Pathogenesis of type 1 diabetes mellitus: Interplay between enterovirus and host

Nature Reviews Endocrinology

Volumn 6, Issue 5, 2010, Pages 279-289

  Hober, Didier ^a   Sauter, Pierre ^a  

^a University Lille   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; BETA INTERFERON; CD4 ANTIGEN; CD8 ANTIGEN; DOUBLE STRANDED RNA; EPITOPE; GAMMA INTERFERON; GLUTAMATE DECARBOXYLASE 65; GLYCOPROTEIN; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; IMMUNOGLOBULIN A; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IMMUNOGLOBULIN G; IMMUNOGLOBULIN M ANTIBODY; INTERLEUKIN 1BETA; NUCLEOPROTEIN; PROTEIN SERINE THREONINE KINASE; PROTEIN VP1; PROTEIN VP2; PROTEIN VP3; PROTEIN VP4; TOLL LIKE RECEPTOR 3; TUMOR NECROSIS FACTOR; VIRUS RNA;

ADAPTIVE IMMUNITY; ALLELE; ANTIBODY DEPENDENT ENHANCEMENT; APOPTOSIS; AUTOIMMUNITY; B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL DAMAGE; CELL DEATH; CELL DIFFERENTIATION; CELL DIVISION; CELL FUNCTION; CELL INFILTRATION; CELL LOSS; CELL MATURATION; CELL STIMULATION; CELL STRESS; COXSACKIE VIRUS B; CYTOKINE PRODUCTION; CYTOLYSIS; CYTOTOXIC T LYMPHOCYTE; DENDRITIC CELL; ENTEROVIRUS; ENZYME ACTIVITY; EPITHELIUM CELL; GENETIC SCREENING; HEART; HISTOLOGY; HOST; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOHISTOCHEMISTRY; IN SITU HYBRIDIZATION; IN VITRO STUDY; INCIDENCE; INSULIN DEPENDENT DIABETES MELLITUS; MACROPHAGE; MAJOR HISTOCOMPATIBILITY COMPLEX; MONOCYTE; NONHUMAN; PANCREAS; PANCREAS ISLET; PANCREATITIS; PATHOGENESIS; PERIPHERAL BLOOD MONONUCLEAR CELL; PICORNAVIRUS; PREVALENCE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; REVIEW; RISK FACTOR; SCREENING; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; SPLEEN; TH1 CELL; THYMOCYTE; THYMUS; UPREGULATION; VIREMIA; VIRUS DETECTION; VIRUS ISOLATION; VIRUS MENINGITIS; VIRUS MYOCARDITIS; VIRUS REPLICATION;

ADAPTIVE IMMUNITY; DIABETES MELLITUS, TYPE 1; ENTEROVIRUS; ENTEROVIRUS INFECTIONS; HUMANS; HYGIENE; IMMUNE TOLERANCE; IMMUNITY, INNATE; INSULIN-SECRETING CELLS; MOLECULAR MIMICRY; PANCREAS;

EID: 77951666052     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2010.27     Document Type: Review

References (126)

1. th century. Diabetes 51, 3353-3361 (2002).
2. Jaïdane, H. & Hober, D. Role of coxsackievirus B4 in the pathogenesis of type 1 diabetes. Diabetes Metab. 34, 537-548 (2008).
3. Kondrashova, A. et al. A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland. Ann. Med. 37, 67-72 (2005).
4. Nejentsev, S. et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450, 887-892 (2007).
5. Smyth, D. J. 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 (2006).
6. Todd, J. A. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857-864 (2007).
7. Concannon, P. et al. A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Diabetes 57, 2858-2861 (2008).
8. Cooper, J. D. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat. Genet. 40, 1399-1401 (2008).
9. Jaïdane, H. et al. Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models. Diabetes Metab. Res. Rev. 25, 591-603 (2009).
10. Bach, J. F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911-920 (2002).
11. Goldberg, E. & Krause, I. Infection and type 1 diabetes mellitus - a two edged sword? Autoimmun. Rev. 8, 682-686 (2009).
12. Yoon, J. W. A new look at viruses in type 1 diabetes. Diabetes Metab. Rev. 11, 83-107 (1995).
13. Richer, M. J. & Horwitz, M. S. Coxsackievirus infection as an environmental factor in the etiology of type 1 diabetes. Autoimmun. Rev. 8, 611-615 (2009).
