KEGG   PATHWAY: pcw04940
Entry
pcw04940                    Pathway                                
Name
Type I diabetes mellitus - Phascolarctos cinereus (koala)
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
pcw04940  Type I diabetes mellitus
pcw04940

Organism
Phascolarctos cinereus (koala) [GN:pcw]
Gene
110197190  INS; insulin [KO:K04526]
110202193  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
110211559  GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
110214718  LOW QUALITY PROTEIN: glutamate decarboxylase 1-like [KO:K01580] [EC:4.1.1.15]
110223901  PTPRN2; receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]
110219418  PTPRN; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
110200932  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
110213315  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
110217575  ICA1; islet cell autoantigen 1 [KO:K19863]
110203296  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
110201282  H-2 class II histocompatibility antigen, E-S beta chain-like [KO:K06752]
110204537  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
110199338  rano class II histocompatibility antigen, A beta chain-like isoform X1 [KO:K06752]
110199339  HLA class II histocompatibility antigen, DQ beta 2 chain-like [KO:K06752]
110199388  H-2 class II histocompatibility antigen, A-R alpha chain-like [KO:K06752]
110199389  mamu class II histocompatibility antigen, DR alpha chain-like [KO:K06752]
110199403  rano class II histocompatibility antigen, A beta chain-like [KO:K06752]
110199459  HLA class II histocompatibility antigen, DM beta chain isoform X1 [KO:K06752]
110199460  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
110208066  CD80; T-lymphocyte activation antigen CD80 isoform X1 [KO:K05412]
110208102  CD86; T-lymphocyte activation antigen CD86 [KO:K05413]
110198515  CD28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
110210080  IL12A; interleukin-12 subunit alpha [KO:K05406]
110212378  IL12B; interleukin-12 subunit beta [KO:K05425]
110223001  interleukin-2-like [KO:K05429]
110211092  IFNG; interferon gamma isoform X1 [KO:K04687]
110203128  class I histocompatibility antigen, Gogo-OKO alpha chain-like isoform X1 [KO:K06751]
110199325  BOLA class I histocompatibility antigen, alpha chain BL3-7-like [KO:K06751]
110199390  DLA class I histocompatibility antigen, A9/A9 alpha chain-like isoform X1 [KO:K06751]
110203695  HLA class I histocompatibility antigen, B-8 alpha chain-like [KO:K06751]
110223003  HLA class I histocompatibility antigen, B-40 alpha chain-like [KO:K06751]
110223021  HLA class I histocompatibility antigen, B-35 alpha chain-like isoform X1 [KO:K06751]
110223022  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
110202415  HLA class I histocompatibility antigen, A-69 alpha chain-like isoform X1 [KO:K06751]
110202416  class I histocompatibility antigen, Gogo-OKO alpha chain-like isoform X1 [KO:K06751]
110218416  zinc-alpha-2-glycoprotein-like isoform X1 [KO:K06751]
110218421  class I histocompatibility antigen, F10 alpha chain-like [KO:K06751]
110218435  zinc-alpha-2-glycoprotein-like isoform X1 [KO:K06751]
110218436  zinc-alpha-2-glycoprotein-like isoform X1 [KO:K06751]
110218438  major histocompatibility complex class I-related gene protein-like isoform X1 [KO:K06751]
110218444  class I histocompatibility antigen, F10 alpha chain-like [KO:K06751]
110199312  H-2 class I histocompatibility antigen, D-D alpha chain-like isoform X1 [KO:K06751]
110218456  zinc-alpha-2-glycoprotein-like [KO:K06751]
110218463  zinc-alpha-2-glycoprotein-like isoform X1 [KO:K06751]
110218465  major histocompatibility complex class I-related gene protein-like isoform X1 [KO:K06751]
110199902  HLA class I histocompatibility antigen, A-11 alpha chain-like [KO:K06751]
110197002  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
110198951  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
110200078  PRF1; LOW QUALITY PROTEIN: perforin-1 [KO:K07818]
110220292  LOW QUALITY PROTEIN: granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
110199296  LTA; lymphotoxin-alpha [KO:K05468]
110199397  TNF; tumor necrosis factor [KO:K03156]
110192428  IL1A; interleukin-1 alpha [KO:K04383]
110192539  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
pcw04210  Apoptosis
pcw04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

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