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Anatomy Research International
Volume 2012 (2012), Article ID 457546, 20 pages
http://dx.doi.org/10.1155/2012/457546
Review Article

Etiopathogenesis of Insulin Autoimmunity

1Department of Clinical Sciences, Skåne University Hospital (SUS), Lund University, CRC Ing 72 Building 91:10, 205 02 Malmö, Sweden
2Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, 47100 Arta, Greece
3Department of Organic Farming, Technological Educational Institute of Ionian Islands, 27100 Argostoli, Greece

Received 2 November 2011; Accepted 12 January 2012

Academic Editor: Ruijin Huang

Copyright © 2012 Norio Kanatsuna et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. J. H. Schaefer, “The normal weight of the pancreas in the adult human being: a biometric study,” The Anatomical Record, vol. 32, no. 2, pp. 119–132, 1926.
  2. P. In't Veld and M. Marichal, “Microscopic anatomy of the human islet of Langerhans,” Advances in Experimental Medicine and Biology, vol. 654, pp. 1–19, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. J. Rahier, Y. Guiot, R. M. Goebbels, C. Sempoux, and J. C. Henquin, “Pancreatic β-cell mass in European subjects with type 2 diabetes,” Diabetes, Obesity and Metabolism, vol. 10, no. 4, pp. 32–42, 2008. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Brissova, M. J. Fowler, W. E. Nicholson et al., “Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy,” Journal of Histochemistry and Cytochemistry, vol. 53, no. 9, pp. 1087–1097, 2005. View at Publisher · View at Google Scholar · View at Scopus
  5. N. Wierup, H. Svensson, H. Mulder, and F. Sundler, “The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas,” Regulatory Peptides, vol. 107, no. 1–3, pp. 63–69, 2002. View at Publisher · View at Google Scholar · View at Scopus
  6. C. Ringström, M. D. Nitert, H. Bennet et al., “Apelin is a novel islet peptide,” Regulatory Peptides, vol. 162, no. 1–3, pp. 44–51, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. K. Tatemoto, M. Hosoya, Y. Habata et al., “Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor,” Biochemical and Biophysical Research Communications, vol. 251, no. 2, pp. 471–476, 1998. View at Publisher · View at Google Scholar · View at Scopus
  8. N. Wierup, M. Björkqvist, M. J. Kuhar, H. Mulder, and F. Sundler, “CART regulates islet hormone secretion and is expressed in the β-cells of type 2 diabetic rats,” Diabetes, vol. 55, no. 2, pp. 305–311, 2006. View at Publisher · View at Google Scholar · View at Scopus
  9. O. Cabrera, D. M. Berman, N. S. Kenyon, C. Ricordi, P. O. Berggren, and A. Caicedo, “The unique cytoarchitecture of human pancreatic islets has implications for islet cell function,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 7, pp. 2334–2339, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. J. Jeon, M. Correa-Medina, C. Ricordi, H. Edlund, and J. A. Diez, “Endocrine cell clustering during human pancreas development,” Journal of Histochemistry and Cytochemistry, vol. 57, no. 9, pp. 811–824, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. L. Orci, D. Baetens, and M. Ravazzola, “Pancreatic polypeptide and glucagon: non random distribution in pancreatic islets,” Life Sciences, vol. 19, no. 12, pp. 1811–1815, 1976.
  12. L. I. Larsson, F. Sundler, and R. Hakanson, “Pancreatic polypeptide. A postulated new hormone: identification of its cellular storage site by light and electron microscopic immunocytochemistry,” Diabetologia, vol. 12, no. 3, pp. 211–226, 1976. View at Scopus
  13. D. M. Kendall, D. E. R. Sutherland, J. S. Najarian, F. C. Goetz, and R. P. Robertson, “Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans,” The New England Journal of Medicine, vol. 322, no. 13, pp. 898–903, 1990. View at Scopus
  14. A. V. Matveyenko, J. D. Veldhuis, and P. C. Butler, “Mechanisms of impaired fasting glucose and glucose intolerance induced by a ~50% pancreatectomy,” Diabetes, vol. 55, no. 8, pp. 2347–2356, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. D. La Torre and A. Lernmark, “Immunology of beta-cell destruction,” Advances in Experimental Medicine and Biology, vol. 654, pp. 537–583, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. G. S. Eisenbarth and J. Jeffrey, “The natural history of type 1A diabetes,” Arquivos Brasileiros de Endocrinologia e Metabologia, vol. 52, no. 2, pp. 146–155, 2008. View at Publisher · View at Google Scholar · View at Scopus
  17. C. Pihoker, L. K. Gilliam, C. S. Hampe, and G. S. Lernmark, “Autoantibodies in diabetes,” Diabetes, vol. 54, no. 2, pp. S52–S61, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. D. Devendra, E. Liu, and G. S. Eisenbarth, “Type 1 diabetes: recent developments,” British Medical Journal, vol. 328, no. 7442, pp. 750–754, 2004. View at Scopus
  19. A. N. Gorsuch, K. M. Spencer, and J. Lister, “Evidence for a long prediabetic period in type I (insulin-dependent) diabetes mellitus,” The Lancet, vol. 2, no. 8260-8261, pp. 1363–1365, 1981.
  20. J. S. Skyler, D. Brown, H. P. Chase et al., “Effects of insulin in relatives of patients with type 1 diabetes mellitus,” The New England Journal of Medicine, vol. 346, no. 22, pp. 1685–1691, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. G. S. Eisenbarth, “Type I diabetes mellitus. A chronic autoimmune disease,” The New England Journal of Medicine, vol. 314, no. 21, pp. 1360–1368, 1986. View at Scopus
  22. J. F. Bach, “Insulin-dependent diabetes mellitus as an autoimmune disease,” Endocrine Reviews, vol. 15, no. 4, pp. 516–542, 1994. View at Publisher · View at Google Scholar · View at Scopus
  23. G. Thomson, W. P. Robinson, M. K. Kuhner et al., “Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of caucasians with insulin-dependent diabetes mellitus,” American Journal of Human Genetics, vol. 43, no. 6, pp. 799–816, 1988. View at Scopus
  24. D. B. Schranz and A. Lernmark, “Immunology in diabetes: an update,” Diabetes/Metabolism Reviews, vol. 14, no. 1, pp. 3–29, 1998. View at Publisher · View at Google Scholar · View at Scopus
  25. H. Peng and W. Hagopian, “Environmental factors in the development of Type 1 diabetes,” Reviews in Endocrine and Metabolic Disorders, vol. 7, no. 3, pp. 149–162, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. K. Larsson, H. Elding-Larsson, E. Cederwall et al., “Genetic and perinatal factors as risk for childhood type 1 diabetes,” Diabetes/Metabolism Research and Reviews, vol. 20, no. 6, pp. 429–437, 2004. View at Publisher · View at Google Scholar · View at Scopus