14. Hyöty, H. Enterovirus infections and type 1 diabetes. Ann. Med. 34, 138-147 (2002).
15. Haverkos, H. W., Battula, N., Drotman, D. P. & Rennert, O. M. Enteroviruses and type 1 diabetes mellitus. Biomed. Pharmacother. 57, 379-385 (2003).
16. Hyöty, H. & Taylor, K. W. The role of viruses in human diabetes. Diabetologia 45, 1353-1361 (2002).
17. Nairn, C., Galbraith, D. N., Taylor, K. W. & Clements, G. B. Enterovirus variants in the serum of children at the onset of type 1 diabetes mellitus. Diabet. Med. 16, 509-513 (1999).
18. Yin, H., Berg, A. K., Tuvemo, T. & Frisk, G. Enterovirus RNA is found in peripheral blood mononuclear cells in a majority of type 1 diabetic children at onset. Diabetes 51, 1964-1971 (2002).
19. Moya-Suri, V. et al. Enterovirus RNA sequences in sera of schoolchildren in the general population and their association with type 1-diabetes-associated autoantibodies. J. Med. Microbiol. 54, 879-883 (2005).
20. Sarmiento, L. et al. Occurrence of enterovirus RNA in serum of children with newly diagnosed type 1 diabetes and islet cell autoantibody-positive subjects in a population with a low incidence of type 1 diabetes. Autoimmunity 40, 540-545 (2007).
21. Elfaitouri, A. et al. Recent enterovirus infection in type 1 diabetes: evidence with a novel IgM method. J. Med. Virol. 79, 1861-1867 (2007).
22. Chehadeh, W. et al. Increased level of interferon-α in blood of patients with insulin-dependent diabetes mellitus: relationship with coxsackievirus B infection. J. Infect. Dis. 181, 1929-1939 (2000).
23. Oikarinen, M. et al. Detection of enteroviruses in the intestine of type 1 diabetic patients. Clin. Exp. Immunol. 151, 71-75 (2008).
24. Elfving, M. et al. Maternal enterovirus infection during pregnancy as a risk factor in offspring diagnosed with type 1 diabetes between 15 and 30 years of age. Exp. Diabetes Res. 2008, 271958 (2008).
25. Imagawa, A., Hanafusa, T., Makino, H., Miyagawa, J. I. & Juto, P. High titres of IgA antibodies to enterovirus in fulminant type-1 diabetes. Diabetologia 48, 290-293 (2005).
26. Akatsuka, H. et al. A case of fulminant type 1 diabetes with coxsackie B4 virus infection diagnosed by elevated serum levels of neutralizing antibody. Diabetes Res. Clin. Pract. 84, e50-e52 (2009).
27. Gerling, I., Chatterjee, N. K. & Nejman, C. Coxsackievirus B4-induced development of antibodies to 64,000-Mr islet autoantigen and hyperglycemia in mice. Autoimmunity 10, 49-56 (1991).
28. Hyöty, H. et al. A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes 44, 652-657 (1995).
29. Sadeharju, K., Knip, M., Hiltunen, M., Akerblom, H. K. & Hyöty, H. The HLA-DR phenotype modulates the humoral immune response to enterovirus antigens. Diabetologia 46, 1100-1105 (2003).
30. Dahlquist, G. G., Boman, J. E. & Juto, P. Enteroviral RNA and IgM antibodies in early pregnancy and risk for childhood-onset IDDM in offspring. Diabetes Care 22, 364-365 (1999).
31. Dahlquist, G. G., Ivarsson, S., Lindberg, B. & Forsgren. M. Maternal enteroviral infection during pregnancy as a risk factor for childhood IDDM. A population-based case-control study. Diabetes 44, 408-413 (1995).
32. Foulis, A. K., Farquharson, M. A. & Meager, A. Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 2, 1423-1427 (1987).
33. Huang, X. et al. Interferon expression in the pancreases of patients with type I diabetes. Diabetes 44, 658-664 (1995).
