Advances in the etiology and mechanisms of type 1 diabetes

Discovery Medicine

Volumn 18, Issue 98, 2014, Pages 141-150

  Pugliese, Alberto ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOANTIBODY; AUTOANTIGEN; C PEPTIDE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 ANTIBODY; GLUTAMATE DECARBOXYLASE; HLA ANTIGEN; INSULIN;

APOPTOSIS; ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CELLULAR IMMUNITY; CLINICAL TRIAL (TOPIC); DISEASE SEVERITY; ENTEROVIRUS; ENVIRONMENTAL FACTOR; GENETIC PREDISPOSITION; HAPLOTYPE; HEREDITY; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; INSULIN DEPENDENT DIABETES MELLITUS; INSULITIS; INTERFERON INDUCED; MEDICAL RESEARCH; MOLECULAR MIMICRY; NONHUMAN; OBESITY; PANCREAS ISLET BETA CELL; CELL DEATH; DIABETES MELLITUS, TYPE 1; ENVIRONMENT; GENETICS; IMMUNOLOGY; PANCREAS ISLET; PATHOLOGY;

AUTOANTIGENS; AUTOIMMUNITY; CELL DEATH; DIABETES MELLITUS, TYPE 1; ENVIRONMENT; HLA ANTIGENS; HUMANS; INSULIN-SECRETING CELLS; ISLETS OF LANGERHANS; SELF TOLERANCE;

EID: 84920757281     PISSN: 15396509     EISSN: 19447930     Source Type: Journal    
DOI: None     Document Type: Article

References (112)

1. Alkanani AK, Rewers M, Dong F, Waugh K, Gottlieb PA, Zipris D. Dysregulated Toll-like receptor-induced interleukin-1beta and interleukin-6 responses in subjects at risk for the development of type 1 diabetes. Diabetes 61(10):2525-2533, 2012.
2. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, Von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D. Projection of an immunological self shadow within the thymus by the aire protein. Science 298(5597):1395-1401, 2002.
3. Barker JM, Barriga KJ, Yu L, Miao D, Erlich HA, Norris JM, Eisenbarth GS, Rewers M. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). J Clin Endocrinol Metab 89(8):3896-3902, 2004.
4. Bogdani M, Johnson PY, Potter-Perigo S, Nagy N, Day AJ, Bollyky PL, Wight TN. Hyaluronan and hyaluronan binding proteins accumulate in both human type 1 diabetic islets and lymphoid tissues and associate with inflammatory cells in insulitis. Diabetes, epub ahead of print, Mar. 27, 2014.
5. Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol 10(12):849-859, 2010.
6. Bulek AM, Cole DK, Skowera A, Dolton G, Gras S, Madura F, Fuller A, Miles JJ, Gostick E, Price DA, Drijfhout JW, Knight RR, Huang GC, Lissin N, Molloy PE, Wooldridge L, Jakobsen BK, Rossjohn J, Peakman M, Rizkallah PJ, et al. Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes. Nat Immunol 13(3):283-289, 2012.
7. Campbell-Thompson ML, Atkinson MA, Butler AE, Chapman NM, Frisk G, Gianani R, Giepmans BN, Von Herrath MG, Hyoty H, Kay TW, Korsgren O, Morgan NG, Powers AC, Pugliese A, Richardson SJ, Rowe PA, Tracy S, In't Veld PA. The diagnosis of insulitis in human type 1 diabetes. Diabetologia 56(11):2541-2543, 2013.
8. Chen YG, Cabrera SM, Jia S, Kaldunski ML, Kramer J, Cheong S, Geoffrey R, Roethle MF, WoodliffJE, Greenbaum CJ, Wang X, Hessner MJ. Molecular signatures differentiate immune states in Type 1 diabetes families. Diabetes, epub ahead of print, Apr. 23, 2014.
9. ChentoufiAA, Polychronakos C. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes 51(5):1383-1390, 2002.
10. Chistiakov DA. Interferon induced with helicase C domain 1 (IFIH1) and virus-induced autoimmunity: a review. Viral Immunol 23(1):3-15, 2010.
11. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, Farr AG, Tung KS, Engelhard VH. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med 207(4):681-688, 2010.
12. Colli ML, Moore F, Gurzov EN, Ortis F, Eizirik DL. 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(1):135-146, 2010.
13. Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TW, Atkinson MA, Roep BO, Von Herrath MG. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 209(1):51-60, 2012.
14. Coppieters KT, Wiberg A, Amirian N, Kay TW, Von Herrath MG. Persistent glucose transporter expression on pancreatic beta cells from longstanding type 1 diabetic individuals. Diabetes Metab Res Rev 27(8):746-754, 2011.
15. Cox SL, Silveira PA. Emerging roles for B lymphocytes in Type 1 diabetes. Expert Rev Clin Immunol 5(3):311-324, 2009.
16. De Jong VM, Abreu JR, Verrijn Stuart AA, Van Der Slik AR, Verhaeghen K, Engelse MA, Blom B, Staal FJ, Gorus FK, Roep BO. Alternative splicing and differential expression of the islet autoantigen IGRP between pancreas and thymus contributes to immunogenicity of pancreatic islets but not diabetogenicity in humans. Diabetologia 56(12):2651-2658, 2013.
17. Diez J, Park Y, Zeller M, Brown D, Garza D, Ricordi C, Hutton J, Eisenbarth GS, Pugliese A. Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen. Diabetes 50(4):895-900, 2001.
18. Dogra RS, Vaidyanathan P, Prabakar KR, Marshall KE, Hutton JC, Pugliese A. Alternative splicing of G6PC2, the gene coding for the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), results in differential expression in human thymus and spleen compared with pancreas. Diabetologia 49(5):953-957, 2006.
19. Dunne JL, Triplett EW, Gevers D, Xavier R, Insel R, Danska J, Atkinson MA. The intestinal microbiome in type 1 diabetes. Clin Exp Immunol 177(1):30-37, 2014.
20. Durinovic-Bello I, Wu RP, Gersuk VH, Sanda S, Shilling HG, Nepom GT. Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin. Genes Immun 11(2):188-193, 2010.
21. Eizirik DL, Miani M, Cardozo AK. Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia 56(2):234-241, 2013.
22. Fan Y, Rudert WA, Grupillo M, He J, Sisino G, Trucco M. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J 28(18):2812-2824, 2009.
23. Ferraro A, Socci C, Stabilini A, Valle A, Monti P, Piemonti L, Nano R, Olek S, MaffiP, Scavini M, Secchi A, Staudacher C, Bonifacio E, Battaglia M. Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. Diabetes 60(11):2903-2913, 2011.
24. Ferreira RC, Guo H, Coulson RM, Smyth DJ, Pekalski ML, Burren OS, Cutler AJ, Doecke JD, Flint S, Mckinney EF, Lyons PA, Smith KG, Achenbach P, Beyerlein A, Dunger DB, Wicker LS, Todd JA, Bonifacio E, Wallace C, Ziegler AG. A type I interferon transcriptional signature precedes autoimmunity in children genetically at-risk of type 1 diabetes. Diabetes, epub ahead of print, Feb. 21, 2014.
25. Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A, Curry MS, Collier AR, Boyd RL, Turley SJ. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med 207(4):689-697, 2010.
26. Foulis AK, Farquharson MA, Hardman R. Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30(5):333-343, 1987a.
27. Foulis AK, Farquharson MA, Meager A. Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 2(8573):1423-1427, 1987b.
28. Fourlanos S, Narendran P, Byrnes GB, Colman PG, Harrison LC. Insulin resistance is a risk factor for progression to type 1 diabetes. Diabetologia 47(10):1661-1667, 2004.
29. Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev 9(1):25-53, 2013.
30. Gardner JM, Metzger TC, Mcmahon EJ, Au-Yeung BB, Krawisz AK, Lu W, Price JD, Johannes KP, Satpathy AT, Murphy KM, Tarbell KV, Weiss A, Anderson MS. Extrathymic aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4 T cells. Immunity (13):10, 2013.
