KEGG   PATHWAY: ecb04940
Entry
ecb04940                    Pathway                                
Name
Type I diabetes mellitus - Equus caballus (horse)
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
ecb04940  Type I diabetes mellitus
ecb04940

Organism
Equus caballus (horse) [GN:ecb]
Gene
111776000  INS; insulin [KO:K04526]
100055419  GAD2; glutamate decarboxylase 2 isoform X1 [KO:K01580] [EC:4.1.1.15]
100052860  GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
100055638  glutamate decarboxylase 1-like [KO:K01580] [EC:4.1.1.15]
111772328  glutamate decarboxylase 2 isoform X1 [KO:K01580] [EC:4.1.1.15]
100056346  PTPRN; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
100067294  PTPRN2; receptor-type tyrosine-protein phosphatase N2 isoform X1 [KO:K07817] [EC:3.1.3.48]
100061513  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
100055147  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
100052438  ICA1; islet cell autoantigen 1 isoform X4 [KO:K19863]
100061035  HLA class II histocompatibility antigen, DM alpha chain-like precursor [KO:K06752]
100060770  HLA class II histocompatibility antigen, DO beta chain isoform X1 [KO:K06752]
100052249  DQA; MHC class II DQ-alpha precursor [KO:K06752]
100052310  DRB; MHC class II DR-beta chain precursor [KO:K06752]
100052364  DRB; MHC class II DR-beta chain precursor [KO:K06752]
100051944  DRA; MHC class II DR alpha chain precursor [KO:K06752]
100052184  DQB; MHC class II DQ-beta chain precursor [KO:K06752]
100061127  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
100060996  HLA class II histocompatibility antigen, DM beta chain isoform X1 [KO:K06752]
100052006  DRB; MHC class II DR-beta chain precursor [KO:K06752]
100052125  DQA; MHC class II DQ-alpha chain precursor [KO:K06752]
100060531  HLA class II histocompatibility antigen, DQ beta 2 chain isoform X1 [KO:K06752]
100052063  DQA; MHC class II DQ-alpha chain [KO:K06752]
100060320  DQB; MHC class II DQ-beta chain precursor [KO:K06752]
111767457  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
100060697  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
100071012  CD80; T-lymphocyte activation antigen CD80 [KO:K05412]
100060767  CD86; T-lymphocyte activation antigen CD86 isoform X5 [KO:K05413]
100067829  CD28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
100034215  IL12A; interleukin-12 subunit alpha [KO:K05406]
100034222  IL12B; interleukin-12 subunit beta precursor [KO:K05425]
100034204  IL2; interleukin-2 precursor [KO:K05429]
100034181  IFNG; interferon gamma precursor [KO:K04687]
100034212  MHCB3; MHC class I heavy chain precursor [KO:K06751]
100056062  MHC class I antigen 9.2 precursor [KO:K06751]
100034210  EQMHCB2; MHC class I heavy chain precursor [KO:K06751]
100054114  HLA class I histocompatibility antigen, alpha chain G isoform X1 [KO:K06751]
100051657  7-51 putative nonclassical MHC class I antigen precursor [KO:K06751]
100057920  HLA class I histocompatibility antigen, Cw-12 alpha chain isoform X2 [KO:K06751]
100050550  EQMCE1; MHC class I antigen 3.7 precursor [KO:K06751]
100056182  HLA class I histocompatibility antigen, B-40 alpha chain isoform X1 [KO:K06751]
100056391  MHCX1; MHC class I antigen 3.5 precursor [KO:K06751]
100034211  EQMHCC1; MHC class I heavy chain precursor [KO:K06751]
100049798  class I histocompatibility antigen, Gogo-OKO alpha chain isoform X12 [KO:K06751]
100050473  class I histocompatibility antigen, Gogo-B*0103 alpha chain isoform X1 [KO:K06751]
100050706  saoe class I histocompatibility antigen, A alpha chain isoform X1 [KO:K06751]
100053918  HLA class I histocompatibility antigen, B-46 alpha chain isoform X2 [KO:K06751]
100054397  saoe class I histocompatibility antigen, A alpha chain [KO:K06751]
100054448  HLA class I histocompatibility antigen, alpha chain G isoform X3 [KO:K06751]
100056309  HLA class I histocompatibility antigen, B-15 alpha chain-like [KO:K06751]
100056099  HLA class I histocompatibility antigen, alpha chain G isoform X1 [KO:K06751]
100056231  saoe class I histocompatibility antigen, A alpha chain-like [KO:K06751]
100059994  HLA class I histocompatibility antigen, B-15 alpha chain isoform X1 [KO:K06751]
100060096  H-2 class I histocompatibility antigen, Q9 alpha chain-like [KO:K06751]
111772100  uncharacterized protein LOC111772100 [KO:K10784]
106783094  uncharacterized protein LOC106783094 [KO:K10785]
100052326  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
100071639  FAS; tumor necrosis factor receptor superfamily member 6 isoform X1 [KO:K04390]
100072744  PRF1; perforin-1 [KO:K07818]
100033978  GZMB; granzyme B precursor [KO:K01353] [EC:3.4.21.79]
100049805  granzyme B [KO:K01353] [EC:3.4.21.79]
100050711  granzyme H isoform X1 [KO:K01353] [EC:3.4.21.79]
100052229  granzyme B-like isoform X1 [KO:K01353] [EC:3.4.21.79]
100052901  granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
100052689  granzyme B [KO:K01353] [EC:3.4.21.79]
100053327  granzyme B-like [KO:K01353] [EC:3.4.21.79]
100052951  granzyme B [KO:K01353] [EC:3.4.21.79]
100055651  granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
111768988  granzyme B-like isoform X1 [KO:K01353] [EC:3.4.21.79]
111767413  granzyme B-like isoform X1 [KO:K01353] [EC:3.4.21.79]
111768996  granzyme B(G,H)-like isoform X1 [KO:K01353] [EC:3.4.21.79]
100053001  granzyme H-like [KO:K01353] [EC:3.4.21.79]
100052638  granzyme B isoform X1 [KO:K01353] [EC:3.4.21.79]
111771745  granzyme B-like [KO:K01353] [EC:3.4.21.79]
111768663  granzyme-like protein 2 [KO:K01353] [EC:3.4.21.79]
100058321  LTA; lymphotoxin-alpha [KO:K05468]
100033834  TNF; tumor necrosis factor [KO:K03156]
100064969  IL1A; interleukin-1 alpha precursor [KO:K04383]
100034237  IL1B; interleukin-1 beta [KO:K04519]
100052414  IL1B; interleukin-1 beta [KO:K04519]
111768185  interleukin-1 beta-like [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
ecb04210  Apoptosis
ecb04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

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