34. Dotta, F. et al. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc. Natl Acad. Sci. USA 104, 5115-5120 (2007).
35. Yoon, J. W., Austin, M., Onodera, T. & Notkins, A. L. Isolation of a virus from the pancreas of a child with diabetic ketoacidosis (virus-induced diabetes mellitus). N. Engl. J. Med. 300, 1173-1179 (1979).
36. Ylipaasto, P. et al. Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia 47, 225-239 (2004).
37. Richardson, S. J., Willcox, A., Bone, A. J., Foulis, A. K. & Morgan, N. G. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia 5, 1143-1151 (2009).
38. Oikarinen, M. et al. Analysis of pancreas tissue in a child positive for islet cell antibodies. Diabetologia 51, 1796-1802 (2008).
39. Oldstone, M. B. Prevention of type I diabetes in nonobese diabetic mice by virus infection. Science 239, 500-502 (1988).
40. Christen, U. et al. Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient. J. Clin. Invest. 113, 74-84 (2004).
41. Bach, J. F. Infections and autoimmune diseases. J. Autoimmun. 25 (Suppl.), 74-80 (2005).
42. Viskari, H. et al. Relationship between the incidence of type 1 diabetes and maternal enterovirus antibodies: time trends and geographical variation. Diabetologia 48, 1280-1287 (2005).
43. Roivainen, M. et al. Mechanisms of coxsackievirus-induced damage to human pancreatic beta-cells. J. Clin. Endocrinol. Metab. 85, 432-440 (2000).
44. Chehadeh, W. et al. Persistent infection of human pancreatic islets by coxsackievirus B is associated with alpha interferon synthesis in beta cells. J. Virol. 74, 10153-10164 (2000).
45. Frisk, G. & Diderholm, H. Tissue culture of isolated human pancreatic islets infected with different strains of coxsackievirus B4: assessment of virus replication and effects on islet morphology and insulin release. Int. J. Exp. Diabetes Res. 1, 165-175 (2000).
46. Klemola, P., Kaijalainen, S., Ylipaasto, P. & Roivainen, M. Diabetogenic effects of the most prevalent enteroviruses in Finnish sewage. Ann. NY Acad. Sci. 1150, 210-212 (2008).
47. Szopa, T. M., Ward, T., Dronfield, D. M., Portwood, N. D. & Taylor, K. W. Coxsackie B4 viruses with the potential to damage beta cells of the islets are present in clinical isolates. Diabetologia 33, 325-328 (1990).
48. Roivainen, M. Enteroviruses: new findings on the role of enteroviruses in type 1 diabetes. Int. J. Biochem. Cell. Biol. 38, 721-725 (2005).
49. Ylipaasto, P. et al. Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets. Diabetologia 48, 1510-1522 (2005).
50. Yoon, J. W., Onodera, T. & Notkins, A. L. Virus-induced diabetes mellitus. XV. Beta cell damage and insulin-dependent hyperglycemia in mice infected with coxsackie virus B4. J. Exp. Med. 148, 1068-1080 (1978). (Pubitemid 9034273)
51. Coppieters, K. T. & von Herrath, M. G. Histopathology of type 1 diabetes: old paradigms and new insights. Rev. Diabet. Stud. 6, 85-96 (2009).
52. Atkinson, M. A. & Gianani, R. The pancreas in human type 1 diabetes: providing new answers to age-old questions. Curr. Opin. Endocrinol. Diabetes Obes. 16, 279-285 (2009).
53. Tracy, S. & Drescher, K. M. Coxsackievirus infections and NOD mice relevant models of protection from, and induction of, type 1 diabetes. Ann. NY Acad. Sci. 1103, 143-151 (2007).
54. Tracy, S. et al. Toward testing the hypothesis that group B coxsackieviruses (CVB) trigger insulin-dependent diabetes: inoculating nonobese diabetic mice with CVB markedly lowers diabetes incidence. J. Virol. 76, 12097-12111 (2002).
55. Bortell, R., Pino, S. C., Greiner, D. L., Zipris, D. & Rossini, A. A. Closing the circle between the bedside and the bench: Toll-like receptors in models of virally induced diabetes. Ann. NY Acad. Sci. 1150, 112-122 (2008).
56. Rossini, A. A. Autoimmune diabetes and the circle of tolerance. Diabetes 53, 267-275 (2004).
57. Eizirik, D. L., Colli, M. L. & Ortis, F. The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat. Rev. Endocrinol. 5, 219-226 (2009).
