KEGG   PATHWAY: plop04940
Entry
plop04940                   Pathway                                
Name
Type I diabetes mellitus - Perognathus longimembris pacificus (Pacific pocket mouse)
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
plop04940  Type I diabetes mellitus
plop04940

Organism
Perognathus longimembris pacificus (Pacific pocket mouse) [GN:plop]
Gene
125366848  Gad2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
125349983  Gad1; glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]
125349897  Ptprn; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
125345730  Ptprn2; LOW QUALITY PROTEIN: receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]
125339531  Cpe; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
125350434  Hspd1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
125347041  Ica1; islet cell autoantigen 1 isoform X1 [KO:K19863]
125353511  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
125352188  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
125352379  HLA class II histocompatibility antigen, DR beta 4 chain-like [KO:K06752]
125352715  HLA class II histocompatibility antigen, DP beta 1 chain [KO:K06752]
125352717  HLA class II histocompatibility antigen, DP alpha 1 chain isoform X1 [KO:K06752]
125352718  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
125352720  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
125352723  HLA class II histocompatibility antigen, DO beta chain-like isoform X1 [KO:K06752]
125352725  HLA class II histocompatibility antigen, DR beta 3 chain-like isoform X1 [KO:K06752]
125352726  HLA class II histocompatibility antigen, DR beta 4 chain-like isoform X1 [KO:K06752]
125352727  HLA class II histocompatibility antigen, DR beta 4 chain-like [KO:K06752]
125352728  HLA class II histocompatibility antigen, DR beta 5 chain-like [KO:K06752]
125352729  HLA class II histocompatibility antigen, DR beta 5 chain-like [KO:K06752]
125352734  mamu class II histocompatibility antigen, DR alpha chain [KO:K06752]
125351083  Cd80; T-lymphocyte activation antigen CD80 [KO:K05412]
125351090  Cd86; T-lymphocyte activation antigen CD86 [KO:K05413]
125350374  Cd28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
125351136  Il12a; interleukin-12 subunit alpha [KO:K05406]
125342078  Il12b; interleukin-12 subunit beta [KO:K05425]
125341318  Il2; interleukin-2 [KO:K05429]
125347731  Ifng; interferon gamma [KO:K04687]
125352790  class I histocompatibility antigen, Gogo-B*0101 alpha chain-like [KO:K06751]
125352791  saoe class I histocompatibility antigen, A alpha chain-like isoform X1 [KO:K06751]
125352794  saoe class I histocompatibility antigen, A alpha chain-like isoform X1 [KO:K06751]
125352795  class I histocompatibility antigen, Gogo-B*0102 alpha chain-like [KO:K06751]
125352797  HLA class I histocompatibility antigen, B alpha chain-like [KO:K06751]
125360260  Faslg; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
125346313  Fas; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
125343343  Prf1; perforin-1 [KO:K07818]
125363502  granzyme B-like [KO:K01353] [EC:3.4.21.79]
125345053  granzyme B-like [KO:K01353] [EC:3.4.21.79]
125353519  Lta; lymphotoxin-alpha [KO:K05468]
125352808  Tnf; tumor necrosis factor [KO:K03156]
125356088  Il1a; interleukin-1 alpha [KO:K04383]
125356827  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
plop04210  Apoptosis
plop04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

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