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Clinical Reviews in Allergy & Immunology
Published in: Clinical Reviews in Allergy & Immunology 2/2014

01-10-2014

Molecular Mechanisms in Autoimmune Type 1 Diabetes: a Critical Review

Authors: Zhiguo Xie, Christopher Chang, Zhiguang Zhou

Published in: Clinical Reviews in Allergy & Immunology | Issue 2/2014

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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.
Literature
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 373:2027–2033PubMed
2.
Ounissi-Benkalha H, Polychronakos C (2008) The molecular genetics of type 1 diabetes: new genes and emerging mechanisms. Trends Mol Med 14:268–275PubMed
3.
4.
Atkinson MA, Eisenbarth GS, Michels AW (2014) Type 1 diabetes. Lancet 383:69–82PubMed
5.
6.
Dabelea D (2009) The accelerating epidemic of childhood diabetes. Lancet 373:1999–2000PubMed
7.
Gale EA (2005) Type 1 diabetes in the young: the harvest of sorrow goes on. Diabetologia 48:1435–1438PubMed
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 23:290–294PubMed
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 23:1516–1526PubMed
10.
Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ (2010) Epidemiology of type 1 diabetes. Endocrinol Metab Clin N Am 39:481–497
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–B80PubMed
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 21:525–529PubMed
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 35:237–241PubMed
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 62:543–550PubMedPubMedCentral
15.
Brahmkshatriya PP, Mehta AA, Saboo BD, Goyal RK (2012) Characteristics and prevalence of latent autoimmune diabetes in adults (LADA). ISRN Pharmacol 2012:580202PubMedPubMedCentral
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 48:2206–2212PubMed
17.
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 20:981–987PubMed
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 33:104–108PubMedPubMedCentral
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 51:3391–3394PubMed
21.
Gale EA (2005) Latent autoimmune diabetes in adults: a guide for the perplexed. Diabetologia 48:2195–2199PubMed
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 91:1654–1659PubMed
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 48:150–157PubMed
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 156:787–796PubMed
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 26:452–457PubMed
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 50:68–73PubMedPubMedCentral
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 55:1890–1894PubMed
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 31:534–538PubMed
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 57:1433–1437PubMed
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 1150:99–102PubMed
31.
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 31:747–750PubMed
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 44:354–362PubMed
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 41:703–707PubMedPubMedCentral
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 359:2767–2777PubMedPubMedCentral
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 57:229–234PubMed
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:e1002293PubMedPubMedCentral
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 55:996–1000PubMedPubMedCentral
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 39:857–864PubMedPubMedCentral
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 38:617–619PubMed
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 11:432–438PubMed
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 5:1075–1080PubMed
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 40:1399–1401PubMedPubMedCentral
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 12:59PubMedPubMedCentral
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 3:238–247PubMedPubMedCentral
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 129:161–176PubMedPubMedCentral
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):31–45PubMedPubMedCentral
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 450:887–892PubMedPubMedCentral
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 10:188–191PubMed
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 36:837–841PubMed
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 60:1041–1044PubMedPubMedCentral
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 12:208–212PubMedPubMedCentral
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 39:1074–1082PubMed
54.
Bell GI, Horita S, Karam JH (1984) A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176–183PubMed
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 53:1884–1889PubMed
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 57:1143–1146PubMed
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 13:66–70PubMedPubMedCentral
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 54:2033–2037PubMed
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 12:127–132PubMed
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 467:460–464PubMedPubMedCentral
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 42:68–71PubMedPubMedCentral
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 46:553–554PubMedPubMedCentral
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 19:2059–2067PubMedPubMedCentral
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 60:3081–3084PubMedPubMedCentral
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 57:2858–2861PubMedPubMedCentral
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 58:331–338PubMed
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–S94PubMedPubMedCentral
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 59:1561–1571PubMedPubMedCentral
69.
Morahan G (2012) Insights into type 1 diabetes provided by genetic analyses. Curr Opin Endocrinol Diabetes Obes 19:263–270PubMed
70.
Singal DP, Blajchman MA (1973) Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes 22:429–432PubMed
71.
