KEGG   PATHWAY: tod04940
Entry
tod04940                    Pathway                                
Name
Type I diabetes mellitus - Talpa occidentalis (Iberian mole)
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
tod04940  Type I diabetes mellitus
tod04940

Organism
Talpa occidentalis (Iberian mole) [GN:tod]
Gene
119249861  INS; LOW QUALITY PROTEIN: insulin [KO:K04526]
119245288  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
119255920  GAD1; glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]
119251627  PTPRN2; receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]
119254848  PTPRN; receptor-type tyrosine-protein phosphatase-like N [KO:K07817] [EC:3.1.3.48]
119257954  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
119256070  LOW QUALITY PROTEIN: 60 kDa heat shock protein, mitochondrial-like [KO:K04077] [EC:5.6.1.7]
119242724  ICA1; islet cell autoantigen 1 isoform X1 [KO:K19863]
119251395  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP alpha 1 chain-like [KO:K06752]
119252077  boLa class II histocompatibility antigen, DQB*0101 beta chain-like [KO:K06752]
119252079  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DO beta chain-like [KO:K06752]
119252300  H-2 class II histocompatibility antigen, E-S beta chain-like [KO:K06752]
119252301  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
119252303  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
119252305  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DQ beta 2 chain-like [KO:K06752]
119252306  boLa class II histocompatibility antigen, DQB*0101 beta chain-like [KO:K06752]
119252307  HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
119252309  boLa class II histocompatibility antigen, DQB*0101 beta chain-like [KO:K06752]
119252310  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
119252317  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
119252318  HLA class II histocompatibility antigen, DQ beta 1 chain-like isoform X1 [KO:K06752]
119252320  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
119252323  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
119252326  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
119253063  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
119253072  LOW QUALITY PROTEIN: RLA class II histocompatibility antigen, DP alpha-1 chain-like [KO:K06752]
119253280  mamu class II histocompatibility antigen, DR alpha chain [KO:K06752]
119253282  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
119256815  CD80; T-lymphocyte activation antigen CD80 [KO:K05412]
119257476  CD86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
119256129  CD28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
119256979  IL12A; interleukin-12 subunit alpha [KO:K05406]
119235953  IL12B; interleukin-12 subunit beta [KO:K05425]
119233628  IL2; interleukin-2 [KO:K05429]
119248294  IFNG; interferon gamma [KO:K04687]
119233314  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119258418  patr class I histocompatibility antigen, A-2 alpha chain-like isoform X2 [KO:K06751]
119258434  class I histocompatibility antigen, Gogo-OKO alpha chain-like isoform X2 [KO:K06751]
119258435  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119242843  class I histocompatibility antigen, Gogo-OKO alpha chain-like isoform X2 [KO:K06751]
119242845  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119243231  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119251067  HLA class I histocompatibility antigen, alpha chain G-like [KO:K06751]
119251071  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119251072  class I histocompatibility antigen, Gogo-C*0203 alpha chain-like [KO:K06751]
119251075  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119251077  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119251117  patr class I histocompatibility antigen, B-2 alpha chain-like isoform X2 [KO:K06751]
119251138  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119251165  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119251167  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119251183  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119251189  HLA class I histocompatibility antigen, A alpha chain-like [KO:K06751]
119251196  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119251199  patr class I histocompatibility antigen, A-108 alpha chain-like isoform X1 [KO:K06751]
119251208  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119251212  patr class I histocompatibility antigen, B-1 alpha chain-like [KO:K06751]
119251215  patr class I histocompatibility antigen, B-1 alpha chain-like isoform X1 [KO:K06751]
119251229  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119251240  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119251268  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119251270  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119251277  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119251278  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119251289  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119251297  HLA class I histocompatibility antigen, alpha chain G-like [KO:K06751]
119251301  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119251308  class I histocompatibility antigen, Gogo-C*0203 alpha chain-like [KO:K06751]
119251309  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119251319  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119251322  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119251332  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119251343  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
119243833  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119251946  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119251966  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119251970  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119251974  class I histocompatibility antigen, Gogo-B*0101 alpha chain-like isoform X1 [KO:K06751]
119251982  patr class I histocompatibility antigen, B-1 alpha chain-like [KO:K06751]
119251983  patr class I histocompatibility antigen, A-2 alpha chain-like isoform X1 [KO:K06751]
119251986  class I histocompatibility antigen, Gogo-C*0202 alpha chain-like isoform X1 [KO:K06751]
119251987  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119251994  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
