Cellular and molecular pathogenesis of type 1A diabetes

Cellular and Molecular Life Sciences

Volumn 64, Issue 7-8, 2007, Pages 865-872

  Jahromi, M M ^a,b   Eisenbarth, G S ^a  

^a UNIVERSITY OF COLORADO DENVER   (United States)

^b SALMANIYA MEDICAL COMPLEX   (Bahrain)

Author keywords

cell; Autoantibody; MHC; Oligogenic; Pathogenesis; Polyendocrinopathy; Polygenic; T1AD

Indexed keywords

CHROMOSOME 10P; CHROMOSOME 11P; CHROMOSOME 1P; CHROMOSOME 2Q; CHROMOSOME 6P; CHROMOSOME 6Q; DISEASE CLASSIFICATION; ENVIRONMENTAL FACTOR; GENE LOCUS; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC TRAIT; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; IPEX SYNDROME; MOLECULAR GENETICS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; NONOBESE DIABETIC MOUSE; PANCREAS ISLET BETA CELL; PATHOGENESIS; PREDICTION; PREGNANCY DIABETES MELLITUS; REVIEW;

ANIMALS; AUTOIMMUNE DISEASES; DIABETES MELLITUS, TYPE 1; GENES, MHC CLASS II; GENETIC PREDISPOSITION TO DISEASE; HLA ANTIGENS; HUMANS; INSULIN-SECRETING CELLS; POLYMORPHISM, GENETIC; RISK FACTORS;

EID: 34247101086     PISSN: 1420682X     EISSN: 15691632     Source Type: Journal    
DOI: 10.1007/s00018-007-6469-4     Document Type: Review

References (88)

