KEGG   PATHWAY: elk04940
Entry
elk04940                    Pathway                                
Name
Type I diabetes mellitus - Enhydra lutris kenyoni (northern sea otter)
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
elk04940  Type I diabetes mellitus
elk04940

Organism
Enhydra lutris kenyoni (northern sea otter) [GN:elk]
Gene
111150279  insulin [KO:K04526]
111154283  LOW QUALITY PROTEIN: glutamate decarboxylase 1-like [KO:K01580] [EC:4.1.1.15]
111139699  glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
111149803  glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]
111143810  receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
111154447  receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]
111154849  carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
111161414  60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
111147277  islet cell autoantigen 1 isoform X1 [KO:K19863]
111152451  LOW QUALITY PROTEIN: RLA class II histocompatibility antigen, DP alpha-1 chain [KO:K06752]
111152452  HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
111152151  SLA class II histocompatibility antigen, DQ haplotype C beta chain-like [KO:K06752]
111152158  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like isoform X1 [KO:K06752]
111152168  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
111152169  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
111152175  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like isoform X1 [KO:K06752]
111152178  LOW QUALITY PROTEIN: DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
111152191  HLA class II histocompatibility antigen, DO beta chain isoform X1 [KO:K06752]
111152200  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
111152259  DLA class II histocompatibility antigen, DR-1 beta chain isoform X1 [KO:K06752]
111152356  HLA class II histocompatibility antigen, DQ beta 1 chain isoform X1 [KO:K06752]
111152358  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DR alpha chain-like [KO:K06752]
111152383  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
111151302  T-lymphocyte activation antigen CD80 [KO:K05412]
111155017  T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
111144043  T-cell-specific surface glycoprotein CD28 [KO:K06470]
111150468  interleukin-12 subunit alpha [KO:K05406]
111141150  interleukin-12 subunit beta [KO:K05425]
111154869  interleukin-2 [KO:K05429]
111142126  interferon gamma [KO:K04687]
111152501  HLA class I histocompatibility antigen, alpha chain G-like isoform X1 [KO:K06751]
111139664  LOW QUALITY PROTEIN: H-2 class I histocompatibility antigen, Q8 alpha chain-like [KO:K06751]
111152201  LOW QUALITY PROTEIN: DLA class I histocompatibility antigen, A9/A9 alpha chain-like [KO:K06751]
111152203  DLA class I histocompatibility antigen, A9/A9 alpha chain-like [KO:K06751]
111152204  DLA class I histocompatibility antigen, A9/A9 alpha chain-like isoform X1 [KO:K06751]
111152405  LOW QUALITY PROTEIN: HLA class I histocompatibility antigen, A-36 alpha chain [KO:K06751]
111150819  tumor necrosis factor ligand superfamily member 6-like [KO:K04389]
111150909  tumor necrosis factor ligand superfamily member 6 [KO:K04389]
111144883  tumor necrosis factor receptor superfamily member 6 [KO:K04390]
111144931  perforin-1 [KO:K07818]
111161254  granzyme B-like isoform X1 [KO:K01353] [EC:3.4.21.79]
111139675  LOW QUALITY PROTEIN: mast cell protease 1A-like [KO:K01353] [EC:3.4.21.79]
111152291  lymphotoxin-alpha [KO:K05468]
111152248  tumor necrosis factor isoform X1 [KO:K03156]
111158458  interleukin-1 alpha [KO:K04383]
111158456  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
  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
  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
  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
  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
  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
  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
Related
pathway
elk04210  Apoptosis
elk04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

DBGET integrated database retrieval system