31. Garg G, Tyler JR, Yang JH, Cutler AJ, Downes K, Pekalski M, Bell GL, Nutland S, Peakman M, Todd JA, Wicker LS, Tree TI. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J Immunol 188(9):4644-4653, 2012.
32. Gerold KD, Zheng P, Rainbow DB, Zernecke A, Wicker LS, Kissler S. The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function. Diabetes 60(7):1955-1963, 2011.
33. Gianani R, Campbell-Thompson M, Sarkar SA, Wasserfall C, Pugliese A, Solis JM, Kent SC, Hering BJ, West E, Steck A, Bonner-Weir S, Atkinson MA, Coppieters K, Von HM, Eisenbarth GS. Dimorphic histopathology of long-standing childhood-onset diabetes. Diabetologia 53(4):690-698, 2010.
34. Greenbaum CJ, Beam CA, Boulware D, Gitelman SE, Gottlieb PA, Herold KC, Lachin JM, Mcgee P, Palmer JP, Pescovitz MD, Krause-Steinrauf H, Skyler JS, Sosenko JM. Fall in C-Peptide During First 2 Years From Diagnosis: Evidence of at Least Two Distinct Phases From Composite Type 1 Diabetes TrialNet Data. Diabetes 61(8):2066-2073, 2012.
35. Grieco FA, Moore F, Vigneron F, Santin I, Villate O, Marselli L, Rondas D, Korf H, Overbergh L, Dotta F, Marchetti P, Mathieu C, Eizirik DL. IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets. Diabetologia 57(3):502-511, 2014.
36. Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, Cagnard N, Carpentier W, Tang Q, Bluestone J, Chatenoud L, Klatzmann D, Salomon BL, Piaggio E. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med 207(9):1871-1878, 2010.
37. Grupillo M, Gualtierotti G, He J, Sisino G, Bottino R, Rudert WA, Trucco M, Fan Y. Essential roles of insulin expression in Aire+ tolerogenic dendritic cells in maintaining peripheral self-tolerance of islet beta-cells. Cell Immunol 273(2):115-123, 2012.
38. Hagopian W, Ferry RJ Jr, Sherry N, Carlin D, Bonvini E, Johnson S, Stein KE, Koenig S, Daifotis AG, Herold KC, Ludvigsson J. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: 2-year results from the randomized, placebo-controlled Protege trial. Diabetes 62(11):3901-3908, 2013.
39. Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, Fonfrede M, Rosenzwajg M, Bernard C, Klatzmann D. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. The lancet. Diabetes Endocrinol 1(4):295-305, 2013.
40. Hilbrands R, Huurman VA, Gillard P, Velthuis JH, De WM, Mathieu C, Kaufman L, Pipeleers-Marichal M, Ling Z, Movahedi B, Jacobs-Tulleneers-Thevissen D, Monbaliu D, Ysebaert D, Gorus FK, Roep BO, Pipeleers DG, Keymeulen B. Differences in baseline lymphocyte counts and autoreactivity are associated with differences in outcome of islet cell transplantation in type 1 diabetic patients. Diabetes 58(10):2267-2276, 2009.
41. In't Veld P. Insulitis in human type 1 diabetes: The quest for an elusive lesion. Islets 3(4):131-138, 2011a.
42. In't Veld P. Insulitis in the human endocrine pancreas: does a viral infection lead to inflammation and beta cell replication? Diabetologia 54(9):2220-2222, 2011b.
43. Jaeger C, Brendel MD, Eckhard M, Bretzel RG. Islet autoantibodies as potential markers for disease recurrence in clinical islet transplantation. Exp Clin Endocrinol Diabetes 108(5):328-333, 2000.
44. Jaidane H, Sane F, Hiar R, Goffard A, Gharbi J, Geenen V, Hober D. Immunology in the clinic review series; focus on type 1 diabetes and viruses: enterovirus, thymus and type 1 diabetes pathogenesis. Clin Exp Immunol 168(1):39-46, 2012.