1. American Diabetes Association (2006) Diagnosis and classification of diabetes mellitus. Diabetes Care 29 (Suppl 1), S43-S48.
2. LaPorte, R. E., Matsushima, M. and Chang, Y-F. (1995) Prevalence and incidence of Insulin-Dependent Diabetes. National Institutes of Health; Bethesda.
3. LaPorte, R. E., Matsushima, M. and Chang, Y. F. (1995) Prevalence and incidence of insulin-dependent diabetes, 2 ed. Bethesda, National Institutes of Health, NIH publ. No. 95-1468.
4. Karvonen, M., Viik-Kajander, M., Moltchanova, E., Libman, I., LaPorte, R. and Tuomilehto, J. (2000) Incidence of childhood type 1 diabetes. Diabetes Care 23, 1516-1526.
5. Green, A. and Patterson, C. C. (2001) Trends in the incidence of childhood-onset diabetes in Europe. Diabetologia 44, B3-B8.
6. Sheehy, M. J., Scharf, S. J., Rowe, J. R., Neme de Gimenez, M. H., Meske, L. M., Erlich, H. A. and Nepom, B. S. (1989) A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles. J. Clin. Invest. 83, 830-835.
7. Morel, P. A., Dorman, J. S., Todd, J. A., McDevitt, H. O. and Trucco, M. (1988) Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. Proc. Natl. Acad. Sci. USA 85, 8111-8115.
8. Barratt, B. J., Payne, F., Lowe, C. E., Hermann, R., Healy, B. C., Harold, D., Concannon, P., Gharani, N., McCarthy, M. I., Olavesen, M. G., McCormack, R., Guja, C., Ionescu-Tirgoviste, C., Undlien, D. E., Ronningen, K. S., Gillespie, K. M., Tuomilehto-Wolf, E., Tuomilehto, J., Bennett, S. T., Clayton, D. G., Cordell, H. J. and Todd, J. A. (2004) Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53, 1884-1889.
9. Kralovicova, J., Gaunt, T. R., Rodriguez, S., Wood, P. J., Day, I. N. and Vorechovsky, I. (2006) Variants in the human insulin gene that affect pre-mRNA splicing: is -23HphI a functional single nucleotide polymorphism at IDDM2? Diabetes 55, 260-2644.
10. Nakayama, M., Abiru, N., Moriyama, H., Babaya, N., Liu, E., Miao, D., Yu, L., Wegmann, D. R., Hutton, J. C., Elliott, J. F. and Eisenbarth, G. S. (2005) Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435, 220-223.
11. Babaya, N., Nakayama, M., Moriyama, H., Gianani, R., Still, T., Miao, D., Yu, L., Hutton, J. C. and Eisenbarth, G. S. (2006) A new model of insulin-deficient diabetes: male NOD mice with a single copy of Ins1 and no Ins2. Diabetologia 49, 1222-1228.
12. Bottini, N., Muscumeci L, Alonso, A., Rahmouni, S., Nika, K., Rostamkhani, M., MacMurray, J., Meloni, G., Lucarelli, P., Pellechia, M., Eisenbarth, G., Comings, D. and Mustelin, T. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337-338.
13. Fife, B. T., Griffin, M. D., Abbas, A. K., Locksley, R. M. and Bluestone, J. A. (2006) Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist. J Clin. Invest. 116, 2252-2261.
14. Van Belzen, M. J., Mulder, C. J., Zhernakova, A., Pearson, P. L., Houwen, R. H. and Wijmenga, C. (2004) CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients. Eur. J. Hum. Genet. 12, 782-785.
15. Smyth, D. J., Cooper, J. D., Bailey, R., Field, S., Burren, O., Smink, L. J., Guja, C., Ionescu-Tirgoviste, C., Widmer, B., Dunger, D. B., Savage, D. A., Walker, N. M., Clayton, D.G. and Todd, J. A. (2006) A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat. Genet. 38, 617-619.
16. Vella, A., Cooper, J. D., Lowe, C. E., Walker, N., Nutland, S., Widmer, B., Jones, R., Ring, S. M., McArdle, W., Pembrey, M. E., Strachan, D. P., Dunger, D. B., Twells, R. C., Clayton, D. G. and Todd, J. A. (2005) Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773-779.
17. Aly, T. A., Eller, E., Ide, A., Gowan, K., Babu, S. R., Erlich, H. A., Rewers, M. J., Eisenbarth, G. S. and Fain, P. R. (2006) Multi-SNP analysis of MHC region: remarkable conservation of HLA-A1-B8-DR3 haplotype. Diabetes 55, 1265-1269.
18. Lee, C., Maull, E., Chapman, N., Tracy, S. and Gauntt, C. (1997) Genomic regions of coxsackievirus B3 associated with cardiovirulence. J. Med. Virol. 52, 341-347.