  27. M. Rewers, J. X. She, A. G. Ziegler et al., “The environmental determinants of diabetes in the young (TEDDY) study,” Annals of the New York Academy of Sciences, vol. 1150, pp. 1–13, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. M. Rewers, T. L. Bugawan, J. M. Norris et al., “Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY),” Diabetologia, vol. 39, no. 7, pp. 807–812, 1996. View at Publisher · View at Google Scholar · View at Scopus
  29. T. Kimpimäki, A. Kupila, A.-M. Hämäläinen et al., “The first signs of β-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the finnish type 1 diabetes prediction and prevention study,” The Journal of Clinical Endocrinology & Metabolism, vol. 86, no. 10, pp. 4782–4788, 2001. View at Publisher · View at Google Scholar
  30. M. Kukko, T. Kimpimäki, A. Kupila et al., “Signs of beta-cell autoimmunity and HLA-defined diabetes susceptibility in the Finnish population: the sib cohort from the Type 1 diabetes prediction and prevention study,” Diabetologia, vol. 46, no. 1, pp. 65–70, 2003. View at Scopus
  31. J. Karjalainen, P. Salmela, J. Ilonen, H. M. Surcel, and M. Knip, “A comparison of childhood and adult Type I diabetes mellitus,” The New England Journal of Medicine, vol. 320, no. 14, pp. 881–886, 1989. View at Scopus
  32. J. Graham, I. Kockum, C. B. Sanjeevi et al., “Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset,” European Journal of Immunogenetics, vol. 26, no. 2-3, pp. 117–127, 1999. View at Publisher · View at Google Scholar
  33. H. Ikegami, Y. Kawaguchi, E. Yamato et al., “Analysis by the polymerase chain reaction of histocompatibility leucocyte antigen-DR9-linked susceptibility to insulin-dependent diabetes mellitus,” The Journal of Clinical Endocrinology & Metabolism, vol. 75, no. 5, pp. 1381–1385, 1992. View at Publisher · View at Google Scholar · View at Scopus
  34. J. Graham, W. A. Hagopian, I. Kockum et al., “Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes,” Diabetes, vol. 51, no. 5, pp. 1346–1355, 2002. View at Scopus
  35. H. Ikegami, Y. Kawabata, S. Noso, T. Fujisawa, and T. Ogihara, “Genetics of type 1 diabetes in Asian and Caucasian populations,” Diabetes Research and Clinical Practice, vol. 77, no. 3, pp. S116–S121, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Murao, H. Makino, Y. Kaino et al., “Differences in the contribution of HLA-DR and -DQ haplotypes to susceptibility to adult- and childhood-onset type 1 diabetes in Japanese patients,” Diabetes, vol. 53, no. 10, pp. 2684–2690, 2004. View at Publisher · View at Google Scholar · View at Scopus
  37. N. Abiru, E. Kawasaki, and K. Eguch, “Current knowledge of Japanese type 1 diabetic syndrome,” Diabetes/Metabolism Research and Reviews, vol. 18, no. 5, pp. 357–366, 2002. View at Publisher · View at Google Scholar · View at Scopus
  38. N. K. Mehra, N. Kumar, G. Kaur, U. Kanga, and N. Tandon, “Biomarkers of susceptibility to type 1 diabetes with special reference to the Indian population,” Indian Journal of Medical Research, vol. 125, no. 3, pp. 321–344, 2007. View at Scopus
  39. J. P. Wang, Z. G. Zhou, J. Lin et al., “Islet autoantibodies are associated with HLA-DQ genotypes in Han Chinese patients with type 1 diabetes and their relatives,” Tissue Antigens, vol. 70, no. 5, pp. 369–375, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. J. M. Wenzlau, K. Juhl, L. Yu et al., “The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 43, pp. 17040–17045, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. C. F. Verge, R. Gianani, E. Kawasaki et al., “Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies,” Diabetes, vol. 45, no. 3, pp. 926–933, 1996. View at Scopus
  42. S. C. Kent, Y. Chen, L. Bregoli et al., “Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope,” Nature, vol. 435, no. 7039, pp. 224–228, 2005. View at Publisher · View at Google Scholar · View at Scopus
  43. S. I. Mannering, S. H. Pang, N. A. Williamson et al., “The A-chain of insulin is a hot-spot for CD4+ T cell epitopes in human type 1 diabetes,” Clinical and Experimental Immunology, vol. 156, no. 2, pp. 226–231, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. C. Taplin and J. Barker, “Autoantibodies in type 1 diabetes,” Autoimmunity, vol. 41, no. 1, pp. 11–18, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. Hirata and Y. Uchigata, “Insulin autoimmune syndrome in Japan,” Diabetes Research and Clinical Practice, vol. 24, pp. S153–S157, 1994. View at Publisher · View at Google Scholar · View at Scopus
  46. Y. Uchigata, K. Tokunaga, G. Nepom et al., “Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata's disease) and monoclonal insulin autoimmune syndrome,” Diabetes, vol. 44, no. 10, pp. 1227–1232, 1995. View at Scopus
  47. Y. Uchigata, S. Kuwata, K. Tokunaga et al., “Strong association of insulin autoimmune syndrome with HLA-DR4,” The Lancet, vol. 339, no. 8790, pp. 393–394, 1992. View at Publisher · View at Google Scholar · View at Scopus
  48. J. M. Jasinski and G. S. Eisenbarth, “Insulin as a primary autoantigen for type 1A diabetes,” Clinical and Developmental Immunology, vol. 12, no. 3, pp. 181–186, 2005. View at Publisher · View at Google Scholar · View at Scopus
  49. T. L. van Belle, K. T. Coppieters, and M. G. Von Herrath, “Type 1 diabetes: etiology, immunology, and therapeutic strategies,” Physiological Reviews, vol. 91, no. 1, pp. 79–118, 2011. View at Publisher · View at Google Scholar
  50. Y. Uchigata and Y. Hirata, “Insulin autoimmune syndrome (Hirata Disease),” in Immunoendocrinology: Scientific and Clinical Aspects (Contemporary Endocrinology), G. S. Eisenbarth, Ed., part 3, pp. 343–367, Humana Press, New Jersey, NJ, USA, 2011.
  51. Y. Uchigata, Y. Hirata, and Y. Iwamoto, “Drug-induced insulin autoimmune syndrome,” Diabetes Research and Clinical Practice, vol. 83, no. 1, pp. e19–e20, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. A. Skowera, R. J. Ellis, R. Varela-Calviño, et al., “CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope,” The Journal of Clinical Investigation, vol. 118, no. 10, pp. 3390–3402, 2008.
  53. A. M. Bulek, D. K. Cole, A. Skowera, et al., “Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes,” Nature Immunology, vol. 13, no. 3, pp. 283–289, 2012.