45. James EA, Mallone R, Schloot NC, Gagnerault MC, Thorpe J, Fitzgerald-Miller L, Reichow J, Wagner R, Pham MN, Jospe N, Lou O, Gottlieb PA, Brooks-Worrell BM, Durinovic-Bello I. Immunology of Diabetes Society T-Cell Workshop: HLA class II tetramer-directed epitope validation initiative. Diabetes Metab Res Rev 27(8):727-736, 2011.
46. Jarchum I, Dilorenzo TP. Ins2 deficiency augments spontaneous HLA-A*0201-restricted T cell responses to insulin. J Immunol 184(2):658-665, 2010.
47. Keenan HA, Sun JK, Levine J, Doria A, Aiello LP, Eisenbarth G, Bonner-Weir S, King GL. Residual insulin production and pancreatic ss-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 59(11):2846-2853, 2010.
48. Kent SC, Chen Y, Bregoli L, Clemmings SM, Kenyon NS, Ricordi C, Hering BJ, Hafler DA. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 435(7039):224-228, 2005.
49. Klinke DJ. Extent of Beta cell destruction is important but insufficient to predict the onset of type 1 diabetes mellitus. PLoS One 3(1):e1374, 2008.
50. Klinke DJ. Age-corrected beta cell mass following onset of type 1 diabetes mellitus correlates with plasma C-peptide in humans. PLoS One 6(11):e26873, 2011.
51. Koreth J, Matsuoka K, Kim HT, Mcdonough SM, Bindra B, Alyea EP, ii, Armand P, Cutler C, Ho VT, Treister NS, Bienfang DC, Prasad S, Tzachanis D, Joyce RM, Avigan DE, Antin JH, Ritz J, Soiffer RJ. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 365(22):2055-2066, 2011.
52. Korpos E, Kadri N, KappelhoffR, Wegner J, Overall CM, Weber E, Holmberg D, Cardell S, Sorokin L. The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. Diabetes 62(2):531-542, 2013.
53. Kronenberg D, Knight RR, Estorninho M, Ellis RJ, Kester MG, De Ru A, Eichmann M, Huang GC, Powrie J, Dayan CM, Skowera A, Van Veelen PA, Peakman M. Circulating Preproinsulin Signal Peptide-Specific CD8 T Cells Restricted by the Susceptibility Molecule HLA-A24 Are Expanded at Onset of Type 1 Diabetes and Kill beta-Cells. Diabetes 61(7):1752-1759, 2012.
54. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol 24:571-606, 2006.
55. Laitinen OH, Honkanen H, Pakkanen O, Oikarinen S, Hankaniemi MM, Huhtala H, Ruokoranta T, Lecouturier V, Andre P, Harju R, Virtanen SM, Lehtonen J, Almond JW, Simell T, Simell O, Ilonen J, Veijola R, Knip M, Hyoty H. Coxsackievirus B1 Is Associated With Induction of beta-Cell Autoimmunity That Portends Type 1 Diabetes. Diabetes 63(2):446-455, 2014.
56. Liu LL, Lawrence JM, Davis C, Liese AD, Pettitt DJ, Pihoker C, Dabelea D, Hamman R, Waitzfelder B, Kahn HS. Prevalence of overweight and obesity in youth with diabetes in USA: the SEARCH for Diabetes in Youth study. Pediatr Diabetes 11(1):4-11, 2010.
57. Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R, Bourget K, Plagnol V, Field S, Atkinson M, Clayton DG, Wicker LS, Todd JA. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 39(9):1074-1082, 2007.
58. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am 39(3):481-497, 2010.
59. Mannering SI, Harrison LC, Williamson NA, Morris JS, Thearle DJ, Jensen KP, Kay TW, Rossjohn J, Falk BA, Nepom GT, Purcell AW. The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J Exp Med 202(9):1191-1197, 2005.
60. Marhfour I, Lopez XM, Lefkaditis D, Salmon I, Allagnat F, Richardson SJ, Morgan NG, Eizirik DL. Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes. Diabetologia 55(9):2417-2420, 2012.
