KEGG   PATHWAY: llv04940
Entry
llv04940                    Pathway                                
Name
Type I diabetes mellitus - Lutra lutra (Eurasian river otter)
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
llv04940  Type I diabetes mellitus
llv04940

Organism
Lutra lutra (Eurasian river otter) [GN:llv]
Gene
125079072  insulin [KO:K04526]
125096055  glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
125106317  glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
125082598  LOW QUALITY PROTEIN: glutamate decarboxylase 1-like [KO:K01580] [EC:4.1.1.15]
125096099  receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
125080937  LOW QUALITY PROTEIN: receptor-type tyrosine-protein phosphatase N2-like [KO:K07817] [EC:3.1.3.48]
125093066  carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
125094970  60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
125080909  islet cell autoantigen 1 isoform X1 [KO:K19863]
125101704  HLA class II histocompatibility antigen, DQ alpha 2 chain-like isoform X1 [KO:K06752]
125101705  HLA class II histocompatibility antigen, DQ beta 1 chain-like isoform X1 [KO:K06752]
125101706  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like isoform X1 [KO:K06752]
125102650  HLA class II histocompatibility antigen, DM beta chain-like isoform X1 [KO:K06752]
125102651  HLA class II histocompatibility antigen, DM alpha chain-like [KO:K06752]
125103079  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
125103096  HLA class II histocompatibility antigen, DO alpha chain-like [KO:K06752]
125103134  RLA class II histocompatibility antigen, DP alpha-1 chain-like [KO:K06752]
125103156  DLA class II histocompatibility antigen, DR-1 beta chain [KO:K06752]
125103158  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
125103275  HLA class II histocompatibility antigen, DO beta chain-like [KO:K06752]
125097777  T-lymphocyte activation antigen CD80-like [KO:K05412]
125103669  T-lymphocyte activation antigen CD86-like isoform X1 [KO:K05413]
125096335  T-cell-specific surface glycoprotein CD28 isoform X1 [KO:K06470]
125099687  interleukin-12 subunit alpha [KO:K05406]
125101014  interleukin-12 subunit beta [KO:K05425]
125093350  interleukin-2 [KO:K05429]
125107054  interferon gamma [KO:K04687]
125099812  H-2 class I histocompatibility antigen, Q10 alpha chain-like [KO:K06751]
125101548  uncharacterized protein LOC125101548 [KO:K06751]
125101549  class I histocompatibility antigen, Gogo-OKO alpha chain-like [KO:K06751]
125101800  HLA class I histocompatibility antigen, alpha chain G-like isoform X1 [KO:K06751]
125101803  DLA class I histocompatibility antigen, A9/A9 alpha chain-like isoform X1 [KO:K06751]
125101804  DLA class I histocompatibility antigen, A9/A9 alpha chain-like [KO:K06751]
125101807  LOW QUALITY PROTEIN: DLA class I histocompatibility antigen, A9/A9 alpha chain-like [KO:K06751]
125101827  DLA class I histocompatibility antigen, A9/A9 alpha chain-like [KO:K06751]
125102525  LOW QUALITY PROTEIN: DLA class I histocompatibility antigen, A9/A9 alpha chain-like [KO:K06751]
125086282  tumor necrosis factor ligand superfamily member 6 [KO:K04389]
125084890  tumor necrosis factor receptor superfamily member 6-like [KO:K04390]
125084642  perforin-1-like isoform X1 [KO:K07818]
125104493  mast cell protease 1A-like [KO:K01353] [EC:3.4.21.79]
125104667  granzyme B-like [KO:K01353] [EC:3.4.21.79]
125103143  lymphotoxin-alpha [KO:K05468]
125103142  tumor necrosis factor isoform X1 [KO:K03156]
125109147  interleukin-1 alpha [KO:K04383]
125109148  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
llv04210  Apoptosis
llv04660  T cell receptor signaling pathway
KO pathway
ko04940   
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