  54. S. Resic-Lindehammer, K. Larsson, E. Örtqvist et al., “Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk,” Acta Diabetologica, vol. 45, no. 4, pp. 231–235, 2008. View at Publisher · View at Google Scholar
  55. H. E. Larsson, G. Hansson, A. Carlsson et al., “Children developing type 1 diabetes before 6 years of age have increased linear growth independent of HLA genotypes,” Diabetologia, vol. 51, no. 9, pp. 1623–1630, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. A. Carlsson, I. Kockum, B. Lindblad et al., “Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in Sweden,” International Journal of Obesity. In press. View at Publisher · View at Google Scholar
  57. V. Guérin, L. Léniaud, B. Pédron, S. Guilmin-Crépon, N. Tubiana-Rufi, and G. Sterkers, “HLA-associated genetic resistance and susceptibility to type I diabetes in French North Africans and French natives,” Tissue Antigens, vol. 70, no. 3, pp. 214–218, 2007. View at Publisher · View at Google Scholar
  58. Y. S. Park, C. Y. Wang, K. W. Ko et al., “Combinations of HLA DR and DQ molecules determine the susceptibility to insulin-dependent diabetes mellitus in Koreans,” Human Immunology, vol. 59, no. 12, pp. 794–801, 1998. View at Publisher · View at Google Scholar · View at Scopus
  59. N. K. Mehra, G. Kaur, U. M. A. Kanga, and N. Tandon, “Immunogenetics of autoimmune diseases in Asian Indians,” Annals of the New York Academy of Sciences, vol. 958, pp. 333–336, 2002. View at Scopus
  60. J. C. Mbanya, E. Sobngwi, and D. N. S. Mbanya, “HLA-DRB1, -DQA1, -DQB1 and DPB1 susceptibility alleles in cameroonian type 1 diabetes patients and controls,” European Journal of Immunogenetics, vol. 28, no. 4, pp. 459–462, 2001. View at Publisher · View at Google Scholar · View at Scopus
  61. R. A. Cifuentes, A. Rojas-Villarraga, and J.-M. Anaya, “Human leukocyte antigen class II and type 1 diabetes in Latin America: a combined meta-analysis of association and family-based studies,” Human Immunology, vol. 72, no. 7, pp. 581–586, 2011. View at Publisher · View at Google Scholar
  62. D. G. Alleva, P. D. Crowe, L. Jin et al., “A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin,” The Journal of Clinical Investigation, vol. 107, no. 2, pp. 173–180, 2001. View at Scopus
  63. P. Eerligh, M. van Lummel, A. Zaldumbide et al., “Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes,” Genes and Immunity, vol. 12, no. 6, pp. 415–427, 2011. View at Publisher · View at Google Scholar
  64. X. Ge, E. A. James, H. Reijonen, and W. W. Kwok, “Differences in self-peptide binding between T1D-related susceptible and protective DR4 subtypes,” Journal of Autoimmunity, vol. 36, no. 2, pp. 155–160, 2011. View at Publisher · View at Google Scholar
  65. S. I. Mannering, L. C. Harrison, N. A. Williamson et al., “The insulin A-chain epitope recognized by human T cells is posttranslationally modified,” The Journal of Experimental Medicine, vol. 202, no. 9, pp. 1191–1197, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. I. Durinovic-Belló, B. O. Boehm, and A. G. Ziegler, “Predominantly recognized ProInsulin T helper cell epitopes in individuals with and without islet cell autoimmunity,” Journal of Autoimmunity, vol. 18, no. 1, pp. 55–66, 2002. View at Publisher · View at Google Scholar · View at Scopus
  67. I. Durinovic-Belló, M. Schlosser, M. Riedl et al., “Pro- and anti-inflammatory cytokine production by autoimmune T cells against preproinsulin in HLA-DRB1*04, DQ8 Type 1 diabetes,” Diabetologia, vol. 47, no. 3, pp. 439–450, 2004. View at Publisher · View at Google Scholar · View at Scopus
  68. Q. Ouyang, N. E. Standifer, H. Qin et al., “Recognition of HLA class I-restricted β-cell epitopes in type 1 diabetes,” Diabetes, vol. 55, no. 11, pp. 3068–3074, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. G. G. M. Pinkse, O. H. M. Tysma, C. A. M. Bergen et al., “Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 51, pp. 18425–18430, 2005. View at Publisher · View at Google Scholar · View at Scopus
  70. A. Toma, S. Haddouk, J. P. Briand et al., “Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 30, pp. 10581–10586, 2005. View at Publisher · View at Google Scholar · View at Scopus
  71. W. W. Unger, J. Velthuis, J. R. F. Abreu et al., “Discovery of low-affinity preproinsulin epitopes and detection of autoreactive CD8 T-cells using combinatorial MHC multimers,” Journal of Autoimmunity, vol. 37, no. 3, pp. 151–159, 2011. View at Publisher · View at Google Scholar
  72. Y. Uchigata, K. Yao, S. Takayama-Hasumi, and Y. Hirata, “Human monoclonal IgG1 insulin autoantibody from insulin autoimmune syndrome directed at determinant at asparagine site on insulin B-chain,” Diabetes, vol. 38, no. 5, pp. 663–666, 1989. View at Scopus
  73. Y. Uchigata, S. Takayama-Hasumi, K. Kawanishi, and Y. Hirata, “Inducement of antibody that mimics insulin action on insulin receptor by insulin autoantibody directed at determinant at asparagine site on human insulin B chain,” Diabetes, vol. 40, no. 8, pp. 966–970, 1991. View at Scopus
  74. P. Achenbach, K. Koczwara, A. Knopff, H. Naserke, A. G. Ziegler, and E. Bonifacio, “Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes,” The Journal of Clinical Investigation, vol. 114, no. 4, pp. 589–597, 2004. View at Publisher · View at Google Scholar · View at Scopus
  75. A. J. K. Williams, P. J. Bingley, R. E. Chance, and E. A. M. Gale, “Insulin autoantibodies: more specific than proinsulin autoantibodies for prediction of type I diabetes,” Journal of Autoimmunity, vol. 13, no. 3, pp. 357–363, 1999. View at Publisher · View at Google Scholar · View at Scopus
  76. J. A. Schroer, T. Bender, R. J. Feldmann, and K. Jin Kim, “Mapping epitopes on the insulin molecule using monoclonal antibodies,” European Journal of Immunology, vol. 13, no. 9, pp. 693–700, 1983. View at Scopus
  77. C. J. Padoa, N. J. Crowther, J. W. Thomas et al., “Epitope analysis of insulin autoantibodies using recombinant Fab,” Clinical and Experimental Immunology, vol. 140, no. 3, pp. 564–571, 2005. View at Publisher · View at Google Scholar · View at Scopus
  78. L. Castano, A. G. Ziegler, R. Ziegler, S. Shoelson, and G. S. Eisenbarth, “Characterization of insulin autoantibodies in relatives of patients with type I diabetes,” Diabetes, vol. 42, no. 8, pp. 1202–1209, 1993. View at Scopus
  79. N. Itoh, T. Hanafusa, A. Miyazaki et al., “Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients,” The Journal of Clinical Investigation, vol. 92, no. 5, pp. 2313–2322, 1993. View at Scopus
  80. R. Tisch and B. Wang, “Chapter 5 dysrulation of T cell peripheral tolerance in type 1 diabetes,” Advances in Immunology, vol. 100, pp. 125–149, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. P. A. Ott, M. T. Dittrich, B. A. Herzog et al., “T cells recognize multiple GAD65 and proinsulin epitopes in human type 1 diabetes, suggesting determinant spreading,” Journal of Clinical Immunology, vol. 24, no. 4, pp. 327–339, 2004. View at Publisher · View at Google Scholar · View at Scopus
  82. B. Keymeulen, E. Vandemeulebroucke, A. G. Ziegler et al., “Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes,” The New England Journal of Medicine, vol. 352, no. 25, pp. 2598–2608, 2005. View at Publisher · View at Google Scholar · View at Scopus
  83. M. D. Pescovitz, C. J. Greenbaum, H. Krause-Steinrauf et al., “Rituximab, B-lymphocyte depletion, and preservation of beta-cell function,” The New England Journal of Medicine, vol. 361, no. 22, pp. 2143–2152, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. K. C. Herold, S. E. Gitelman, U. Masharani et al., “A single course of anti-CD3 monoclonal antibody hOKT3γ1(ala-ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes,” Diabetes, vol. 54, no. 6, pp. 1763–1769, 2005. View at Publisher · View at Google Scholar · View at Scopus
  85. K. C. Herold, S. Gitelman, C. Greenbaum et al., “Treatment of patients with new onset Type 1 diabetes with a single course of anti-CD3 mAb teplizumab preserves insulin production for up to 5years,” Clinical Immunology, vol. 132, no. 2, pp. 166–173, 2009. View at Publisher · View at Google Scholar · View at Scopus
  86. B. Keymeulen, M. Walter, C. Mathieu et al., “Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass,” Diabetologia, vol. 53, no. 4, pp. 614–623, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. A. G. Ziegler, M. Hummel, M. Schenker, and E. Bonifacio, “Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study,” Diabetes, vol. 48, no. 3, pp. 460–468, 1999. View at Scopus
