ENTRY ko04940 Pathway NAME Type I diabetes mellitus DESCRIPTION Type I diabetes mellitus is a disease that results from autoimmune destruction of the insulin-producing beta-cells. Certain beta-cell proteins act as autoantigens after being processed by antigen-presenting cell (APC), such as macrophages and dendritic cells, and presented in a complex with MHC-II molecules on the surface of the APC. Then immunogenic signals from APC activate CD4+ T cells, predominantly of the Th1 subset. Antigen-activated Th1 cells produce IL-2 and IFNgamma. They activate macrophages and cytotoxic CD8+ T cells, and these effector cells may kill islet beta-cells by one or both of two types of mechanisms: (1) direct interactions of antigen-specific cytotoxic T cells with a beta-cell autoantigen-MHC-I complex on the beta-cell, and (2) non-specific inflammatory mediators, such as free radicals/oxidants and cytokines (IL-1, TNFalpha, TNFbeta, IFNgamma). Type I diabetes is a polygenic disease. One of the principle determining genetic factors in diabetes incidence is the inheritance of mutant MHC-II alleles. Another plausible candidate gene is the insulin gene. CLASS Human Diseases; Endocrine and metabolic disease PATHWAY_MAP ko04940 Type I diabetes mellitus DISEASE H00408 Type 1 diabetes mellitus ORTHOLOGY K04526 insulin K01580 glutamate decarboxylase [EC:4.1.1.15] K07817 receptor-type tyrosine-protein phosphatase N [EC:3.1.3.48] K01294 carboxypeptidase E [EC:3.4.17.10] K04077 chaperonin GroEL [EC:5.6.1.7] K19863 islet cell auto antigen 1 K06752 MHC class II antigen K05412 CD80 antigen K05413 CD86 antigen K06470 CD28 antigen K05406 interleukin 12A K05425 interleukin 12B K05429 interleukin 2 K04687 interferon gamma K06751 MHC class I antigen K10784 T cell receptor alpha chain V region K10785 T-cell receptor beta chain V region K04389 tumor necrosis factor ligand superfamily member 6 K04390 tumor necrosis factor receptor superfamily member 6 K07818 perforin 1 K01353 granzyme B [EC:3.4.21.79] K05468 lymphotoxin alpha (TNF superfamily, member 1) K03156 tumor necrosis factor superfamily, member 2 K04383 interleukin 1 alpha K04519 interleukin 1 beta COMPOUND C00027 Hydrogen peroxide C00533 Nitric oxide C00704 Superoxide REFERENCE PMID:9719467 AUTHORS Rabinovitch A, Suarez-Pinzon WL. TITLE Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. JOURNAL Biochem Pharmacol 55:1139-49 (1998) DOI:10.1016/S0006-2952(97)00492-9 REFERENCE PMID:11507694 AUTHORS Cox NJ, Wapelhorst B, Morrison VA, Johnson L, Pinchuk L, Spielman RS, Todd JA, Concannon P TITLE Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families. JOURNAL Am J Hum Genet 69:820-30 (2001) DOI:10.1086/323501 REFERENCE PMID:8072542 AUTHORS Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM, et al. TITLE A genome-wide search for human type 1 diabetes susceptibility genes. JOURNAL Nature 371:130-6 (1994) DOI:10.1038/371130a0 REFERENCE PMID:8786033 AUTHORS Fujisawa T, Ikegami H, Kawaguchi Y, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Shima K, Ogihara T. TITLE Class I HLA is associated with age-at-onset of IDDM, while class II HLA confers susceptibility to IDDM. JOURNAL Diabetologia 38:1493-5 (1995) DOI:10.1007/BF00400620 REFERENCE PMID:12796471 AUTHORS Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H. TITLE Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase. JOURNAL J Exp Med 197:1635-44 (2003) DOI:10.1084/jem.20030215 REFERENCE PMID:15889095 AUTHORS Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS. TITLE Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. JOURNAL Nature 435:220-3 (2005) DOI:10.1038/nature03523 REFERENCE PMID:15889096 AUTHORS Kent SC, Chen Y, Bregoli L, Clemmings SM, Kenyon NS, Ricordi C, Hering BJ, Hafler DA. TITLE Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. JOURNAL Nature 435:224-8 (2005) DOI:10.1038/nature03625 REFERENCE PMID:14617043 AUTHORS Lieberman SM, DiLorenzo TP. TITLE A comprehensive guide to antibody and T-cell responses in type 1 diabetes. JOURNAL Tissue Antigens 62:359-77 (2003) DOI:10.1034/j.1399-0039.2003.00152.x REFERENCE PMID:12752668 AUTHORS Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC. TITLE Granzyme B: a natural born killer. JOURNAL Immunol Rev 193:31-8 (2003) DOI:10.1034/j.1600-065X.2003.00044.x REL_PATHWAY ko04210 Apoptosis ko04660 T cell receptor signaling pathway ///