Mehers KL, Gillespie KM (2008) The genetic basis for type 1 diabetes. Br Med Bull 88:115–129PubMed
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 5:889–899PubMed
73.
Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. Nature. 1999;401:921-3
74.
75.
van Belle TL, Coppieters KT, von Herrath MG (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79–118PubMed
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 70:110–127PubMed
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 57:1084–1092PubMedPubMedCentral
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 19:931–934PubMed
79.
She JX (1996) Susceptibility to type I diabetes: HLA-DQ and DR revisited. Immunol Today 17:323–329PubMed
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 46:143–149PubMed
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 51:545–551PubMed
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 69:284–289PubMed
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 59:794–801PubMed
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 85:4538–4542PubMed
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 122:980–986PubMed
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 44:210–219PubMed
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 59:1134–1148PubMedPubMedCentral
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–S121PubMed
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 54:543–551PubMed
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 47:1971–1973PubMed
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 35:419–424PubMed
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 320:881–886PubMed
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
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 4PubMed
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 33:2062–2064PubMedPubMedCentral
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
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 9:284–292PubMed
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 11:188–193PubMedPubMedCentral
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 15:289–292PubMed
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 15:293–297PubMed
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 86:3705–3710PubMed
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 423:506–511PubMed
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 322:271–275PubMed
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 35:2157–2162PubMed
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–e57PubMed
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 12:758–767PubMed
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 12:1171–1176PubMed
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 53:3020–3023PubMed
109.
Gregersen PK, Behrens TW (2006) Genetics of autoimmune diseases—disorders of immune homeostasis. Nat Rev Genet 7:917–928PubMed
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 37:1317–1319PubMed
111.
Gregersen PK (2005) Gaining insight into PTPN22 and autoimmunity. Nat Genet 37:1300–1302PubMed
112.
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 12:717–725PubMed
114.
Zheng J, Petersen F, Yu X (2014) The role of PTPN22 in autoimmunity: learning from mice. Autoimmun Rev 13:266–271PubMed
115.
116.
Askenasy N (2013) Enhanced killing activity of regulatory T cells ameliorates inflammation and autoimmunity. Autoimmun Rev 12:972–975PubMed
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 2-3PubMed
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 337:1308–1318PubMed
119.
Caamano J, Hunter CA (2002) NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions. Clin Microbiol Rev 15:414–429PubMedPubMedCentral
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 1150:93–98PubMed
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 164:4659–4664PubMed
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 22:191–200PubMed
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 84:4008–4027PubMed
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 59:302–310PubMedPubMedCentral
125.
Howson JM, Rosinger S, Smyth DJ, Boehm BO, Group A-ES, Todd JA (2011) Genetic analysis of adult-onset autoimmune diabetes. Diabetes 60:2645–2653PubMedPubMedCentral
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
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 35:1060–1067PubMed
128.
Dang MN, Buzzetti R, Pozzilli P (2013) Epigenetics in autoimmune diseases with focus on type 1 diabetes. Diabetes Metab Res Rev 29:8–18PubMed
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–S136PubMed
130.
Akerblom HK, Knip M (1998) Putative environmental factors in Type 1 diabetes. Diabetes Metab Rev 14:31–67PubMed
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 46:420–425PubMed
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 364:1699–1700PubMed
133.
EURODIAB ACE Study Group (2000) Variation and trends in incidence of childhood diabetes in Europe. Lancet 355:873–876
134.
Karagkouni A, Alevizos M, Theoharides TC (2013) Effect of stress on brain inflammation and multiple sclerosis. Autoimmun Rev 12:947–953PubMed
135.
Selmi C (2013) Autoimmunity in 2012. Clin Rev Allergy Immunol 45:290–301PubMed
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 45:1–5PubMed
137.
Brooks WH (2012) Autoimmune diseases and polyamines. Clin Rev Allergy Immunol 42:58–70PubMed
138.
Rook GA (2012) Hygiene hypothesis and autoimmune diseases. Clin Rev Allergy Immunol 42:5–15PubMed
139.
Longnecker MP, Daniels JL (2001) Environmental contaminants as etiologic factors for diabetes. Environ Health Perspect 109(Suppl 6):871–876PubMedPubMedCentral
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 78:1053–1067PubMed
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 66:479–481PubMed
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
143.