  88. M. Kukko, T. Kimpimäki, S. Korhonen et al., “Dynamics of diabetes-associated autoantibodies in young children with human leukocyte antigen-conferred risk of type 1 diabetes recruited from the general population,” The Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 5, pp. 2712–2717, 2005. View at Publisher · View at Google Scholar · View at Scopus
  89. T. P. Di Lorenzo, M. Peakman, and B. O. Roep, “Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes,” Clinical and Experimental Immunology, vol. 148, no. 1, pp. 1–16, 2007. View at Publisher · View at Google Scholar · View at Scopus
  90. Y. Hassainya, F. Garcia-Pons, R. Kratzer et al., “Identification of naturally processed HLA-A2—restricted proinsulin epitopes by reversed immunology,” Diabetes, vol. 54, no. 7, pp. 2053–2059, 2005. View at Publisher · View at Google Scholar · View at Scopus
  91. C. Baker, L. G. Petrich de Marquesini, A. J. Bishop, A. J. Hedges, C. M. Dayan, and F. S. Wong, “Human CD8 responses to a complete epitope set from preproinsulin: implications for approaches to epitope discovery,” Journal of Clinical Immunology, vol. 28, no. 4, pp. 350–360, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. N. C. Schloot, B. O. Roep, D. Wegmann et al., “Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects,” Diabetologia, vol. 40, no. 5, pp. 564–572, 1997. View at Publisher · View at Google Scholar · View at Scopus
  93. N. C. Schloot, S. Willemen, G. Duinkerken, R. R. P. De Vries, and B. O. Roep, “Cloned T cells from a recent onset IDDM patient reactive with insulin B- chain,” Journal of Autoimmunity, vol. 11, no. 2, pp. 169–175, 1998. View at Publisher · View at Google Scholar · View at Scopus
  94. L. Douglas Petersen, M. van Der Keur, R. R. P. De Vries, and B. O. Roep, “Autoreactive and immunoregulatory T-cell subsets in insulin-dependent diabetes mellitus,” Diabetologia, vol. 42, no. 4, pp. 443–449, 1999. View at Publisher · View at Google Scholar · View at Scopus
  95. G. Semana, R. Gausling, R. A. Jackson, and D. A. Hafler, “T cell autoreactivity to proinsulin epitopes in diabetic patients and healthy subjects,” Journal of Autoimmunity, vol. 12, no. 4, pp. 259–267, 1999. View at Publisher · View at Google Scholar · View at Scopus
  96. R. G. Naik, C. Beckers, R. Wentwoord et al., “Precursor frequencies of T-cells reactive to insulin in recent onset type 1 diabetes mellitus,” Journal of Autoimmunity, vol. 23, no. 1, pp. 55–61, 2004. View at Publisher · View at Google Scholar · View at Scopus
  97. S. I. Mannering, J. S. Morris, N. L. Stone, K. P. Jensen, P. M. van Endert, and L. C. Harrison, “CD4+ T cell proliferation in response to GAD and proinsulin in healthy, pre-diabetic, and diabetic donors,” Annals of the New York Academy of Sciences, vol. 1037, pp. 16–21, 2004. View at Publisher · View at Google Scholar · View at Scopus
  98. G. K. Papadopoulos, G. Bondinas, and A. K. Moustakas, “The murine pro-insulin II molecule contains strong-binding motifs for several H2-A and H2-E alleles that protect NOD mice from diabetes,” Diabetologia, vol. 51, supplement 1, p. S227, 2008.
  99. M. Nakayama, N. Abiru, H. Moriyama et al., “Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice,” Nature, vol. 435, no. 7039, pp. 220–223, 2005. View at Publisher · View at Google Scholar · View at Scopus
  100. F. S. Wong, J. Karttunen, C. Dumont et al., “Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library,” Nature Medicine, vol. 5, no. 9, pp. 1026–1031, 1999. View at Publisher · View at Google Scholar · View at Scopus
  101. M. G. Levisetti, A. Suri, S. J. Petzold, and E. R. Unanue, “The insulin-specific T cells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form,” The Journal of Immunology, vol. 178, no. 10, pp. 6051–6057, 2007. View at Scopus
  102. D. G. Alleva, R. A. Maki, A. L. Putnam et al., “Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B(9-23) epitope,” Scandinavian Journal of Immunology, vol. 63, no. 1, pp. 59–69, 2006. View at Publisher · View at Google Scholar · View at Scopus
  103. M. Hahn, M. J. Nicholson, J. Pyrdol, and K. W. Wucherpfennig, “Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor,” Nature Immunology, vol. 6, no. 5, pp. 490–496, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. Y. Li, Y. Huang, J. Lue, J. A. Quandt, R. Martin, and R. A. Mariuzza, “Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule,” The EMBO Journal, vol. 24, no. 17, pp. 2968–2979, 2005. View at Publisher · View at Google Scholar · View at Scopus
  105. D. K. Sethi, D. A. Schubert, A.-K. Anders et al., “A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC,” The Journal of Experimental Medicine, vol. 208, no. 1, pp. 91–102, 2011. View at Publisher · View at Google Scholar
  106. A. K. Moustakas and G. K. Papadopoulos, “Use of MHC II structural features in the design of vaccines for organ-specific autoimmune diseases,” Current Pharmaceutical Design, vol. 15, no. 28, pp. 3262–3273, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. B. Sauter, M. L. Albert, L. Francisco, M. Larsson, S. Somersan, and N. Bhardwaj, “Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells,” The Journal of Experimental Medicine, vol. 191, no. 3, pp. 423–433, 2000. View at Publisher · View at Google Scholar · View at Scopus
  108. F. P. Huang, N. Platt, M. Wykes et al., “A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes,” The Journal of Experimental Medicine, vol. 191, no. 3, pp. 435–443, 2000. View at Publisher · View at Google Scholar · View at Scopus
  109. R. Medzhitov, P. Preston-Hurlburt, and C. A. Janeway, “A human homologue of the Drosophila toll protein signals activation of adaptive immunity,” Nature, vol. 388, no. 6640, pp. 394–397, 1997. View at Publisher · View at Google Scholar · View at Scopus
  110. F. Dotta, S. Censini, A. G. S. van Halteren et al., “Coxsackie B4 virus infection of β cells and natural killer cell insulitis in recent-onset type 1 diabetic patients,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 12, pp. 5115–5120, 2007. View at Publisher · View at Google Scholar · View at Scopus
  111. O. Vaarala, “Is type 1 diabetes a disease of the gut immune system triggered by cow's milk insulin?” Advances in Experimental Medicine and Biology, vol. 569, pp. 151–156, 2005. View at Publisher · View at Google Scholar · View at Scopus
  112. J. Lempainen, S. Tauriainen, and O. Vaarala, “Interaction of enterovirus infection and Cow's milk-based formula nutrition in type 1 diabetes-associated autoimmunity,” Diabetes/Metabolism Research and Reviews, vol. 28, no. 2, pp. 177–185, 2011. View at Publisher · View at Google Scholar
  113. C. Andersson, K. Larsson, F. Vaziri-Sani et al., “The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes,” Autoimmunity, vol. 44, no. 5, pp. 394–405, 2011. View at Publisher · View at Google Scholar
  114. M. Elfving, B. Lindberg, K. Lynch et al., “Number of islet autoantibodies present in newly diagnosed type 1 diabetes children born to non-diabetic mothers is affected by islet autoantibodies present at birth,” Pediatric Diabetes, vol. 9, no. 2, pp. 127–134, 2008. View at Publisher · View at Google Scholar · View at Scopus
  115. A. Imagawa, T. Hanafusa, J.-I. Miyagawa, and Y. Matsuzawa, “A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies,” The New England Journal of Medicine, vol. 342, no. 5, pp. 301–307, 2000. View at Publisher · View at Google Scholar
  116. T. Hanafusa and A. Imagawa, “Fulminant type 1 diabetes: a novel clinical entity requiring special attention by all medical practitioners,” Nature Clinical Practice Endocrinology and Metabolism, vol. 3, no. 1, pp. 36–45, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. A. Imagawa and T. Hanafusa, “Fulminant type 1 diabetes as an important exception to the new diagnostic criteria using HbA1c-response to the International Expert Committee,” Diabetologia, vol. 52, no. 11, pp. 2464–2465, 2009. View at Publisher · View at Google Scholar · View at Scopus
  118. A. Imagawa and T. Hanafusa, “Fulminant type 1 diabetes mellitus,” in Immunoendocrinology: Scientific and Clinical Aspects (Contemporary Endocrinology), G. S. G. S. Eisenbarth, Ed., part 3, pp. 331–342, Humana Press, New Jersey, NJ, USA, 2011.
