KEGG   PATHWAY: phas04940
Entry
phas04940                   Pathway                                
Name
Type I diabetes mellitus - Phyllostomus hastatus (greater spear-nosed bat)
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
phas04940  Type I diabetes mellitus
phas04940

Organism
Phyllostomus hastatus (greater spear-nosed bat) [GN:phas]
Gene
123807354  INS; insulin isoform X1 [KO:K04526]
123814172  GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
123831197  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
123827030  PTPRN; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
123817963  PTPRN2; receptor-type tyrosine-protein phosphatase N2 isoform X1 [KO:K07817] [EC:3.1.3.48]
123814186  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
123814497  LOW QUALITY PROTEIN: 60 kDa heat shock protein, mitochondrial-like [KO:K04077] [EC:5.6.1.7]
123824498  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
123812050  ICA1; islet cell autoantigen 1 isoform X1 [KO:K19863]
123815923  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
123816020  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
123816129  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
123816250  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
123816448  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
123810280  LOW QUALITY PROTEIN: DLA class II histocompatibility antigen, DR-1 beta chain [KO:K06752]
123810358  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
123827267  CD80; T-lymphocyte activation antigen CD80 [KO:K05412]
123827458  CD86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
123828916  CD28; T-cell-specific surface glycoprotein CD28 isoform X1 [KO:K06470]
123827188  IL12A; interleukin-12 subunit alpha [KO:K05406]
123811597  IL12B; interleukin-12 subunit beta [KO:K05425]
123814106  IL2; interleukin-2 [KO:K05429]
123812973  IFNG; interferon gamma [KO:K04687]
123827873  patr class I histocompatibility antigen, A-2 alpha chain-like isoform X1 [KO:K06751]
123827876  HLA class I histocompatibility antigen, alpha chain F-like isoform X1 [KO:K06751]
123827879  HLA class I histocompatibility antigen, alpha chain F-like [KO:K06751]
123827882  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
123827889  class I histocompatibility antigen, Gogo-C*0203 alpha chain-like [KO:K06751]
123813010  H-2 class I histocompatibility antigen, Q10 alpha chain-like [KO:K06751]
123828142  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
123828143  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
123828144  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
123828146  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
123828149  patr class I histocompatibility antigen, A-2 alpha chain-like isoform X1 [KO:K06751]
123828150  class I histocompatibility antigen, B alpha chain-like [KO:K06751]
123828151  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
123828154  HLA class I histocompatibility antigen, alpha chain G-like [KO:K06751]
123813377  class I histocompatibility antigen, Gogo-C*0203 alpha chain-like isoform X1 [KO:K06751]
123813380  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
123813381  class I histocompatibility antigen, B alpha chain-like [KO:K06751]
123813382  patr class I histocompatibility antigen, A-2 alpha chain-like isoform X1 [KO:K06751]
123813383  class I histocompatibility antigen, Gogo-C*0202 alpha chain-like [KO:K06751]
123813384  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
123813606  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
123821898  HLA class I histocompatibility antigen, alpha chain G-like isoform X1 [KO:K06751]
123815167  LOW QUALITY PROTEIN: patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
123822856  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
123822859  HLA class I histocompatibility antigen, alpha chain G-like [KO:K06751]
123822862  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
123816372  popy Class I histocompatibility antigen, A-1 alpha chain-like [KO:K06751]
123816992  HLA class I histocompatibility antigen, alpha chain F-like [KO:K06751]
123810292  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
123825277  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
123825288  HLA class I histocompatibility antigen, B alpha chain-like isoform X1 [KO:K06751]
123825316  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
123825325  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
123825342  patr class I histocompatibility antigen, A-108 alpha chain-like [KO:K06751]
123818210  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
123818211  patr class I histocompatibility antigen, A-2 alpha chain-like isoform X1 [KO:K06751]
123818213  class I histocompatibility antigen, Gogo-C*0202 alpha chain-like isoform X1 [KO:K06751]
123818217  class I histocompatibility antigen, Gogo-B*0102 alpha chain-like isoform X1 [KO:K06751]
123825908  class I histocompatibility antigen, Gogo-B*0201 alpha chain-like isoform X1 [KO:K06751]
123825918  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
123825922  class I histocompatibility antigen, B alpha chain-like isoform X1 [KO:K06751]
123825923  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
123816833  uncharacterized protein LOC123816833 [KO:K10784]
123818449  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
123829139  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
123820944  PRF1; perforin-1 [KO:K07818]
123820443  granzyme H-like [KO:K01353] [EC:3.4.21.79]
123820457  granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
123810385  LTA; lymphotoxin-alpha isoform X1 [KO:K05468]
123810433  TNF; tumor necrosis factor isoform X1 [KO:K03156]
123811865  IL1A; interleukin-1 alpha [KO:K04383]
123811854  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
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
phas04210  Apoptosis
phas04660  T cell receptor signaling pathway
KO pathway
ko04940   
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