KEGG   PATHWAY: bta04940
Entry
bta04940                    Pathway                                
Name
Type I diabetes mellitus - Bos taurus (cow)
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
bta04940  Type I diabetes mellitus
bta04940

Organism
Bos taurus (cow) [GN:bta]
Gene
280829  INS; insulin preproprotein [KO:K04526]
512459  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
517552  GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
529488  glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
286810  PTPRN; receptor-type tyrosine-protein phosphatase-like N precursor [KO:K07817] [EC:3.1.3.48]
616515  PTPRN2; receptor-type tyrosine-protein phosphatase N2 isoform X1 [KO:K07817] [EC:3.1.3.48]
280753  CPE; carboxypeptidase E precursor [KO:K01294] [EC:3.4.17.10]
511913  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
535346  ICA1; islet cell autoantigen 1 [KO:K19863]
282490  BOLA-DMA; HLA class II histocompatibility antigen, DM alpha chain precursor [KO:K06752]
282491  BOLA-DMB; major histocompatibility complex, class II, DM beta precursor [KO:K06752]
282493  BOLA-DOB; HLA class II histocompatibility antigen, DO beta chain precursor [KO:K06752]
282494  BOLA-DQA5; major histocompatibility complex, class II, DQ alpha 5 precursor [KO:K06752]
282495  BOLA-DQB; major histocompatibility complex, class II, DQ beta precursor [KO:K06752]
282498  BOLA-DYB; major histocompatibility complex, class II, DY beta precursor [KO:K06752]
282535  BOLA-DQA2; major histocompatibility complex, class II, DQ alpha 2 [KO:K06752]
282530  BOLA-DRB3; major histocompatibility complex, class II, DRB3 [KO:K06752]
525727  BOLA-DOA; HLA class II histocompatibility antigen, DO alpha chain precursor [KO:K06752]
506214  BOLA-DRA; major histocompatibility complex, class II, DR alpha precursor [KO:K06752]
539241  BLA-DQB; boLa class II histocompatibility antigen, DQB*0101 beta chain precursor [KO:K06752]
100848815  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like precursor [KO:K06752]
282497  BOLA-DYA; major histocompatibility complex, class II, DY alpha precursor [KO:K06752]
618722  DSB; MHC class II antigen DS beta [KO:K06752]
538700  BOLA-DRB2; HLA class II histocompatibility antigen, DR beta 5 chain isoform X3 [KO:K06752]
407131  CD80; T-lymphocyte activation antigen CD80 [KO:K05412]
414345  CD86; T-lymphocyte activation antigen CD86 [KO:K05413]
281050  CD28; T-cell-specific surface glycoprotein CD28 precursor [KO:K06470]
281856  IL12A; interleukin-12 subunit alpha precursor [KO:K05406]
281857  IL12B; interleukin-12 subunit beta precursor [KO:K05425]
280822  IL2; interleukin-2 precursor [KO:K05429]
281237  IFNG; interferon gamma precursor [KO:K04687]
407173  JSP.1; MHC Class I JSP.1 precursor [KO:K06751]
512672  major histocompatibility complex, class I precursor [KO:K06751]
515712  BOLA; MHC class I heavy chain isoform 1 precursor [KO:K06751]
767904  MGC126945; LOW QUALITY PROTEIN: uncharacterized protein LOC767904 [KO:K06751]
507917  BOLA class I histocompatibility antigen, alpha chain BL3-6 isoform X1 [KO:K06751]
510417  BOLA-NC1; non-classical MHC class I antigen precursor [KO:K06751]
533050  BoLA; major histocompatibility complex, class I, A precursor [KO:K06751]
616942  major histocompatibility complex, class I, A-like precursor [KO:K06751]
100300850  T cell receptor alpha variable 18 [KO:K10784]
509513  uncharacterized LOC509513 precursor [KO:K10785]
100300510  T cell receptor beta constant 1 [KO:K10785]
407111  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
282488  FAS; tumor necrosis factor receptor superfamily member 6 precursor [KO:K04390]
369025  PRF1; perforin-1 precursor [KO:K07818]
508646  granzyme B [KO:K01353] [EC:3.4.21.79]
281731  GZMB; duodenase-1 precursor [KO:K01353] [EC:3.4.21.79]
505326  mast cell protease 1A [KO:K01353] [EC:3.4.21.79]
508858  duodenase-1 [KO:K01353] [EC:3.4.21.79]
786126  duodenase-1 [KO:K01353] [EC:3.4.21.79]
280845  LTA; lymphotoxin-alpha precursor [KO:K05468]
280943  TNF; tumor necrosis factor [KO:K03156]
281250  IL1A; interleukin-1 alpha precursor [KO:K04383]
281251  IL1B; interleukin-1 beta precursor [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
bta04210  Apoptosis
bta04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

DBGET integrated database retrieval system