  119. A. Imagawa, T. Hanafusa, Y. Uchigata et al., “Fulminant type 1 diabetes: a nationwide survey in Japan,” Diabetes Care, vol. 26, no. 8, pp. 2345–2352, 2003. View at Publisher · View at Google Scholar · View at Scopus
  120. T. Hanafusa, “Report of Japan diabetes society committee on fulminant type 1 diabetes mellitus: epidemiological and clinical analysis and proposal of diagnostic criteria,” Journal of the Japan Diabetes Society, vol. 48, supplement 1, pp. A1–A13, 2005.
  121. A. Imagawa, T. Hanafusa, Y. Uchigata et al., “Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus,” Diabetologia, vol. 48, no. 2, pp. 294–300, 2005. View at Publisher · View at Google Scholar · View at Scopus
  122. I. Shimizu, H. Makino, A. Imagawa et al., “Clinical and immunogenetic characteristics of fulminant type 1 diabetes associated with pregnancy,” The Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 2, pp. 471–476, 2006. View at Publisher · View at Google Scholar · View at Scopus
  123. T. Hanafusa and A. Imagawa, “Insulitis in human type 1 diabetes,” Annals of the New York Academy of Sciences, vol. 1150, pp. 297–299, 2008. View at Publisher · View at Google Scholar · View at Scopus
  124. M. C. Honeyman, B. S. Coulson, and L. C. Harrison, “A novel subtype of type 1 diabetes mellitus,” The New England Journal of Medicine, vol. 342, no. 24, pp. 1835–1837, 2000. View at Publisher · View at Google Scholar
  125. S. Shibasaki, A. Imagawa, S. Tauriainen et al., “Expression of toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes,” Endocrine Journal, vol. 57, no. 3, pp. 211–219, 2010. View at Scopus
  126. S. Tanaka, Y. Nishida, K. Aida et al., “Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated β-cell failure in fulminant type 1 diabetes,” Diabetes, vol. 58, no. 10, pp. 2285–2291, 2009. View at Publisher · View at Google Scholar · View at Scopus
  127. K. Aida, Y. Nishida, S. Tanaka et al., “RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates β-cell death in fulminant type 1 diabetes,” Diabetes, vol. 60, no. 3, pp. 884–889, 2011. View at Publisher · View at Google Scholar
  128. M. Sue, A. Yoshihara, T. Otani, Y. Tsuchida, M. Higa, and N. Hiroi, “Characteristics of fulminant type 1 diabetes mellitus,” Medical Science Monitor, vol. 14, no. 10, pp. CS97–CS101, 2008. View at Scopus
  129. Y. M. Cho, J. T. Kim, K. S. Ko et al., “Fulminant type 1 diabetes in Korea: high prevalence among patients with adult-onset type 1 diabetes,” Diabetologia, vol. 50, no. 11, pp. 2276–2279, 2007. View at Publisher · View at Google Scholar · View at Scopus
  130. C. Zheng, Z. Zhou, L. Yang et al., “Fulminant type 1 diabetes mellitus exhibits distinct clinical and autoimmunity features from classical type 1 diabetes mellitus in Chinese,” Diabetes/Metabolism Research and Reviews, vol. 27, no. 1, pp. 70–78, 2011. View at Publisher · View at Google Scholar
  131. C. Moreau, D. Drui, G. Arnault-Ouary, B. Charbonnel, L. Chaillous, and B. Cariou, “Fulminant type 1 diabetes in Caucasians: a report of three cases,” Diabetes and Metabolism, vol. 34, no. 5, pp. 529–532, 2008. View at Publisher · View at Google Scholar · View at Scopus
  132. P. Höglund, J. Mintern, C. Waltzinger, W. Heath, C. Benoist, and D. Mathis, “Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes,” The Journal of Experimental Medicine, vol. 189, no. 2, pp. 331–339, 1999. View at Publisher · View at Google Scholar · View at Scopus
  133. J. Petrovc Berglund, E. Mariotti-Ferrandiz, E. Rosmaraki et al., “TCR repertoire dynamics in the pancreatic lymph nodes of non-obese diabetic (NOD) mice at the time of disease initiation,” Molecular Immunology, vol. 45, no. 11, pp. 3059–3064, 2008. View at Publisher · View at Google Scholar
  134. A. Geluk, K. E. van Meijgaarden, N. C. Schloot, J. W. Drijfhout, T. H. M. Ottenhoff, and B. O. Roep, “HLA-DR binding analysis of peptides from islet antigens in IDDM,” Diabetes, vol. 47, no. 10, pp. 1594–1601, 1998. View at Publisher · View at Google Scholar · View at Scopus
  135. R. S. Abraham and C. S. David, “Identification of HLA-class-II-restricted epitopes of autoantigens in transgenic mice,” Current Opinion in Immunology, vol. 12, no. 1, pp. 122–129, 2000. View at Publisher · View at Google Scholar · View at Scopus
  136. K. H. Lee, K. W. Wucherpfennig, and D. C. Wiley, “Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type I diabetes,” Nature Immunology, vol. 2, no. 6, pp. 501–507, 2001. View at Publisher · View at Google Scholar · View at Scopus
  137. A. K. Moustakas and G. K. Papadopoulos, “Molecular properties of HLA-DQ alleles conferring susceptibility to or protection from insulin-dependent diabetes mellitus: keys to the fate of islet β-cells,” American Journal of Medical Genetics, vol. 115, no. 1, pp. 37–47, 2002. View at Publisher · View at Google Scholar · View at Scopus
  138. M. van Lummel, P. A. van Veelen, A. Zaldumbide, et al., “The type 1 diabetes associated HLA-DQ8-trans dimer accomodates a unique peptide repertoire,” The Journal of Biological Chemistry, vol. 287, no. 12, pp. 9514–9524, 2012. View at Publisher · View at Google Scholar
  139. R. A. Ettinger and W. W. Kwok, “A peptide binding motif for HLA-DQA1*0102/DQB1*0602, the class II MHC molecule associated with dominant protection in insulin-dependent diabetes mellitus,” The Journal of Immunology, vol. 160, no. 5, pp. 2365–2373, 1998. View at Scopus
  140. R. A. Ettinger, G. K. Papadopoulos, A. K. Moustakas, G. T. Nepom, and W. W. Kwok, “Allelic variation in key peptide-binding pockets discriminates between closely related diabetes-protective and diabetes-susceptible HLA-DQB1*06 alleles,” The Journal of Immunology, vol. 176, no. 3, pp. 1988–1998, 2006. View at Scopus
  141. F. Susan Wong, A. K. Moustakas, L. Wen, G. K. Papadopoulos, and C. A. Janeway, “Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2Kd that stimulates CD8 T cells in insulin-dependent diabetes mellitus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 8, pp. 5551–5556, 2002. View at Publisher · View at Google Scholar · View at Scopus
  142. N. R. Martinez, P. Augstein, A. K. Moustakas et al., “Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide,” The Journal of Clinical Investigation, vol. 111, no. 9, pp. 1365–1371, 2003. View at Publisher · View at Google Scholar · View at Scopus
  143. K. T. Coppieters, F. Dotta, and N. Amirian, “Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients,” The Journal of Experimental Medicine, vol. 209, no. 1, article 51, 2012. View at Publisher · View at Google Scholar
  144. C. M. Bearden, A. Agarwal, B. K. Book et al., “Rituximab inhibits the in vivo primary and secondary antibody response to a neoantigen, bacteriophage phiX174,” American Journal of Transplantation, vol. 5, no. 1, pp. 50–57, 2005. View at Publisher · View at Google Scholar · View at Scopus
  145. L. Yu, K. Herold, H. Krause-Steinrauf et al., “Rituximab selectively suppresses specific islet antibodies,” Diabetes, vol. 60, no. 10, pp. 2560–2565, 2011. View at Publisher · View at Google Scholar
  146. T. Mandrup-Poulsen, J. Molvig, H. U. Andersen, S. Helqvist, G. A. Spinas, and M. Munck, “Lack of predictive value of islet cell antibodies, insulin antibodies, and HLA-DR phenotype for remission in cyclosporin-treated IDDM patients,” Diabetes, vol. 39, no. 2, pp. 204–210, 1990.