Knip M, Virtanen SM, Akerblom HK (2010) Infant feeding and the risk of type 1 diabetes. Am J Clin Nutr 91:1506S–1513SPubMed
144.
Vaarala O (2002) The gut immune system and type 1 diabetes. Ann N Y Acad Sci 958:39–46PubMed
145.
Sepa A, Ludvigsson J (2006) Psychological stress and the risk of diabetes-related autoimmunity: a review article. Neuroimmunomodulation 13:301–308PubMed
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 169:1428–1436PubMed
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:d35PubMedPubMedCentral
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 60:276–279PubMedPubMedCentral
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 59:3174–3180PubMedPubMedCentral
150.
Javierre BM, Hernando H, Ballestar E (2011) Environmental triggers and epigenetic deregulation in autoimmune disease. Discov Med 12:535–545PubMed
151.
Lu Q (2013) The critical importance of epigenetics in autoimmunity. J Autoimmun 41:1–5PubMed
152.
Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057–1068PubMed
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 333:1303–1307PubMedPubMedCentral
154.
Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21PubMed
155.
156.
Sananbenesi F, Fischer A (2009) The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Biol Chem 390:1145–1153PubMed
157.
Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610PubMed
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
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:e1002300PubMedPubMedCentral
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 41:50–59PubMed
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:e36278PubMedPubMedCentral
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 108:19018–19023PubMedPubMedCentral
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 154:3476–3481PubMedPubMedCentral
164.
165.
Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45PubMed
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 102:10604–10609PubMedPubMedCentral
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 12:814–820PubMed
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 57:3189–3198PubMedPubMedCentral
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 28:177–187PubMed
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 287:16335–16345PubMedPubMedCentral
171.
Chen K, Rajewsky N (2007) The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet 8:93–103PubMed
172.
Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114PubMed
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 12:1160–1165PubMed
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.
Iborra M, Bernuzzi F, Invernizzi P, Danese S (2012) MicroRNAs in autoimmunity and inflammatory bowel disease: crucial regulators in immune response. Autoimmun Rev 11:305–314PubMed
176.
Fernandez-Valverde SL, Taft RJ, Mattick JS (2011) MicroRNAs in beta-cell biology, insulin resistance, diabetes and its complications. Diabetes 60:1825–1831PubMedPubMedCentral
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 27:862–866PubMed
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 260:70–74PubMed
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 218:733–737PubMed
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 2012:896362PubMedPubMedCentral
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
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 108:12030–12035PubMedPubMedCentral
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 12:1046–1051PubMedPubMedCentral
184.
De Santis M, Selmi C (2012) The therapeutic potential of epigenetics in autoimmune diseases. Clin Rev Allergy Immunol 42:92–101PubMed
185.
Hyoty H, Taylor KW (2002) The role of viruses in human diabetes. Diabetologia 45:1353–1361PubMed
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 49:1319–1324PubMed
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
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 51:769–772PubMed
189.
Coppieters KT, Wiberg A, von Herrath MG (2012) Viral infections and molecular mimicry in type 1 diabetes. APMIS 120:941–949PubMed
190.
Blank M, Barzilai O, Shoenfeld Y (2007) Molecular mimicry and auto-immunity. Clin Rev Allergy Imunol 32:111–118
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 94:2125–2129PubMedPubMedCentral
192.
Cusick MF, Libbey JE, Fujinami RS (2012) Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Imunol 42:102–111
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 66:340–350PubMed
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 98:3988–3991PubMedPubMedCentral
195.
Singh B, Delovitch TL (2000) Immune mechanisms that regulate susceptibility to autoimmune type I diabetes. Clin Rev Allergy Imunol 19:247–264
196.
197.
198.
Delong T, Baker RL, He J, Haskins K (2013) Novel autoantigens for diabetogenic CD4 T cells in autoimmune diabetes. Immunol Res 55:167–172PubMedPubMedCentral
199.
Brooks-Worrell B, Warsen A, Palmer JP (2009) Improved T cell assay for identification of type 1 diabetes patients. J Immunol Methods 344:79–83PubMed
200.
Knip M, Siljander H (2008) Autoimmune mechanisms in type 1 diabetes. Autoimmun Rev 7:550–557PubMed
201.