61. Marroqui L, Santin I, Dos Santos RS, Marselli L, Marchetti P, Eizirik DL. BACH2, a candidate risk gene for type 1 diabetes, regulates apoptosis in pancreatic beta-cells via JNK1 modulation and crosstalk with the candidate gene PTPN2. Diabetes, epub ahead of print, Mar. 7, 2014.
62. Mcginty JW, Chow IT, Greenbaum C, Odegard J, Kwok WW, James EA. Recognition of post-translationally modified GAD65 epitopes in subjects with type 1 diabetes. Diabetes, epub ahead of print, Apr. 4, 2014.
63. Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48(11):2221-2228, 2005.
64. Menard L, Saadoun D, Isnardi I, Ng YS, Meyers G, Massad C, Price C, Abraham C, Motaghedi R, Buckner JH, Gregersen PK, Meffre E. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest 121(9):3635-3644, 2011.
65. Mizrahi M, Ilan Y. The gut mucosa as a site for induction of regulatory T-cells. Curr Pharm Des 15(11):1191-1202, 2009.
66. Mohan JF, Petzold SJ, Unanue ER. Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion. J Exp Med 208(12):2375-2383, 2011.
67. Monti P, Heninger AK, Bonifacio E. Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus. Curr Diab Rep 9(2):113-118, 2009.
68. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435(7039):220-223, 2005.
69. Noble JA, Valdes AM, Varney MD, Carlson JA, Moonsamy P, Fear AL, Lane JA, Lavant E, Rappner R, Louey A, Concannon P, Mychaleckyj JC, Erlich HA. HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes 59(11):2972-2979, 2010.
70. Oikarinen M, Tauriainen S, Oikarinen S, Honkanen T, Collin P, Rantala I, Maki M, Kaukinen K, Hyoty H. Type 1 diabetes is associated with enterovirus infection in gut mucosa. Diabetes 61(3):687-691, 2012.
71. Oram RA, Jones AG, Besser RE, Knight BA, Shields BM, Brown RJ, Hattersley AT, Mcdonald TJ. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia 57(1):187-191, 2014.
72. Orban T, Bundy B, Becker DJ, Dimeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, Moran A, Peakman M, Raskin P, Russell WE, Schatz D, Wherrett DK, Wilson DM, Krischer JP, Skyler JS. Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment. Diabetes Care 37(4):1069-1075, 2014.
73. Oresic M, Simell S, Sysi-Aho M, Nanto-Salonen K, Seppanen-Laakso T, Parikka V, Katajamaa M, Hekkala A, Mattila I, Keskinen P, Yetukuri L, Reinikainen A, Lahde J, Suortti T, Hakalax J, Simell T, Hyoty H, Veijola R, Ilonen J, Lahesmaa R, et al. Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med 205(13):2975-2984, 2008.
74. Pang TT, Narendran P. Addressing insulin resistance in Type 1 diabetes. Diabet Med 25(9):1015-1024, 2008.
75. Pflueger M, Seppanen-Laakso T, Suortti T, Hyotylainen T, Achenbach P, Bonifacio E, Oresic M, Ziegler AG. Age- and islet autoimmunity-associated differences in amino acid and lipid metabolites in children at risk for type 1 diabetes. Diabetes 60(11):2740-2747, 2011.
76. Pociot F, Akolkar B, Concannon P, Erlich HA, Julier C, Morahan G, Nierras CR, Todd JA, Rich SS, Nerup J. Genetics of Type 1 Diabetes: What's Next? Diabetes 59(7):1561-1571, 2010.
77. Poliani PL, Kisand K, Marrella V, Ravanini M, Notarangelo LD, Villa A, Peterson P, Facchetti F. Human peripheral lymphoid tissues contain autoimmune regulator-expressing dendritic cells. Am J Pathol 176(3):1104-1112, 2010.
78. Pugliese A. The multiple origins of Type 1 diabetes. Diabet Med 30(2):135-146, 2013.
79. Pugliese A, Brown D, Garza D, Murchison D, Zeller M, Redondo MJ, Diez J, Eisenbarth GS, Patel DD, Ricordi C. Self-antigen presenting cells expressing IDDM-associated autoantigens exist in both thymus and peripheral lymphoid organs in humans. J Clin Invest 107:585-593, 2001.