  147. N. Katoh, M. Matsuda, W. Ishii, H. Morita, and S. I. Ikeda, “Successful treatment with rituximab in a patient with stiff-person syndrome complicated by dysthyroid ophthalmopathy,” Internal Medicine, vol. 49, no. 3, pp. 237–241, 2010. View at Publisher · View at Google Scholar · View at Scopus
  148. J. L. Dupond, L. Essalmi, H. Gil, N. Meaux-Ruault, and C. Hafsaoui, “Rituximab treatment of stiff-person syndrome in a patient with thymoma, diabetes mellitus and autoimmune thyroiditis,” Journal of Clinical Neuroscience, vol. 17, no. 3, pp. 389–391, 2010. View at Publisher · View at Google Scholar · View at Scopus
  149. C. F. Verge, D. Stenger, E. Bonifacio et al., “Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes. Combinatorial islet autoantibody workshop,” Diabetes, vol. 47, no. 12, pp. 1857–1866, 1998. View at Scopus
  150. J. P. Palmer, C. M. Asplin, and P. Clemons, “Insulin antibodies in insulin-dependent diabetics before insulin treatment,” Science, vol. 222, no. 4630, pp. 1337–1339, 1983.
  151. P. Freychet, J. Roth, and D. M. Neville, “Insulin receptors in the liver: specific binding of ( 125 I)insulin to the plasma membrane and its relation to insulin bioactivity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 68, no. 8, pp. 1833–1837, 1971. View at Scopus
  152. S. Linde, B. Hansen, and A. Lernmark, “Stable iodinated polypeptide hormones prepared by polyacrylamide gel electrophoresis,” Analytical Biochemistry, vol. 107, no. 1, pp. 165–176, 1980. View at Scopus
  153. J. L. Diaz and T. J. Wilkin, “Effect of iodination site on binding of radiolabeled ligand by insulin antibodies and insulin autoantibodies,” Clinical Chemistry, vol. 34, no. 2, pp. 356–359, 1988. View at Scopus
  154. M. N. Lioubin, M. D. Meier, and B. H. Ginsberg, “A rapid, high-yield method of producing mono-[125I]A14 iodoinsulin,” Preparative Biochemistry, vol. 14, no. 4, pp. 303–311, 1984. View at Scopus
  155. F. B. Stentz, R. K. Wright, and A. E. Kitabchi, “A rapid means of separating A14-125I-insulin from heterogeneously labeled insulin molecules for biologic studies,” Diabetes, vol. 31, no. 12, pp. 1128–1131, 1982. View at Scopus
  156. H. E. Naserke, N. Dozio, A. G. Ziegler, and E. Bonifacio, “Comparison of a novel micro-assay for insulin autoantibodies with the conventional radiobinding assay,” Diabetologia, vol. 41, no. 6, pp. 681–683, 1998. View at Publisher · View at Google Scholar · View at Scopus
  157. A. J. K. Williams, P. J. Bingley, E. Bonifacio, J. P. Palmer, and E. A. M. Gale, “A novel micro-assay for insulin autoantibodies,” Journal of Autoimmunity, vol. 10, no. 5, pp. 473–478, 1997. View at Publisher · View at Google Scholar · View at Scopus
  158. M. Schlosser, P. W. Mueller, C. Törn, E. Bonifacio, and P. J. Bingley, “Diabetes Antibody Standardization Program: evaluation of assays for insulin autoantibodies,” Diabetologia, vol. 53, no. 12, pp. 2611–2620, 2010. View at Publisher · View at Google Scholar · View at Scopus
  159. P. J. Bingley, E. Bonifacio, and P. W. Mueller, “Diabetes antibody standardization program: first assay proficiency evaluation,” Diabetes, vol. 52, no. 5, pp. 1128–1136, 2003. View at Publisher · View at Google Scholar · View at Scopus
  160. T. Wilkin, J. Palmer, E. Bonifacio, J. L. Diaz, and V. Kruse, “First international workshop on the standardisation of insulin autoantibodies—held in Perth, Australia in January 1987,” Diabetologia, vol. 30, no. 8, pp. 676–677, 1987. View at Publisher · View at Google Scholar · View at Scopus
  161. T. J. Wilkin, S. L. Schoenfeld, J. L. Diaz, V. Kruse, E. Bonifacio, and J. P. Palmer, “Systemic variation and differences in insulin-autoantibody measurements,” Diabetes, vol. 38, no. 2, pp. 172–181, 1989. View at Scopus
  162. C. J. Greenbaum, J. P. Palmer, B. Kuglin et al., “Insulin autoantibodies measured by radioimmunoassay methodology are more related to insulin-dependent diabetes mellitus than those measured by enzyme- linked immunosorbent assay: results of the Fourth International Workshop on the Standardization of Insulin Autoantibody Measurement,” The Journal of Clinical Endocrinology & Metabolism, vol. 74, no. 5, pp. 1040–1044, 1992. View at Publisher · View at Google Scholar · View at Scopus
  163. P. Vardi, S. A. Dib, M. Tuttleman et al., “Competitive insulin autoantibody assay. Prospective evaluation of subjects at high risk for development of type I diabetes mellitus,” Diabetes, vol. 36, no. 11, pp. 1286–1291, 1987. View at Scopus
  164. A. G. Ziegler, R. Ziegler, P. Vardi, R. A. Jackson, J. S. Soeldner, and G. S. Eisenbarth, “Life-table analysis of progression to diabetes of anti-insulin autoantibody-positive relatives of individuals with type I diabetes,” Diabetes, vol. 38, no. 10, pp. 1320–1325, 1989. View at Scopus
  165. H. E. Naserke, E. Bonifacio, and A. G. Ziegler, “Immunoglobulin G insulin autoantibodies in BABYDIAB offspring appear postnatally: sensitive early detection using a protein A/G-based radiobinding assay,” The Journal of Clinical Endocrinology & Metabolism, vol. 84, no. 4, pp. 1239–1243, 1999. View at Scopus
  166. H. T. A. Siljander, S. Simell, A. Hekkala et al., “Predictive characteristics of diabetes-associated autoantibodies among children with HLA-conferred disease susceptibility in the general population,” Diabetes, vol. 58, no. 12, pp. 2835–2842, 2009. View at Publisher · View at Google Scholar
  167. L. Yu, D. T. Robles, N. Abiru et al., “Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 4, pp. 1701–1706, 2000. View at Publisher · View at Google Scholar · View at Scopus
  168. A. K. Steck, K. Johnson, K. J. Barriga et al., “Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: diabetes autoimmunity study in the young,” Diabetes Care, vol. 34, no. 6, pp. 1397–1399, 2011. View at Publisher · View at Google Scholar
