ENTRY       hsa04940                    Pathway
NAME        Type I diabetes mellitus - Homo sapiens (human)
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 hsa04940  Type I diabetes mellitus
DISEASE     H00408  Type 1 diabetes mellitus
DRUG        D04748  Lisofylline (USAN/INN)
ORGANISM    Homo sapiens (human) [GN:hsa]
GENE        3630  INS; insulin [KO:K04526]
            2571  GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
            2572  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
            5798  PTPRN; protein tyrosine phosphatase receptor type N [KO:K07817] [EC:3.1.3.48]
            5799  PTPRN2; protein tyrosine phosphatase receptor type N2 [KO:K07817] [EC:3.1.3.48]
            1363  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
            3329  HSPD1; heat shock protein family D (Hsp60) member 1 [KO:K04077] [EC:5.6.1.7]
            3382  ICA1; islet cell autoantigen 1 [KO:K19863]
            3108  HLA-DMA; major histocompatibility complex, class II, DM alpha [KO:K06752]
            3109  HLA-DMB; major histocompatibility complex, class II, DM beta [KO:K06752]
            3111  HLA-DOA; major histocompatibility complex, class II, DO alpha [KO:K06752]
            3112  HLA-DOB; major histocompatibility complex, class II, DO beta [KO:K06752]
            3113  HLA-DPA1; major histocompatibility complex, class II, DP alpha 1 [KO:K06752]
            3115  HLA-DPB1; major histocompatibility complex, class II, DP beta 1 [KO:K06752]
            3117  HLA-DQA1; major histocompatibility complex, class II, DQ alpha 1 [KO:K06752]
            3118  HLA-DQA2; major histocompatibility complex, class II, DQ alpha 2 [KO:K06752]
            3119  HLA-DQB1; major histocompatibility complex, class II, DQ beta 1 [KO:K06752]
            3122  HLA-DRA; major histocompatibility complex, class II, DR alpha [KO:K06752]
            3123  HLA-DRB1; major histocompatibility complex, class II, DR beta 1 [KO:K06752]
            3125  HLA-DRB3; major histocompatibility complex, class II, DR beta 3 [KO:K06752]
            3126  HLA-DRB4; major histocompatibility complex, class II, DR beta 4 [KO:K06752]
            3127  HLA-DRB5; major histocompatibility complex, class II, DR beta 5 [KO:K06752]
            941  CD80; CD80 molecule [KO:K05412]
            942  CD86; CD86 molecule [KO:K05413]
            940  CD28; CD28 molecule [KO:K06470]
            3592  IL12A; interleukin 12A [KO:K05406]
            3593  IL12B; interleukin 12B [KO:K05425]
            3558  IL2; interleukin 2 [KO:K05429]
            3458  IFNG; interferon gamma [KO:K04687]
            3105  HLA-A; major histocompatibility complex, class I, A [KO:K06751]
            3106  HLA-B; major histocompatibility complex, class I, B [KO:K06751]
            3107  HLA-C; major histocompatibility complex, class I, C [KO:K06751]
            3134  HLA-F; major histocompatibility complex, class I, F [KO:K06751]
            3135  HLA-G; major histocompatibility complex, class I, G [KO:K06751]
            3133  HLA-E; major histocompatibility complex, class I, E [KO:K06751]
            356  FASLG; Fas ligand [KO:K04389]
            355  FAS; Fas cell surface death receptor [KO:K04390]
            5551  PRF1; perforin 1 [KO:K07818]
            3002  GZMB; granzyme B [KO:K01353] [EC:3.4.21.79]
            4049  LTA; lymphotoxin alpha [KO:K05468]
            7124  TNF; tumor necrosis factor [KO:K03156]
            3552  IL1A; interleukin 1 alpha [KO:K04383]
            3553  IL1B; interleukin 1 beta [KO:K04519]
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 hsa04210  Apoptosis
            hsa04660  T cell receptor signaling pathway
KO_PATHWAY  ko04940
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