80. Pugliese A, Gianani R, Moromisato R, Awdeh ZL, Alper CA, Erlich HA, Jackson RA, Eisenbarth GS. HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM. Diabetes 44(6):608-613, 1995.
81. Pugliese A, Yang M, Kusmarteva I, Heiple T, Vendrame F, Wasserfall C, Rowe P, Moraski JM, Ball S, Jebson L, Schatz DA, Gianani R, Burke GW, Nierras C, Staeva T, Kaddis JS, Campbell-Thompson M, Atkinson MA. The Juvenile Diabetes Research Foundation Network for Pancreatic Organ Donors with Diabetes (nPOD) Program: goals, operational model and emerging findings. Pediatr Diabetes 15(1):1-9, 2014.
82. Pugliese A, Zeller M, Fernandez A, Jr, Zalcberg LJ, Bartlett RJ, Ricordi C, Pietropaolo M, Eisenbarth GS, Bennett ST, Patel DD. 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(3):293-297, 1997.
83. Richardson SJ, Leete P, Bone AJ, Foulis AK, Morgan NG. Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1. Diabetologia 56(1):185-193, 2013.
84. Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia 52(6):1143-1151, 2009.
85. Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, Sene D, Cacoub P, Klatzmann D. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 365(22):2067-2077, 2011.
86. Santin I, Moore F, Colli ML, Gurzov EN, Marselli L, Marchetti P, Eizirik DL. PTPN2, a candidate gene for type 1 diabetes, modulates pancreatic beta-cell apoptosis via regulation of the BH3-only protein Bim. Diabetes 60(12):3279-3288, 2011.
87. Sarkar SA, Lee CE, Victorino F, Nguyen TT, Walters JA, Burrack A, Eberlein J, Hildemann SK, Homann D. Expression and regulation of chemokines in murine and human type 1 diabetes. Diabetes 61(2):436-446, 2012.
88. Schloot NC, MeierhoffG, Karlsson FM, Ott P, Putnam A, Lehmann P, Gottlieb P, Roep BO, Peakman M, Tree T. Comparison of cytokine ELISpot assay formats for the detection of islet antigen autoreactive T cells. Report of the third immunology of diabetes society T-cell workshop. J Autoimmun 21(4):365-376, 2003.
89. Schubert DA, Gordo S, Sabatino JJ Jr, Vardhana S, Gagnon E, Sethi DK, Seth NP, Choudhuri K, Reijonen H, Nepom GT, Evavold BD, Dustin ML, Wucherpfennig KW. Self-reactive human CD4 T cell clones form unusual immunological synapses. J Exp Med 209(2):335-352, 2012.
90. Schulte BM, Lanke KH, Piganelli JD, Kers-Rebel ED, Bottino R, Trucco M, Huijbens RJ, Radstake TR, Engelse MA, De Koning EJ, Galama JM, Adema GJ, Van Kuppeveld FJ. Cytokine and chemokine production by human pancreatic islets upon enterovirus infection. Diabetes 61(8):2030-2036, 2012.
91. Sherr JL, Ghazi T, Wurtz A, Rink L, Herold KC. Characterization of residual beta cell function in long-standing type 1 diabetes. Diabetes Metab Res Rev 30(2):154-162, 2014.
92. Sherry NA, Tsai EB, Herold KC. Natural History of {beta}-Cell Function in Type 1 Diabetes. Diabetes 54(Suppl 2):S32-S39, 2005.
93. Skowera A, Ellis RJ, Varela-Calvino R, Arif S, Huang GC, Van-Krinks C, Zaremba A, Rackham C, Allen JS, Tree TI, Zhao M, Dayan CM, Sewell AK, Unger W, Drijfhout JW, Ossendorp F, Roep BO, Peakman M. CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope. J Clin Invest 118(10):3390-3402, 2008.