Wildner G, Kaufmann U (2013) What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells. Autoimmun Rev 12:1070–1075PubMed
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
203.
Stadinski B, Kappler J, Eisenbarth GS (2010) Molecular targeting of islet autoantigens. Immunity 32:446–456PubMed
204.
Askenasy EM, Askenasy N (2013) Is autoimmune diabetes caused by aberrant immune activity or defective suppression of physiological self-reactivity? Autoimmun Rev 12:633–637PubMed
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 62:299–309PubMed
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 44:40–48PubMed
207.
Leslie RD, Atkinson MA, Notkins AL (1999) Autoantigens IA-2 and GAD in type I (insulin-dependent) diabetes. Diabetologia 42:3–14PubMed
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 222:1337–1339PubMed
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 104:17040–17045PubMedPubMedCentral
210.
Bottazzo GF, Florin-Christensen A, Doniach D (1974) Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2:1279–1283PubMed
211.
Taplin CE, Barker JM (2008) Autoantibodies in type 1 diabetes. Autoimmunity 41:11–18PubMed
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 26:579–584PubMedPubMedCentral
213.
Pihoker C, Gilliam LK, Hampe CS, Lernmark A (2005) Autoantibodies in diabetes. Diabetes 54(Suppl 2):S52–S61PubMed
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 9:379–383PubMed
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 49:327–331PubMed
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 51:1346–1355PubMed
217.
Miao D, Yu L, Eisenbarth GS (2007) Role of autoantibodies in type 1 diabetes. Front Biosci J Virtual Libr 12:1889–1898
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 63:657–664PubMedPubMedCentral
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 59:2972–2979PubMedPubMedCentral
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 43:78–84PubMedPubMedCentral
221.
Cui Y, Sheng Y, Zhang X (2013) Genetic susceptibility to SLE: recent progress from GWAS. J Autoimmun 41:25–33PubMed
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 19:2534–2538PubMed
223.
Schaschl H, Aitman TJ, Vyse TJ (2009) Copy number variation in the human genome and its implication in autoimmunity. Clin Exp Immunol 156:12–16PubMedPubMedCentral
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:e15393PubMedPubMedCentral
225.
Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD (2008) MicroRNAs: new regulators of immune cell development and function. Nat Immunol 9:839–845PubMed
226.
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
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 47:83–93PubMed
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 61:1907–1914PubMedPubMedCentral
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 20:299–306PubMed
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 202:1191–1197PubMedPubMedCentral
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 56:2347–2354PubMed
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.
Edwards LJ, Evavold BD (2013) Destabilization of peptide:MHC interaction induces IL-2 resistant anergy in diabetogenic T cells. J Autoimmun 44:82–90PubMed
235.
Gravano DM, Hoyer KK (2013) Promotion and prevention of autoimmune disease by CD8+ T cells. J Autoimmun 45:68–79PubMed
236.
Vaarala O (2012) Is the origin of type 1 diabetes in the gut? Immunol Cell Biol 90:271–276PubMed
237.
Kosiewicz MM, Zirnheld AL, Alard P (2011) Gut microbiota, immunity, and disease: a complex relationship. Front Microbiol 2:180PubMedPubMedCentral
238.
Pillai S (2013) Rethinking mechanisms of autoimmune pathogenesis. J Autoimmun 45:97–103PubMed
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 11:46PubMedPubMedCentral
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 139:485–498PubMedPubMedCentral
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 19:73–80PubMedPubMedCentral
242.
Vaarala O (2013) Human intestinal microbiota and type 1 diabetes. Curr Diabetes Rep 13:601–607
243.
Brooks WH (2012) Mechanisms and pathophysiology of autoimmune disease. Clin Rev Allergy Immunol 42:1–4PubMed
Metadata
Title
Molecular Mechanisms in Autoimmune Type 1 Diabetes: a Critical Review
Authors
Zhiguo Xie
Christopher Chang
Zhiguang Zhou
Publication date
01-10-2014
Publisher
Springer US
Published in
Clinical Reviews in Allergy & Immunology / Issue 2/2014
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI
https://doi.org/10.1007/s12016-014-8422-2

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