58. Hultcrantz, M. et al. Interferons induce an antiviral state in human pancreatic islet cells. Virology 367, 92-101 (2007).
59. Wen, L., Peng, J., Li, Z. & Wong, F. S. The effect of innate immunity on autoimmune diabetes and the expression of Toll-like receptors on pancreatic islets. J. Immunol. 172, 3173-3180 (2004).
60. Rasschaert, J. et al. Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA+ interferon-gamma-induced apoptosis in primary pancreatic beta-cells. J. Biol. Chem. 280, 33984-33991 (2005).
61. Liu, D., Cardozo, A. K., Darville, M. I. & Eizirik, D. L. Double-stranded RNA cooperates with interferon-gamma and IL-1 beta to induce both chemokine expression and nuclear factor-kappa B-dependent apoptosis in pancreatic beta-cells: potential mechanisms for viral-induced insulitis and beta-cell death in type 1 diabetes mellitus. Endocrinology 143, 1225-1234 (2002).
62. Dogusan, Z. et al. Double-stranded RNA induces pancreatic beta-cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways. Diabetes 57, 1236-1245 (2008).
63. Stewart, T. A. et al. Induction of type 1 diabetes by interferon-alpha in transgenic mice. Science 260, 1942-1946 (1993).
64. Chakrabarti, D., Hultgren, B. & Stewart, T. A. IFN-alpha induces autoimmune T cells through the induction of intracellular adhesion molecule-1 and B7.2. J. Immunol. 157, 522-528 (1996).
65. Scarim, A. L. et al. Mechanisms of beta-cell death in response to double-stranded (ds) RNA and interferon-gamma: dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent necrosis. Am. J. Pathol. 159, 273-283 (2001).
66. Flodström-Tullberg, M. et al. RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection. J. Immunol. 174, 1171-1177 (2005).
67. Colbère-Garapin, F. in Molecular Biology of Picornaviruses (eds Semler, B. L. & Wimmer, E.) (American Society for Microbiology, Washington DC, 2002).
68. Frisk, G., Jansson, K., Ericsson, M. & Diderholm, H. Differences in inhibition of replication between Coxsackie B4 virus strains in various cell lines by antibodies to some cell surface proteins. Virus Res. 73, 121-130 (2001).
69. Skarsvik, S. et al. Decreased in vitro type 1 immune response against coxsackie virus B4 in children with type 1 diabetes. Diabetes 55, 996-1003 (2006).
70. See, D. M. & Tilles, J. G. Pathogenesis of virus-induced diabetes in mice. J. Infect. Dis. 171, 1131-1138 (1995).
71. Merkler, D. et al. "Viral déjà vu" elicits organ-specific immune disease independent of reactivity to self. J. Clin. Invest. 116, 1254-1263 (2006).
72. von Herrath, M., Sanda, S. & Herold, K. Type 1 diabetes as a relapsing-remitting disease? Nat. Rev. Immunol. 7, 988-994 (2007).
73. Lehmann, P. V., Sercarz, E. E., Forsthuber, T., Dayan, C. M. & Gammon, G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol. Today 14, 203-208 (1993).
74. Paronen, J. et al. Glutamate decarboxylase-reactive peripheral blood lymphocytes from patients with IDDM express gut-specific homing receptor alpha4beta7-integrin. Diabetes 46, 583-588 (1997).
75. Horwitz, M. S. et al. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat. Med. 4, 781-785 (1998).
76. Serreze, D. V., Ottendorfer, E. W., Ellis, T. M., Gauntt, C. J. & Atkinson, M. A. Acceleration of type 1 diabetes by a coxsackievirus infection requires preexisting critical mass of autoreactive T-cells in pancreatic islets. Diabetes 49, 708-711 (2000).
77. Horwitz, M. S., Fine, C., Ilic, A. & Sarvetnick, N. Requirements for viral-mediated autoimmune diabetes: beta-cell damage and immune infiltration. J. Autoimmun. 16, 211-217 (2001).
78. Horwitz, M. S., Ilic, A., Fine, C., Rodriguez, E. & Sarvetnick, N. Presented antigen from damaged pancreatic beta cells activates autoreactive T cells in virus-mediated autoimmune diabetes. J. Clin. Invest. 109, 79-87 (2002).