  169. M. Knip, “Prediction and prevention of type 1 diabetes,” Acta Paediatrica, International Journal of Paediatrics, Supplement, vol. 87, no. 425, pp. 54–62, 1998. View at Scopus
  170. T. Orban, J. M. Sosenko, D. Cuthbertson et al., “Pancreatic islet autoantibodies as predictors of type 1 diabetes in the diabetes prevention trial-type 1,” Diabetes Care, vol. 32, no. 12, pp. 2269–2274, 2009. View at Publisher · View at Google Scholar · View at Scopus
  171. C. F. Verge, R. Gianani, E. Kawasaki et al., “Number of autoantibodies (against insulin, GAD or ICA512/IA2) rather than particular autoantibody specificities determines risk of type I diabetes,” Journal of Autoimmunity, vol. 9, no. 3, pp. 379–383, 1996. View at Publisher · View at Google Scholar · View at Scopus
  172. M. Schlosser, K. Koczwara, H. Kenk et al., “In insulin-autoantibody-positive children from the general population, antibody affinity identifies those at high and low risk,” Diabetologia, vol. 48, no. 9, pp. 1830–1832, 2005. View at Publisher · View at Google Scholar · View at Scopus
  173. W. Liu, T. Meckel, P. Tolar, H. W. Sohn, and S. K. Pierce, “Antigen affinity discrimination is an intrinsic function of the B cell receptor,” The Journal of Experimental Medicine, vol. 207, no. 5, pp. 1095–1111, 2010. View at Publisher · View at Google Scholar · View at Scopus
  174. B. M. Brooks-Worrell, D. Nielson, and J. P. Palmer, “Insulin autoantibodies and insulin antibodies have similar binding characteristics,” Proceedings of the Association of American Physicians, vol. 111, no. 1, pp. 92–96, 1999. View at Publisher · View at Google Scholar · View at Scopus
  175. J. Ludvigsson, C. Binder, and T. Mandrup-Poulsen, “Insulin autoantibodies are associated with islet cell antibodies; their relation to insulin antibodies and B-cell function in diabetic children,” Diabetologia, vol. 31, no. 9, pp. 647–651, 1988. View at Scopus
  176. M. Nakamura, W. Nishida, Y. Yamada et al., “Insulin administration may trigger pancreatic β-cell destruction in patients with type 2 diabetes,” Diabetes Research and Clinical Practice, vol. 79, no. 2, pp. 220–229, 2008. View at Publisher · View at Google Scholar · View at Scopus
  177. H. Holmberg, H. Mersebach, K. Kanc, and J. Ludvigsson, “Antibody response to insulin in children and adolescents with newly diagnosed Type 1 diabetes,” Diabetic Medicine, vol. 25, no. 7, pp. 792–797, 2008. View at Publisher · View at Google Scholar · View at Scopus
  178. J. W. Chen, J. Frystyk, T. Lauritzen, and J. S. Christiansen, “Impact of insulin antibodies on insulin aspart pharmacokinetics and pharmacodynamics after 12-week treatment with multiple daily injections of biphasic insulin aspart 30 in patients with type 1 diabetes,” European Journal of Endocrinology, vol. 153, no. 6, pp. 907–913, 2005. View at Publisher · View at Google Scholar · View at Scopus
  179. A. Lindholm, L. B. Jensen, P. D. Home, P. Raskin, B. O. Boehm, and J. Råstam, “Immune responses to insulin aspart and biphasic insulin aspart in people with type 1 and type 2 diabetes,” Diabetes Care, vol. 25, no. 5, pp. 876–882, 2002. View at Publisher · View at Google Scholar · View at Scopus
  180. S. E. Fineberg, J. Huang, R. Brunelle, K. S. Gulliya, and J. H. Anderson, “Effect of long-term exposure to insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes,” Diabetes Care, vol. 26, no. 1, pp. 89–96, 2003. View at Publisher · View at Google Scholar · View at Scopus
  181. T. Ishizuka, S. Ogawa, T. Mori et al., “Characteristics of the antibodies of two patients who developed daytime hyperglycemia and morning hypoglycemia because of insulin antibodies,” Diabetes Research and Clinical Practice, vol. 84, no. 2, pp. e21–e23, 2009. View at Publisher · View at Google Scholar · View at Scopus
  182. H. Yanai, H. Adachi, and H. Hamasaki, “Diabetic ketosis caused by the insulin analog aspart-induced anti-insulin antibody: successful treatmentwith the newest insulin analog glulisine,” Diabetes Care, vol. 34, no. 6, article e108, 2011. View at Publisher · View at Google Scholar
  183. A. Itoh, Y. Saisho, M. Mitsuishi et al., “Insulin glulisine may ameliorate nocturnal hypoglycemia related to insulin antibody—a case report,” Diabetes Research and Clinical Practice, vol. 94, no. 2, pp. e53–e54, 2011. View at Publisher · View at Google Scholar
  184. V. Castéra, A. Dutour-Meyer, M. C. Koeppel, C. Petitjean, and P. Darmon, “Systemic allergy to human insulin and its rapid and long acting analogs: successful treatment by continuous subcutaneous insulin lispro infusion,” Diabetes and Metabolism, vol. 31, no. 4, pp. 391–400, 2005. View at Scopus
  185. S. T. Bennett and J. A. Todd, “Human type 1 diabetes and the insulin gene: principles of mapping polygenes,” Annual Review of Genetics, vol. 30, pp. 343–370, 1996. View at Publisher · View at Google Scholar · View at Scopus
  186. V. Butty, C. Campbell, D. Mathis, and C. Benoist, “Impact of diabetes susceptibility loci on progression from pre-diabetes to diabetes in at-risk individuals of the diabetes prevention trial-type 1 (DPT-1),” Diabetes, vol. 57, no. 9, pp. 2348–2359, 2008. View at Publisher · View at Google Scholar · View at Scopus
  187. G. P. Pérez De Nanclares, J. R. Bilbao, and L. Castaño, “No association of INS-VNTR genotype and IAA autoantibodies,” Annals of the New York Academy of Sciences, vol. 1037, pp. 127–130, 2004. View at Publisher · View at Google Scholar
  188. M. Walter, E. Albert, M. Conrad et al., “IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of Type 1 diabetes and associated autoimmunity,” Diabetologia, vol. 46, no. 5, pp. 712–720, 2003. View at Scopus
  189. A.-P. Laine, H. Holmberg, A. Nilsson et al., “Two insulin gene single nucleotide polymorphisms associated with type 1 diabetes risk in the Finnish and Swedish populations,” Disease Markers, vol. 23, no. 3, pp. 139–145, 2007.