19. Roach, J. C., Deutsch, K., Li, S., Siegel, A. F., Bekris, L. M., Einhaus, D. C., Sheridan, C. M., Glusman, G., Hood, L., Lernmark, A. and Janer, M. (2006) Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in Sweden. Am. J. Hum. Genet. 79, 614-627.
20. Velaga, M. R., Wilson, V., Jennings, C. E., Owen, C. J., Herington, S., Donaldson, P. T., Ball, S. G., James, R. A., Quinton, R., Perros, P. and Pearce, S. H. (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. J Clin. Endocrinol. Metab 89, 5862-5865.
21. Aly, T. A., Ide, A., Jahromi, M. M., Barker, J. M., Fernando, M. S., Babu, S. R., Yu, L., Miao, D., Erlich, H. A., Fain, P. R., Barriga, K. J., Norris, J. M., Rewers, M. J. and Eisenbarth, G. S. (2006) Extreme genetic risk for type 1A diabetes. Proc. Natl. Acad. Sci. USA 103, 14074-14079.
22. Lie, B. A., Sollid, L. M., Ascher, H., Ek, J., Akselsen, H. E., Ronningen, K. S., Thorsby, E. and Undlien, D. E. (1999)Agene telomeric of the HLA class I region is involved in predisposition to both type 1 diabetes and coeliac disease. Tissue Antigens 54, 162-168.
23. Johansson, S., Lie, B. A., Todd, J. A., Pociot, F., Nerup, J., Cambon-Thomsen, A., Kockum, I., Akselsen, H. E., Thorsby, E. and Undlien, D. E. (2003) Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and -DRB1. Genes Immun. 4, 46-53.
24. Alper, C. A., Awdeh, Z. and Yunis, E. J. (1992) Conserved, extended MHC haplotypes. Exp. Clin. Immunogenet. 9, 58-71.
25. Yunis, E. J., Larsen, C. E., Fernandez-Vina, M., Awdeh, Z. L., Romero, T., Hansen, J. A. and Alper, C. A. (2003) Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks. Tissue Antigens 62, 1-20.
26. Bilbao, J. R., Calvo, B., Aransay, A. M., Martin-Pagola, A., Perez, d. N., Aly, T. A., Rica, I., Vitoria, J. C., Gaztambide, S., Noble, J., Fain, P. R., Awdeh, Z. L., Alper, C. A. and Castano, L. (2006) Conserved extended haplotypes discriminate HLADR3-homozygous basque patients with type 1 diabetes mellitus and celiac disease. Genes Immun. 7, 550-554.
27. Ahonen, P., Myllarniemi, S., Sipila, I. and Perheentupa, J. (1990) Clinical variation of autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy (APECED) in a series of 68 patients. N. Engl. J. Med. 322, 1829-1836.
28. Patel, D. D. (2001) Escape from tolerance in the human X-linked autoimmunity-allergic disregulation syndrome and the scurfy mouse. J. Clin. Invest. 107, 155-157.
29. Nishimaki, K., Kawamura, T., Inada, H., Yagawa, K., Nose, Y., Nabeya, N., Isshiki, G., Tatsumi, N. and Niihira, S. (2000)HLA DPB1*0201 Gene confers disease susceptibility in Japanese with childhood onset type I diabetes, independent of HLA-DR and DQ genotypes. Diabetes Res. Clin. Pract. 47, 49-55.
30. Blomhoff, A., Lie, B. A., Myhre, A. G., Kemp, E. H., Weetman, A. P., Akselsen, H. E., Huseby, E. S. and Undlien, D. E. (2004) Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison s disease. J Clin. Endocrinol. Metab 89, 3474-3476.
31. Gambelunghe, G., Falorni, A., Ghaderi M, Laureti S, Tortoioli, C., Santeusanio, F., Brunetti, P. and Sanjeevi, C. B. (1999) Microsatellite polymorphism of the MHC class I chain-related (MIC-A and MIC-B) genes marks the risk for autoimmune Addison's disease. J. Clin. Endocrinol. Metab. 84, 3701-3707.
32. Yu, L., Brewer, K. W., Gates, S., Wu, A., Wang, T., Babu, S., Gottlieb, P., Freed, B. M., Noble, J., Erlich, H., Rewers, M. and Eisenbarth, G. (1999) DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease. J. Clin. Endocrinol. Metab. 84, 328-335.
33. Wallaschofski, H., Meyer, A., Tuschy, U. and Lohmann, T. (2003) HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III. Horm. Metab. Res. 35, 120-124.
34. Robles, D. T., Fain, P. R., Gottlieb, P. A. and Eisenbarth, G. S. (2002) The genetics of autoimmune polyendocrine syndrome type II. In Autoimmune Polyendocrine Syndromes, 31, Eisenbarth, G. S. (Ed.), pp. 353-368, Saunders, Philadelphia.