79. Filippi, C. M. & von Herrath, M. G. Viral trigger for type 1 diabetes: pros and cons. Diabetes 57, 2863-2871 (2008).
80. Christen, U. & von Herrath, M. G. Induction, acceleration or prevention of autoimmunity by molecular mimicry. Mol. Immunol. 40, 1113-1120 (2004).
81. Vreugdenhil, G. R. et al. Molecular mimicry in diabetes mellitus: the homologous domain in coxsackie B virus protein 2C and islet autoantigen GAD65 is highly conserved in the coxsackie B-like enteroviruses and binds to the diabetes associated HLA-DR3 molecule. Diabetologia 41, 40-46 (1998).
82. Schloot, N. C. et al. 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 (2001).
83. Härkönen, T. et al. Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans. J. Med. Virol. 69, 426-440 (2003).
84. Oldstone, M. B., Nerenberg, M., Southern, P., Price, J. & Lewicki, H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65, 319-331 (1991).
85. Christen, U., Hintermann, E., Holdener, M. & von Herrath, M. G. Viral triggers for autoimmunity: Is the 'glass of molecular mimicry' half full or half empty? J. Autoimmun. 34, 38-44 (2010).
86. Sevilla, N. et al. Virus-induced diabetes in a transgenic model: role of cross-reacting viruses and quantitation of effector T cells needed to cause disease. J. Virol. 74, 3284-3292 (2000).
87. Christen, U. et al. A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes. J. Clin. Invest. 114, 1290-1298 (2004).
88. Brehm, M. A. et al. T cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens. Nat. Immunol. 3, 627-634 (2002).
89. Selin, L. K. & Welsh, R. M. Plasticity of T cell memory responses to viruses. Immunity 20, 5-16 (2004).
90. Filippi, C. M., Estes, E. A., Oldham, J. E. & von Herrath, M. G. Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice. J. Clin. Invest. 119, 1515-1523 (2009).
91. Ansari, M. J. et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J. Exp. Med. 198, 63-69 (2003).
92. Fife, B. T. et al. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J. Exp. Med. 203, 2737-2747 (2006).
93. Zipris, D. et al. Infections that induce autoimmune diabetes in BBDR rats modulate CD4+CD25+ T cell populations. J. Immunol. 170, 3592-3602 (2003).
94. Johnston, C. et al. Alterations in T-lymphocyte subpopulations in type I diabetes. Exploration of genetic influence in identical twins. Diabetes 37, 1484-1488 (1988).
95. Faustman, D., Schoenfeld, D. & Ziegler, R. T-lymphocyte changes linked to autoantibodies. Association of insulin autoantibodies with CD4+CD45R+ lymphocyte subpopulation in prediabetic subjects. Diabetes 40, 590-597 (1991).
96. Chatterjee, N. K., Hou, J., Dockstader, P. & Charbonneau, T. Coxsackievirus B4 infection alters thymic, splenic, and peripheral lymphocyte repertoire preceding onset of hyperglycemia in mice. J. Med. Virol. 38, 124-131 (1992).
97. Brilot, F., Jaïdane, H., Geenen, V. & Hober, D. Coxsackievirus B4 infection of murine foetal thymus organ cultures. J. Med. Virol. 80, 659-666 (2008).
98. Brilot, F. et al. Persistent infection of human thymic epithelial cells by coxsackievirus B4. J. Virol. 76, 5260-5265 (2002).
99. Brilot, F., Geenen, V., Hober, D. & Stoddart, C. A. Coxsackievirus B4 infection of human fetal thymus cells. J. Virol. 78, 9854-9861 (2004).
100. Sauter, P. & Hober, D. Mechanisms and results of the antibody-dependent enhancement of viral infections and role in the pathogenesis of coxsackievirus B-induced diseases. Microbes Infect. 11, 443-451 (2009).
101. Girn, J., Kavoosi, M. & Chantler, J. Enhancement of coxsackievirus B3 infection by antibody to a different coxsackievirus strain. J. Gen. Virol. 83, 351-358 (2002).
