KEGG   PATHWAY: tge04940
Entry
tge04940                    Pathway                                
Name
Type I diabetes mellitus - Theropithecus gelada (gelada)
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
tge04940  Type I diabetes mellitus
tge04940

Organism
Theropithecus gelada (gelada) [GN:tge]
Gene
112636168  GAD1; glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]
112631453  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
112620498  PTPRN2; receptor-type tyrosine-protein phosphatase N2 isoform X1 [KO:K07817] [EC:3.1.3.48]
112636722  PTPRN; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
112624226  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
112636000  HSPD1; 60 kDa heat shock protein, mitochondrial isoform X1 [KO:K04077] [EC:5.6.1.7]
112621166  ICA1; islet cell autoantigen 1 isoform X1 [KO:K19863]
112622042  HLA class II histocompatibility antigen, DP beta 1 chain isoform X1 [KO:K06752]
112622043  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
112622088  HLA class II histocompatibility antigen, DRB1-9 beta chain isoform X1 [KO:K06752]
112622413  HLA class II histocompatibility antigen, DRB1-1 beta chain-like isoform X1 [KO:K06752]
112622414  HLA class II histocompatibility antigen, DRB1-10 beta chain-like isoform X1 [KO:K06752]
112622415  HLA class II histocompatibility antigen, DR beta 5 chain isoform X1 [KO:K06752]
112622416  HLA class II histocompatibility antigen, DP alpha 1 chain [KO:K06752]
112622558  HLA class II histocompatibility antigen, DP alpha 1 chain-like [KO:K06752]
112622838  HLA class II histocompatibility antigen, DO alpha chain isoform X1 [KO:K06752]
112622959  mamu class II histocompatibility antigen, DR alpha chain isoform X1 [KO:K06752]
112623006  HLA class II histocompatibility antigen, DM beta chain isoform X1 [KO:K06752]
112623007  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
112623510  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
112623518  HLA class II histocompatibility antigen, DQ beta 1 chain isoform X1 [KO:K06752]
112623519  HLA class II histocompatibility antigen, DQ alpha 2 chain [KO:K06752]
112618508  CD80; T-lymphocyte activation antigen CD80 [KO:K05412]
112618619  CD86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
112636226  CD28; T-cell-specific surface glycoprotein CD28 isoform X1 [KO:K06470]
112619066  IL12A; interleukin-12 subunit alpha isoform X1 [KO:K05406]
112626411  IL12B; interleukin-12 subunit beta [KO:K05425]
112624904  IL2; interleukin-2 [KO:K05429]
112634767  IFNG; interferon gamma [KO:K04687]
112622167  LOW QUALITY PROTEIN: patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
112622184  popy class I histocompatibility antigen, alpha chain E-like isoform X1 [KO:K06751]
112622185  popy class I histocompatibility antigen, alpha chain E-like isoform X1 [KO:K06751]
112622400  HLA class I histocompatibility antigen, A-3 alpha chain isoform X1 [KO:K06751]
112622401  class I histocompatibility antigen, Gogo-B*0101 alpha chain isoform X1 [KO:K06751]
112622403  HLA class I histocompatibility antigen, B-14 alpha chain isoform X1 [KO:K06751]
112622405  HLA class I histocompatibility antigen, A-11 alpha chain-like isoform X1 [KO:K06751]
112622406  class I histocompatibility antigen, Gogo-B*0102 alpha chain-like isoform X1 [KO:K06751]
112622407  class I histocompatibility antigen, Gogo-B*0101 alpha chain-like isoform X1 [KO:K06751]
112622412  HLA class I histocompatibility antigen, B-14 alpha chain-like isoform X1 [KO:K06751]
112622432  LOW QUALITY PROTEIN: class I histocompatibility antigen, Gogo-B*0103 alpha chain-like [KO:K06751]
112616913  class I histocompatibility antigen, Gogo-B*0103 alpha chain-like isoform X1 [KO:K06751]
112616914  HLA class I histocompatibility antigen, Cw-12 alpha chain-like [KO:K06751]
112617631  HLA class I histocompatibility antigen, A-74 alpha chain-like [KO:K06751]
112617695  HLA class I histocompatibility antigen, B-14 alpha chain-like [KO:K06751]
112617731  HLA class I histocompatibility antigen, A-11 alpha chain-like isoform X1 [KO:K06751]
112617747  class I histocompatibility antigen, Gogo-B*0101 alpha chain-like isoform X1 [KO:K06751]
112617766  HLA class I histocompatibility antigen, B-40 alpha chain-like [KO:K06751]
112617801  HLA class I histocompatibility antigen, B-14 alpha chain-like isoform X1 [KO:K06751]
112617929  class I histocompatibility antigen, Gogo-B*0103 alpha chain-like [KO:K06751]
112617939  mamu class I histocompatibility antigen, alpha chain F isoform X1 [KO:K06751]
112621713  uncharacterized protein LOC112621713 [KO:K10785]
112621718  uncharacterized protein LOC112621718 [KO:K10785]
112620195  immunoglobulin delta heavy chain-like [KO:K10785]
112620205  uncharacterized protein LOC112620205 [KO:K10785]
112636918  FASLG; tumor necrosis factor ligand superfamily member 6 isoform X1 [KO:K04389]
112631569  FAS; tumor necrosis factor receptor superfamily member 6 isoform X1 [KO:K04390]
112631415  PRF1; perforin-1 [KO:K07818]
112628753  granzyme B isoform X1 [KO:K01353] [EC:3.4.21.79]
112623174  LTA; lymphotoxin-alpha [KO:K05468]
112622917  TNF; tumor necrosis factor [KO:K03156]
112604839  IL1A; interleukin-1 alpha [KO:K04383]
112604696  IL1B; interleukin-1 beta isoform X1 [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
Related
pathway
tge04210  Apoptosis
tge04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

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