35. Bosi, E., Becker, F., Bonifacio, E., Wagner, R., Collins, P., Gale, E. A. and Bottazzo, G. F. (1991) Progression to type I diabetes in autoimmune endocrine patients with islet cell antibodies. Diabetes 40, 977-984.
36. Meager, A., Visvalingam, K., Peterson, P., Moll, K., Murumagi, A., Krohn, K., Eskelin, P., Perheentupa, J., Husebye, E., Kadota, Y. and Willcox, N. (2006) Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 3, e289.
37. Wildin, R. S. and Freitas, A. (2005) IPEX and FOXP3: Clinical and research perspectives. J. Autoimmun. 25 (Suppl), 56-62.
38. Bindl, L., Torgerson, T., Perroni, L., Youssef, N., Ochs, H. D., Goulet, O. and Ruemmele, F. M. (2005) Successful use of the new immune-suppressor sirolimus in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). J. Pediatr. 147, 256-259.
39. Hornum, L., Romer, J. and Markholst, H. (2002) The diabetesprone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1. Diabetes 51, 1972-1979.
40. Makino, S., Kunimoto, K., Muraoka, Y., Mizushima, Y., Katagiri, K. and Tochino, Y. (1980) Breeding of a non-obese, diabetic strain of mice. Exp. Anim. 29, 1-13.
41. Lenzen, S., Tiedge, M., Elsner, M., Lortz, S., Weiss, H., Jorns, A., Kloppel, G., Wedekind, D., Prokop, C.M. and Hedrich, H. J. (2001) The LEW.1AR1/Ztm-Iddm Rat: a new model of spontaneous insulin-dependent diabetes mellitus. Diabetologia 44, 1189-1196.
42. Ikegami, H., Makino, S. (1993) Genetic susceptibility to insulin-dependent diabetes mellitus: from NOD mice to humans. In: Lessons from animal diabetes, Shafrir, E. (Ed.), pp. 39 -50, Smith-Gordon, London.
43. Lonnrot, M., Salminen, K., Knip, M., Savola, K., Kulmala, P., Leinikki, P., Hyypia, T., Akerblom, H.K. and Hyoty, H. (2000) Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. J. Med. Virol. 61, 214-220.
44. Graves, P. M., Rotbart, H. A., Nix, W. A., Pallansch, M. A., Erlich, H. A., Norris, J. M., Hoffman, M., Eisenbarth, G. S. and Rewers, M. (2003) Prospective study of enteroviral infections and development of beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY). Diabetes Res. Clin. Pract. 59, 51-61.
45. Viskari, H., Ludvigsson, J., Uibo, R., Salur, L., Marciulionyte, D., Hermann, R., Soltesz, G., Fuchtenbusch, M., Ziegler, A. G., Kondrashova, A., Romanov, A., Knip, M. and Hyoty, H. (2004) Relationship between the incidence of type 1 diabetes and enterovirus infections in different European populations: Results from the EPIVIR project. J. Med. Virol. 72, 610-617.
46. Akerblom, H. K., Virtanen, S. M., Ilonen, J., Savilahti, E., Vaarala, O., Reunanen, A., Teramo, K., Hamalainen, A. M., Paronen, J., Riikjarv, M. A., Ormisson, A., Ludvigsson, J., Dosch, H. M., Hakulinen, T. and Knip, M. (2005) Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study. Diabetologia 48, 829-837.
47. Hermann, R., Knip, M., Veijola, R., Simell, O., Laine, A. P., Akerblom, H. K., Groop, P. H., Forsblom, C., Pettersson-Fernholm, K. and Ilonen, J. (2003) Temporal changes in the frequencies of HLA genotypes in patients with type 1 diabetes-indication of an increased environmental pressure? Diabetologia 46, 420-425.
48. Bach, J. F. (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911-920.
49. Devendra, D., Liu, E. and Eisenbarth, G. S. (2004) Type 1 diabetes: recent developments. BMJ 328, 750-754.
50. Eisenbarth, G. S. (2002) Autoimmune polyendocrine syndromes. In: Type 1 Diabetes: Molecular, Cellular and Clinical Immunology. Plenum, New York.
51. Daaboul, J. and Schatz, D. (2003) Overview of prevention and intervention trials for type 1 diabetes. Rev. Endocr. Metab. Disord. 4, 317-323.
52. Abiru, N., Kawasaki, E. and Eguch, K. (2002) Current knowledge of Japanese type 1 diabetic syndrome. Diabetes Metab. Res. Rev. 18, 357-366.