102. Kishimoto, C., Kurokawa, M. & Ochiai, H. Antibody-mediated immune enhancement in coxsackievirus B3 myocarditis. J. Mol. Cell. Cardiol. 34, 1227-1238 (2002).
103. Hober, D., Chehadeh, W., Bouzidi, A. & Wattré, P. Antibody-dependent enhancement of coxsackievirus B4 infectivity of human peripheral blood mononuclear cells results in increased interferon-alpha synthesis. J. Infect. Dis. 184, 1098-1108 (2001).
104. Hober, D. et al. Circulating and cell-bound antibodies increase coxsackievirus B4-induced production of IFN-alpha by peripheral blood mononuclear cells from patients with type 1 diabetes. J. Gen. Virol. 83, 2169-2176 (2002).
105. Chehadeh, W. et al. Viral protein VP4 is a target of human antibodies enhancing coxsackievirus B4- and B3-induced synthesis of alpha interferon. J. Virol. 79, 13882-13891 (2005).
106. Sauter, P. et al. Role of the capsid protein VP4 in the plasma-dependent enhancement of the Coxsackievirus B4E2-infection of human peripheral blood cells. Virus Res. 125, 183-190 (2007).
107. Sauter, P. et al. A part of the VP4 capsid protein exhibited by coxsackievirus B4 E2 is the target of antibodies contained in plasma from patients with type 1 diabetes. J. Med. Virol. 80, 866-878 (2008).
108. Mardis, E. R. The impact of next-generation sequencing technology on genetics. Trends Genet. 24, 133-141 (2008).
109. Concannon, P., Risch, S. S. & Nepom, G. T. Genetics of type 1A diabetes. N. Engl. J. Med. 360, 1646-1654 (2009).
110. Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506-511 (2003).
111. Lowe, C. E. et al. Large-scale genetic fine mapping and genetic-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat. Genet. 39, 1074-1082 (2007).
112. Field, L. L. et al. OAS1 splice site polymorphism controlling antiviral enzyme activity influences susceptibility to type 1 diabetes. Diabetes 54, 1588-1591 (2005).
113. Bonnevie-Nielsen, V. et al. Variation in antiviral 2′,5′- oligoadenylate synthetase (2′5′OAS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene. Am. J. Hum. Genet. 76, 623-633 (2005).
114. Ghosh, A., Sarkar, S. N., Rowe, T. M. & Sen, G. C. A specific isozyme of 2′-5′ oligoadenylate synthetase is a dual function proapoptotic protein of the Bcl-2 family. J. Biol. Chem. 276, 25447-25455 (2001).
115. Burton, P. R. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329-1337 (2006).
116. Nejentsev, S., walker, N., Riches, D., Egholm, M. & Todd, J. A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387-389 (2009).
117. Shigemoto, T. et al. Identification of loss of function mutations in human genes encoding RIG-I and MDA5: implications for resistance to type I diabetes. J. Biol. Chem. 284, 13348-13354 (2009).
118. Yoneyama, M. et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175, 2851-2858 (2005).
119. Meylan, E., Tschopp, J. & Karin, M. Intracellular pattern recognition receptors in the host response. Nature 442, 39-44 (2006).
120. Liu, S. et al. IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells. Hum. Mol. Genet. 18, 358-365 (2009).
121. Gröschel, S. et al. TLR-mediated induction of negative regulatory ligands on dendritic cells. J. Mol. Med. 86, 443-455 (2008).
122. Viskari, H. et al. Relationship between the incidence of type 1 diabetes and enterovirus infections in different European populations: results from the EPIVIR project. J. Med. Virol. 72, 610-617 (2004).
123. von Herrath, M. Diabetes: A virus-gene collaboration. Nature 459, 518-519 (2009).
124. von Herrath, M. Can we learn from viruses how to prevent type 1 diabetes? The role of viral infections in the pathogenesis of type 1 diabetes and the development of novel combination therapies. Diabetes 58, 2-11 (2009).
125. Kawai, T. & Akira, S. Toll-like receptor and RIG-I-like receptor signaling. Ann. NY Acad. Sci. 1143, 1-20 (2008).
126. Colli, M. L., Moore, F., Gurzov, E. N., Ortis, F. & Eizirik D. L. MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double stranded RNA. Hum. Mol. Genet. 19, 135-146 (2010).