  190. T. Awata, E. Kawasaki, H. Ikegami et al., “Insulin gene/IDDM2 locus in Japanese type 1 diabetes: contribution of class I alleles and influence of class I subdivision in susceptibility to type 1 diabetes,” The Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 5, pp. 1791–1795, 2007. View at Publisher · View at Google Scholar · View at Scopus
  191. P. Vafiadis, S. T. Bennett, J. A. Todd et al., “Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus,” Nature Genetics, vol. 15, no. 3, pp. 289–292, 1997. View at Publisher · View at Google Scholar · View at Scopus
  192. A. Pugliese, M. Zeller, A. Fernandez Jr. et al., “The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes,” Nature Genetics, vol. 15, no. 3, pp. 293–297, 1997. View at Publisher · View at Google Scholar · View at Scopus
  193. H. Takase, C. R. Yu, R. M. Mahdi et al., “Thymic expression of peripheral tissue antigens in humans: a remarkable variability among individuals,” International Immunology, vol. 17, no. 8, pp. 1131–1140, 2005. View at Publisher · View at Google Scholar · View at Scopus
  194. I. Durinovic-Belló, E. Jelinek, M. Schlosser et al., “Class III alleles at the insulin VNTR polymorphism are associated with regulatory T-cell responses to proinsulin epitopes in HLA-DR4, DQ8 individuals,” Diabetes, vol. 54, no. 2, pp. S18–S24, 2005. View at Publisher · View at Google Scholar · View at Scopus
  195. K. Murphy, P. Travers, and M. J. Walport, Janeway's Immunobiology, Garland Science, New York, NY, USA, 7th edition, 2008.
  196. A. Pugliese, D. Brown, D. Garza et al., “Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs,” The Journal of Clinical Investigation, vol. 107, no. 5, pp. 555–564, 2001. View at Scopus
  197. J. N. Cohen, C. J. Guidi, E. F. Tewalt et al., “Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation,” The Journal of Experimental Medicine, vol. 207, no. 4, pp. 681–688, 2010. View at Publisher · View at Google Scholar · View at Scopus
  198. P. Peterson, K. Nagamine, H. Scott et al., “APECED: a monogenic autoimmune disease providing new clues to self- tolerance,” Immunology Today, vol. 19, no. 9, pp. 384–386, 1998. View at Publisher · View at Google Scholar · View at Scopus
  199. A. W. Michels and P. A. Gottlieb, “Autoimmune polyglandular syndromes,” Nature Reviews Endocrinology, vol. 6, no. 5, pp. 270–277, 2010. View at Publisher · View at Google Scholar · View at Scopus
  200. A. L. Fletcher, V. Lukacs-Kornek, E. D. Reynoso et al., “Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions,” The Journal of Experimental Medicine, vol. 207, no. 4, pp. 689–697, 2010. View at Publisher · View at Google Scholar · View at Scopus
  201. H. Lv, E. Havari, S. Pinto et al., “Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans,” The Journal of Clinical Investigation, vol. 121, no. 4, pp. 1561–1573, 2011. View at Publisher · View at Google Scholar
  202. S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, and M. Toda, “Immunologic self-tolerance maintained by activated T cells expressing IL- 2 receptor α-chains (CD25): breakdown of a single mechanism of self- tolerance causes various autoimmune diseases,” The Journal of Immunology, vol. 155, no. 3, pp. 1151–1164, 1995. View at Scopus
  203. M. Miyara, Y. Yoshioka, A. Kitoh et al., “Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor,” Immunity, vol. 30, no. 6, pp. 899–911, 2009. View at Publisher · View at Google Scholar · View at Scopus
  204. C. L. Bennett, J. Christie, F. Ramsdell et al., “The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3,” Nature Genetics, vol. 27, no. 1, pp. 20–21, 2001. View at Publisher · View at Google Scholar · View at Scopus
  205. S. F. Ziegler, “FOXP3: of mice and men,” Annual Review of Immunology, vol. 24, pp. 209–226, 2006. View at Publisher · View at Google Scholar · View at Scopus
  206. A. Rao, N. Kamani, A. Filipovich et al., “Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning,” Blood, vol. 109, no. 1, pp. 383–385, 2007. View at Publisher · View at Google Scholar · View at Scopus
  207. S. Lindley, C. M. Dayan, A. Bishop, B. O. Roep, M. Peatman, and T. I. M. Tree, “Defective suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes,” Diabetes, vol. 54, no. 1, pp. 92–99, 2005. View at Publisher · View at Google Scholar · View at Scopus
  208. J. H. Buckner, “Mechanisms of impaired regulation by CD4+ CD25+ FOXP3+ regulatory T cells in human autoimmune diseases,” Nature Reviews Immunology, vol. 10, no. 12, pp. 849–859, 2010. View at Publisher · View at Google Scholar · View at Scopus
  209. S. A. Long and J. H. Buckner, “CD4+FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game,” The Journal of Immunology, vol. 187, no. 5, pp. 2061–2066, 2011. View at Publisher · View at Google Scholar
  210. J. M. Lawson, J. Tremble, C. Dayan et al., “Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes,” Clinical and Experimental Immunology, vol. 154, no. 3, pp. 353–359, 2008. View at Publisher · View at Google Scholar · View at Scopus
  211. A. Schneider, M. Rieck, S. Sanda, C. Pihoker, C. Greenbaum, and J. H. Buckner, “The effector T cells of diabetic subjects are resistant to regulation via CD4+FOXP3+ regulatory T cells,” The Journal of Immunology, vol. 181, no. 10, pp. 7350–7355, 2008. View at Scopus
  212. S. A. Long, M. Rieck, M. Tatum et al., “Low-dose antigen promotes induction of FOXP3 in human CD4+ T cells,” The Journal of Immunology, vol. 187, no. 7, pp. 3511–3520, 2011. View at Publisher · View at Google Scholar
  213. E. A. James and W. W. Kwok, “CD8+ suppressor-mediated regulation of human CD4+ T cell responses to glutamic acid decarboxylase 65,” European Journal of Immunology, vol. 37, no. 1, pp. 78–86, 2007. View at Publisher · View at Google Scholar · View at Scopus
  214. A. Willcox, S. J. Richardson, A. J. Bone, A. K. Foulis, and N. G. Morgan, “Analysis of islet inflammation in human type 1 diabetes,” Clinical and Experimental Immunology, vol. 155, no. 2, pp. 173–181, 2009. View at Publisher · View at Google Scholar · View at Scopus
  215. N. Dozio, F. Sodoyez-Goffaux, M. Koch, B. Ziegler, and J. C. Sodoyez, “Polymorphism of insulin antibodies in six patients with insulin-immune hypoglycaemic syndrome,” Clinical and Experimental Immunology, vol. 85, no. 2, pp. 282–287, 1991. View at Scopus
  216. Y. Hirata, “Methimazole and insulin autoimmune syndrome with hypoglycaemia,” The Lancet, vol. 2, no. 8357, pp. 1037–1038, 1983. View at Scopus
  217. N. Furukawa, N. Miyamura, K. Nishida, H. Motoshima, K. Taketa, and E. Araki, “Possible relevance of alpha lipoic acid contained in a health supplement in a case of insulin autoimmune syndrome,” Diabetes Research and Clinical Practice, vol. 75, no. 3, pp. 366–367, 2007. View at Publisher · View at Google Scholar · View at Scopus
  218. Y. Takeuchi, T. Miyamoto, T. Kakizawa, S. Shigematsu, and K. Hashizume, “Insulin autoimmune syndrome possibly caused by alpha lipoic acid,” Internal Medicine, vol. 46, no. 5, pp. 237–239, 2007. View at Publisher · View at Google Scholar · View at Scopus
  219. T. Yamada, J. Imai, Y. Ishigaki, Y. Hinokio, Y. Oka, and H. Katagiri, “Possible relevance of HLA-DRB1 *0403 haplotype in insulin autoimmune syndrome induced by α-lipoic acid, used as a dietary supplement,” Diabetes Care, vol. 30, no. 12, article e131, 2007. View at Publisher · View at Google Scholar · View at Scopus