53. Rabin, D. U., Pleasic, S. M., Shapiro, J. A., Yoo-Warren, H., Oles, J., Hicks, J. M., Goldstein, D. E. and Rae, P. M. M. (1994) Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases. J. Immunol. 152, 3183-3188.
54. Leslie, R. D., Atkinson, M. A. and Notkins, A. L. (1999) Autoantigens IA-2 and GAD in type I (insulin-dependent) diabetes. Diabetologia 42, 3-14.
55. Bach, J. F. (1999) Etiology and pathogenesis of human insulindependent diabetes mellitus. In: Contemporary Endocrinology: Autoimmune Endocrinopathies, , Volpe, R. (Ed.), pp. 293-307. Humana, Totowa.
56. Abiru, N. and Eisenbarth, G. S. (1999) Autoantibodies and autoantigens in type 1 diabetes: role in pathogenesis, prediction and prevention. Can. J. Diabetes Care 23, 59-65.
57. Bonifacio, E., Scirpoli, M., Kredel, K., Fuchtenbusch, M. and Ziegler, A. G. (1999) Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. J. Immunol. 163, 525-532.
58. Colman, P. G., McNair, P., Margetts, H., Schmidli, R. S., Werther, G. A., Alford, F. P., Ward, G. M., Tait, B. D., Honeyman, M. C. and Harrison, L. C. (1998) The Melbourne pre-diabetes study: prediction of type 1 diabetes mellitus using antibody and metabolic testing. Med. J. Aust. 169, 81-84.
59. Bingley, P. J., Bonifacio, E., Williams, A. J. K., Genovese, S., Bottazzo, G. F. and Gale, E. A. M. (1997) Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes 46, 1701-1710.
60. Greenbaum, C. J., Palmer, J. P., Kuglin, B. and Kolb, H. (1992) 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. J. Clin. Endocrinol. Metab. 74, 1040-1044.
61. Baekkeskov, S., Aanstoot, H.-J., Christgau, S., Reetz, A., Solimena, M., Cascalho, M., Folli, F., Richter-Olesen, H. and DeCamilli, P. (1990) Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347, 151-156.
62. Rabin, D. U., Pleasic, S. M., Palmer-Crocker, R. and Shapiro, J. A. (1992) Cloning and expression of IDDM-specific human autoantigens. Diabetes 41, 183-186.
63. Lan, M. S., LU,J., Goto, Y. and Notkins, A. L. (1994) Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol. 13, 505-514.
64. Wasmeier, C. and Hutton, J. C. (1996) Molecular cloning of phogrin, a protein-tyrosine phosphatase homologue localized to insulin secretory granule membranes. J. Biol. Chem. 271, 18161-18170.
65. Lu, J., Li, Q., Xie, H., Chen, Z.-J., Borovitskaya, A. E., Maclaren, N. K., Notkins, A. L. and Lan, M. S. (1996) Identification of a second transmembrane protein tyrosine phosphatase, IA-2β, as an autoantigen in insulin-dependent diabetes mellitus: precursor of the 37-KDa tryptic fragment. Proc. Natl. Acad. Sci. USA 93, 2307-2311.
66. Koczwara, K., Bonifacio, E. and Ziegler, A. G. (2004) Transmission of maternal islet antibodies and risk of autoimmune diabetes in offspring of mothers with type 1 diabetes. Diabetes 53, 1-4.
67. Roll, U., Christie, M. R., Füchtenbusch, M., Payton, M. A., Hawkes, C. J. and Ziegler, A.G. (1996) Perinatal autoimmunity in offspring of diabetic parents. The German Multi-Center BABY-DIAB Study: detection of humoral immune responses to islet antigens in early childhood. Diabetes 45, 967-973.
68. Martin, S., Wolf-Eichbaum, D., Duinkerken, G., Scherbaum, W. A., Kolb, H., Noordzij, J. G. and Roep, B. O. (2001) Development of type 1 diabetes despite severe hereditary Blymphocyte deficiency. N. Engl. J. Med. 345, 1036-1040.
69. Serreze, D. V., Fleming, S. A., Chapman, H. D., Richard, S. D., Leiter, E. H. and Tisch, R. M. (1998)B Lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J. Immunol. 161, 3912-3918.
70. Greeley, S. A., Katsumata, M., Yu, L., Eisenbarth, G. S., Moore, D. J., Goodarzi, H., Barker, C. F., Naji, A. and Noorchashm, H. (2002) Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice. Nat. Med. 8, 399-402.
71. Verge, C. F., Gianani, R., Kawasaki, E., Yu, L., Pietropaolo, M., Jackson, R. A., Chase, H. P. and Eisenbarth, G. S. (1996) Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 45, 926-933.