94. Skyler JS. Immune intervention for type 1 diabetes, 2012-2013. Diabetes Tech Ther 16(Suppl 1):S85-S91, 2014.
95. Sosenko JM, Palmer JP, Greenbaum CJ, Mahon J, Cowie C, Krischer JP, Chase HP, White NH, Buckingham B, Herold KC, Cuthbertson D, Skyler JS. Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 29(3):643-649, 2006.
96. Suri A, Walters JJ, Gross ML, Unanue ER. Natural peptides selected by diabetogenic DQ8 and murine I-A(g7) molecules show common sequence specificity. J Clin Invest 115(8):2268-2276, 2005.
97. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, Piccirillo CA, Salomon BL, Bluestone JA. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28(5):687-697, 2008.
98. Unger WW, Pearson T, Abreu JR, Laban S, Van Der Slik AR, Der Kracht SM, Kester MG, Serreze DV, Shultz LD, Griffioen M, Drijfhout JW, Greiner DL, Roep BO. Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/scid/IL2RG null mice. PLoS One 7(11):e49213, 2012.
99. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15(3):289-292, 1997.
100. Vang T, Miletic AV, Bottini N, Mustelin T. Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity 40(6):453-461, 2007.
101. Velthuis JH, Unger WW, Abreu JR, Duinkerken G, Franken K, Peakman M, Bakker AH, Reker-Hadrup S, Keymeulen B, Drijfhout JW, Schumacher TN, Roep BO. Simultaneous detection of circulating autoreactive CD8+ T-cells specific for different islet cell-associated epitopes using combinatorial MHC multimers. Diabetes 59(7):1721-1730, 2010.
102. Vendrame F, Pileggi A, Laughlin E, Allende G, Martin-Pagola A, Molano RD, Diamantopoulos S, Standifer N, Geubtner K, Falk BA, Ichii H, Takahashi H, Snowhite I, Chen Z, Mendez A, Chen L, Sageshima J, Ruiz P, Ciancio G, Ricordi C, et al. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes 59(4):947-957, 2010.
103. Vetere A, Choudhary A, Burns SM, Wagner BK. Targeting the pancreatic beta-cell to treat diabetes. Nat Rev Drug Discov 13(4):278-289, 2014.
104. Viehmann Milam AA, Maher SE, Gibson JA, Lebastchi J, Wen L, Ruddle NH, Herold KC, Bothwell AL. A humanized mouse model of autoimmune insulitis. Diabetes 63(5):1712-1724, 2014.
105. Viskari H, Knip M, Tauriainen S, Huhtala H, Veijola R, Ilonen J, Simell O, Surcel HM, Hyoty H. Maternal enterovirus infection as a risk factor for type 1 diabetes in the exposed offspring. Diabetes Care 35(6):1328-1332, 2012.
106. Wang L, Lovejoy NF, Faustman DL. Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay. Diabetes Care 35(3):465-470, 2012.
107. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol 155(2):173-181, 2009.
108. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Immunohistochemical analysis of the relationship between islet cell proliferation and the production of the enteroviral capsid protein, VP1, in the islets of patients with recent-onset type 1 diabetes. Diabetologia 54(9):2417-2420, 2011.
109. Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, Gonzalez-Munoz A, Clark J, Veijola R, Cubbon R, Chen SL, Rosa R, Cumiskey AM, Serreze DV, Gregory S, Rogers J, Lyons PA, Healy B, Smink LJ, Todd JA, et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet 39(3):329-337, 2007.
110. Yip L, Creusot RJ, Pager CT, Sarnow P, Fathman CG. Reduced DEAF1 function during type 1 diabetes inhibits translation in lymph node stromal cells by suppressing Eif4g3. J Mol Cell Biol 5(2):99-110, 2013.
111. Yip L, Su L, Sheng D, Chang P, Atkinson M, Czesak M, Albert PR, Collier AR, Turley SJ, Fathman CG, Creusot RJ. Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes. Nat Immunol 10(9):1026-1033, 2009.
112. Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, Winkler C, Ilonen J, Veijola R, Knip M, Bonifacio E, Eisenbarth GS. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309(23):2473-2479, 2013.