Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (pro)insulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and -DQ8 is reviewed and illustrated by molecular modeling. The importance of the cellular immune reaction involving cytotoxic CD8-positive T cells to kill beta cells through Class I MHC is discussed along with speculations of the possible role of B lymphocytes in presenting the proinsulin autoantigen over and over again through insulin-carrying insulin autoantibodies. In contrast to autoantibodies against other islet autoantigens such as GAD65, IA-2, and ZnT8 transporters, it has not been possible yet to standardize the insulin autoantibody test. As islet autoantibodies predict type 1 diabetes, it is imperative to clarify the mechanisms of insulin autoimmunity. 1. Introduction The pancreatic islets constitute about 2-3% of the pancreas weight that is about 100 grams in adults [1]. The islets represent the endocrine portion of the pancreas and are present as more than a million well-defined cellular clusters throughout the pancreas [2, 3]. Each pancreatic islet (Figure 1) is composed of about 54% beta cells, 35% alpha cells, and 11% delta cells in addition to connective tissue and capillary cells [4]. Proinsulin, converted to insulin (Figure 2), is the major hormone produced in the beta cells while glucagon and GLP-1 are produced by the alpha cells, somatostatin by the delta cells, and pancreatic polypeptide by the PP cells. Pancreatic islet cells are also reported to produce ghrelin [5], apelin [6, 7], and CART [8–10]. These polypeptide hormones may be coexpressed with insulin in the beta cells or with other hormone-producing cells [8]. PP cells are more often seen in the head of the pancreas, while alpha cells dominate the tail [11, 12]. Insulin is the life-saving hormone for people suffering from type 1 and at times type 2 diabetes (see what follows). More beta cells are available than necessary to main blood glucose at normal levels. However, loss of insulin has catastrophic consequences. It has been estimated that 50% of the pancreas may be removed by surgery without a development of diabetes [13, 14]. Type 1 diabetes (T1D) is an autoimmune disease leading to a
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.
[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.
[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.
[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.
[6]
C. Ringstr？m, M. D. Nitert, H. Bennet et al., “Apelin is a novel islet peptide,” Regulatory Peptides, vol. 162, no. 1–3, pp. 44–51, 2010.
[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.
[8]
N. Wierup, M. Bj？rkqvist, 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.
[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.
[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.
[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.
[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.
[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.
[15]
D. La Torre and A. Lernmark, “Immunology of beta-cell destruction,” Advances in Experimental Medicine and Biology, vol. 654, pp. 537–583, 2010.
[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.
[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.
[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.
[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.
[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.
[22]
J. F. Bach, “Insulin-dependent diabetes mellitus as an autoimmune disease,” Endocrine Reviews, vol. 15, no. 4, pp. 516–542, 1994.
[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.
[24]
D. B. Schranz and A. Lernmark, “Immunology in diabetes: an update,” Diabetes/Metabolism Reviews, vol. 14, no. 1, pp. 3–29, 1998.
[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.
[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.
[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.
[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.
[29]
T. Kimpim？ki, A. Kupila, A.-M. H？m？l？inen 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.
[30]
M. Kukko, T. Kimpim？ki, 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[44]
C. Taplin and J. Barker, “Autoantibodies in type 1 diabetes,” Autoimmunity, vol. 41, no. 1, pp. 11–18, 2008.
[45]
Y. Hirata and Y. Uchigata, “Insulin autoimmune syndrome in Japan,” Diabetes Research and Clinical Practice, vol. 24, pp. S153–S157, 1994.
[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.
[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.
[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.
[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.
[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.
[52]
A. Skowera, R. J. Ellis, R. Varela-Calvi？o, 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. ？rtqvist 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[88]
M. Kukko, T. Kimpim？ki, 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[132]
P. H？glund, 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[158]
M. Schlosser, P. W. Mueller, C. T？rn, 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[179]
A. Lindholm, L. B. Jensen, P. D. Home, P. Raskin, B. O. Boehm, and J. R？stam, “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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[187]
G. P. Pérez De Nanclares, J. R. Bilbao, and L. Casta？o, “No association of INS-VNTR genotype and IAA autoantibodies,” Annals of the New York Academy of Sciences, vol. 1037, pp. 127–130, 2004.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[199]
A. W. Michels and P. A. Gottlieb, “Autoimmune polyglandular syndromes,” Nature Reviews Endocrinology, vol. 6, no. 5, pp. 270–277, 2010.
[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.
[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.
[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.
[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.
[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.
[205]
S. F. Ziegler, “FOXP3: of mice and men,” Annual Review of Immunology, vol. 24, pp. 209–226, 2006.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[216]
Y. Hirata, “Methimazole and insulin autoimmune syndrome with hypoglycaemia,” The Lancet, vol. 2, no. 8357, pp. 1037–1038, 1983.
[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.
[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.
[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.