72. Bach, J. F. (1994) Insulin-dependent diabetes mellitus as an autoimmune disease. [Review]. Endocr. Rev. 15, 516-542.
73. Reijonen, H., Mallone, R., Heninger, A. K., Laughlin, E. M., Kochik, S. A., Falk, B., Kwok, W. W., Greenbaum, C. and Nepom, G. T. (2004) GAD65-specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes. Diabetes 53, 1987-1994.
74. Kent, S. C., Chen, Y., Bregoli, L., Clemmings, S. M., Kenyon, N. S., Ricordi, C., Hering, B. J. and Hafler, D. A. (2005) Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 435, 224-228.
75. Du, W., Wong, F. S., Li, M. O., Peng, J., Qi, H., Flavell, R. A., Sherwin, R. and Wen, L. (2006) TGF-beta signaling is required for the function of insulin-reactive T regulatory cells. J. Clin. Invest. 116, 1360-1370.
76. Jasinski, J. M., Yu, L., Nakayama, M., Li, M. M., Lipes, M. A., Eisenbarth, G. S. and Liu, E. (2006) Transgenic insulin (B:9-23) T-cell receptor mice develop autoimmune diabetes dependent upon RAG genotype, H-2g7 homozygosity, and insulin 2 gene knockout. Diabetes 55, 1978-1984.
77. Bresson, D., Togher, L., Rodrigo, E., Chen, Y. L., Bluestone, J. A., Herold, K. C. and von Herrath, M. (2006) Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing tregs. J. Clin. Invest. 116, 1371-1381.
78. Dai, Y. D., Jensen, K. P., Lehuen, A., Masteller, E. L., Bluestone, J. A., Wilson, D. B. and Sercarz, E. E. (2005) A peptide of glutamic acid decarboxylase 65 can recruit and expand a diabetogenic T cell clone, BDC2.5, in the pancreas. J. Immunol. 175, 3621-3627.
79. Andre, I., Gonzalez, A., Wang, B., Katz, J., Benoist, C. and Mathis, D. (1996) Checkpoints in the progression of autoimmune disease: lessons from diabetes models. Proc. Natl. Acad. Sci. USA 93, 2260-2263.
80. Frigeri, C., Martin, C. C., Svitek, C. A., Oeser, J. K., Hutton, C., Gannon, M. and O'Brien, R. M. (2004) The proximal isletspecific glucose-6-phosphatase catalytic subunit-related protein autoantigen promoter is sufficient to initiate but not maintain transgene expression in mouse islets in vivo.Diabetes 53, 1754-1764.
81. DiLorenzo, T. P. and Serreze, D. V. (2005) The Good Turned Ugly: Immunopathogenic basis for diabetogenic CD8+ T cells in NOD mice. Immunol. Rev. 204, 250-263.
82. Jaeckel, E., Klein, L., Martin-Orozco, N. and von Boehmer, H. (2003) Normal Incidence of Diabetes in NOD Mice Tolerant to Glutamic Acid Decarboxylase. J Exp. Med 197, 1635-44.
83. Kubosaki, A., Nakamura, S. and Notkins, A. L. (2005) Dense core vesicle proteins IA-2 and IA-2{beta}: metabolic alterations in double knockout mice. Diabetes 54 (Suppl 2), S46-S51.
84. Moriyama, H., Abiru, N., Paronen, J., Sikora, K., Liu, E., Miao, D., Devendra, D., Beilke, J., Gianani, R., Gill, R.G. and Eisenbarth, G. S. (2003) Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. Proc. Natl. Acad. Sci. USA 100, 10376-10381.
85. Homann, D. and Eisenbarth, G. S. (2006) An immunologic homunculus for type 1 diabetes. J. Clin. Invest. 116, 1212-1215.
86. Skyler, J. S., Krischer, J. P. , Wolfsdorf, J., Cowie, C., Palmer, P., Greenbaum, C., Cuthberturn, D., Rafkin-(2005) Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial-type 1. Diabetes Care 28, 1068 1076.
87. Keymeulen, B., Vandemeulebroucke, E., Ziegler, A. G., Mathieu, C., Kaufman, L., Hale, G., Gorus, F., Goldman, M., Walter, M., Candon, S., Schandene, L., Crenier, L., De Block, C., Seigneurin, J. M., De Pauw, P., Pierard, D., Weets, I., Rebello, P., Bird, P., Berrie, E., Frewin, M., Waldmann, H., Bach, J. F., Pipeleers, D. and Chatenoud, L. (2005) Insulin needs after CD3-antibody therapy in new-onset type diabetes. N. Engl. J. Med. 352, 2598-2608.
88. Herold, K. C., Hagopian, W., Auger, J. A., Poumian-Ruiz, E., Taylor, L., Donaldson, D., Gitelman, S. E., Harlan, D. M., Xu, D., Zivin, R. A. and Bluestone, J. A. (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692-1698.