KEGG   PATHWAY: mpuf04940
Entry
mpuf04940                   Pathway                                
Name
Type I diabetes mellitus - Mustela putorius furo (domestic ferret)
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
mpuf04940  Type I diabetes mellitus
mpuf04940

Organism
Mustela putorius furo (domestic ferret) [GN:mpuf]
Gene
101684928  INS; insulin [KO:K04526]
101676657  GAD1; glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]
101670399  LOW QUALITY PROTEIN: glutamate decarboxylase 1-like [KO:K01580] [EC:4.1.1.15]
101690464  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
101679207  PTPRN; receptor-type tyrosine-protein phosphatase-like N isoform X2 [KO:K07817] [EC:3.1.3.48]
101682161  PTPRN2; receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]
101678770  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
101684214  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
101676262  ICA1; islet cell autoantigen 1 isoform X4 [KO:K19863]
101691795  DLA class II histocompatibility antigen, DR-1 beta chain [KO:K06752]
101692125  RLA class II histocompatibility antigen, DP beta chain [KO:K06752]
101673877  boLa class II histocompatibility antigen, DQB*0101 beta chain-like [KO:K06752]
101674777  HLA class II histocompatibility antigen, DM beta chain isoform X1 [KO:K06752]
106003441  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DR alpha chain-like [KO:K06752]
101675687  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
101682907  HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
101670362  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
101683191  HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
101683501  HLA class II histocompatibility antigen, DQ beta 2 chain-like [KO:K06752]
101677272  HLA class II histocompatibility antigen, DO alpha chain isoform X1 [KO:K06752]
101690706  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
101671551  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
101678035  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP alpha 1 chain [KO:K06752]
101678178  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
101684722  HLA class II histocompatibility antigen, DQ beta 2 chain-like [KO:K06752]
101673746  CD80; T-lymphocyte activation antigen CD80 [KO:K05412]
101686613  CD86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
101689176  CD28; T-cell-specific surface glycoprotein CD28 isoform X1 [KO:K06470]
101689314  IL12A; interleukin-12 subunit alpha [KO:K05406]
101676232  IL12B; interleukin-12 subunit beta [KO:K05425]
101674110  IL2; interleukin-2 [KO:K05429]
101693741  IFNG; interferon gamma [KO:K04687]
101693321  DLA class I histocompatibility antigen, A9/A9 alpha chain-like [KO:K06751]
101693860  HLA class I histocompatibility antigen, A-34 alpha chain-like [KO:K06751]
106004724  HLA class I histocompatibility antigen, Cw-8 alpha chain-like [KO:K06751]
101689041  HLA class I histocompatibility antigen, A-80 alpha chain-like isoform X1 [KO:K06751]
101690568  LOW QUALITY PROTEIN: DLA class I histocompatibility antigen, A9/A9 alpha chain [KO:K06751]
101690739  uncharacterized protein LOC101690739 [KO:K10784]
101686008  uncharacterized protein LOC101686008 [KO:K10785]
101687517  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
101677976  FAS; tumor necrosis factor receptor superfamily member 6 isoform X1 [KO:K04390]
101688524  PRF1; perforin-1 isoform X1 [KO:K07818]
101693455  granzyme B [KO:K01353] [EC:3.4.21.79]
101687624  LTA; lymphotoxin-alpha [KO:K05468]
101687148  TNF; tumor necrosis factor isoform X1 [KO:K03156]
101691850  IL1A; interleukin-1 alpha [KO:K04383]
101688006  IL1B; 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
mpuf04210  Apoptosis
mpuf04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

DBGET integrated database retrieval system