywords

  • Type 1 diabetes
  • HLA
  • Epigenetics
  • Molecular mimicry
  • Autoantigen
  • Autoantibody