119251995  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
119251996  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119251998  HLA class I histocompatibility antigen, A alpha chain-like isoform X1 [KO:K06751]
119252000  patr class I histocompatibility antigen, A-108 alpha chain-like isoform X4 [KO:K06751]
119252001  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119252003  class I histocompatibility antigen, Gogo-OKO alpha chain-like isoform X2 [KO:K06751]
119252004  saoe class I histocompatibility antigen, A alpha chain-like [KO:K06751]
119252005  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119252018  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119252020  HLA class I histocompatibility antigen, A alpha chain-like isoform X1 [KO:K06751]
119252022  class I histocompatibility antigen, Gogo-OKO alpha chain-like isoform X2 [KO:K06751]
119252031  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119252033  class I histocompatibility antigen, Gogo-B*0201 alpha chain-like [KO:K06751]
119252034  class I histocompatibility antigen, Gogo-OKO alpha chain-like isoform X3 [KO:K06751]
119252037  class I histocompatibility antigen, Gogo-B*0201 alpha chain-like [KO:K06751]
119252039  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
119252040  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
119252045  HLA class I histocompatibility antigen, alpha chain G-like [KO:K06751]
119252048  patr class I histocompatibility antigen, A-108 alpha chain-like isoform X3 [KO:K06751]
119252056  saoe class I histocompatibility antigen, A alpha chain-like [KO:K06751]
119252057  class I histocompatibility antigen, Gogo-B*0201 alpha chain-like isoform X2 [KO:K06751]
119252059  patr class I histocompatibility antigen, A-2 alpha chain-like isoform X2 [KO:K06751]
119252060  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119252067  patr class I histocompatibility antigen, A-2 alpha chain-like isoform X2 [KO:K06751]
119252069  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X2 [KO:K06751]
119252072  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119252075  class I histocompatibility antigen, Gogo-B*0101 alpha chain-like isoform X1 [KO:K06751]
119252076  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119252098  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119252138  HLA class I histocompatibility antigen, B alpha chain-like [KO:K06751]
119252140  HLA class I histocompatibility antigen, alpha chain G-like isoform X1 [KO:K06751]
119252145  HLA class I histocompatibility antigen, B alpha chain-like isoform X2 [KO:K06751]
119252149  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119252151  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119252154  class I histocompatibility antigen, Gogo-C*0202 alpha chain-like [KO:K06751]
119252156  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
119252157  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119252159  class I histocompatibility antigen, Gogo-B*0103 alpha chain-like isoform X1 [KO:K06751]
119252162  patr class I histocompatibility antigen, B-2 alpha chain-like [KO:K06751]
119252164  saoe class I histocompatibility antigen, A alpha chain-like isoform X1 [KO:K06751]
119252165  HLA class I histocompatibility antigen, alpha chain G-like isoform X2 [KO:K06751]
119252167  HLA class I histocompatibility antigen, alpha chain G-like isoform X1 [KO:K06751]
119252170  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
119252172  class I histocompatibility antigen, Gogo-B*0201 alpha chain-like isoform X5 [KO:K06751]
119252178  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119252180  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119252182  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119252186  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119252187  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119252189  uncharacterized protein LOC119252189 isoform X3 [KO:K06751]
119252191  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
119236634  H-2 class I histocompatibility antigen, Q10 alpha chain-like [KO:K06751]
119252311  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
119253123  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119253126  patr class I histocompatibility antigen, A-108 alpha chain-like isoform X1 [KO:K06751]
119253172  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119253179  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119253184  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
119253185  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119253190  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119253192  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119253199  class I histocompatibility antigen, Gogo-B*0103 alpha chain-like [KO:K06751]
119253215  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119253216  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
119253231  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
119253263  class I histocompatibility antigen, Gogo-B*0103 alpha chain-like [KO:K06751]
119253903  class I histocompatibility antigen, Gogo-OKO alpha chain-like isoform X1 [KO:K06751]
119253926  HLA class I histocompatibility antigen, alpha chain G-like [KO:K06751]
119248584  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
119238019  uncharacterized protein LOC119238019 [KO:K10784]
119240071  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
119233895  FAS; tumor necrosis factor receptor superfamily member 6 isoform X1 [KO:K04390]
119234362  perforin-1-like [KO:K07818]
119233556  perforin-1-like [KO:K07818]
119233901  perforin-1-like [KO:K07818]
119233902  perforin-1-like [KO:K07818]
119234298  PRF1; perforin-1 [KO:K07818]
119238086  mast cell protease 3-like [KO:K01353] [EC:3.4.21.79]
119238241  mast cell protease 3-like [KO:K01353] [EC:3.4.21.79]
119238975  granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
119239511  mast cell protease 3-like [KO:K01353] [EC:3.4.21.79]
119253236  LTA; lymphotoxin-alpha [KO:K05468]
119253235  TNF; tumor necrosis factor isoform X1 [KO:K03156]
119259186  interleukin-1 alpha-like isoform X2 [KO:K04383]
119259187  interleukin-1 alpha-like isoform X3 [KO:K04383]
119259188  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
tod04210  Apoptosis
tod04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

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