KEGG   PATHWAY: tmu04940
Entry
tmu04940                    Pathway                                
Name
Type I diabetes mellitus - Trichechus manatus latirostris (Florida manatee)
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
tmu04940  Type I diabetes mellitus
tmu04940

Organism
Trichechus manatus latirostris (Florida manatee) [GN:tmu]
Gene
101346705  insulin [KO:K04526]
101347498  glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]
101343351  glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
101353299  receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]
101351674  receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
101342305  carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
101358584  60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
101356668  islet cell autoantigen 1 isoform X1 [KO:K19863]
101343312  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
101343065  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
101344101  LOW QUALITY PROTEIN: boLa class II histocompatibility antigen, DQB*0101 beta chain-like [KO:K06752]
101345015  boLa class II histocompatibility antigen, DQB*0101 beta chain-like [KO:K06752]
101361245  LOW QUALITY PROTEIN: DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
101342567  HLA class II histocompatibility antigen, DP beta 1 chain [KO:K06752]
101342817  HLA class II histocompatibility antigen, DP alpha 1 chain isoform X2 [KO:K06752]
101342571  HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
101343573  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
101345267  HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
101345522  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
101348755  HLA class II histocompatibility antigen, DP alpha 1 chain-like [KO:K06752]
101349613  T-lymphocyte activation antigen CD80 isoform X1 [KO:K05412]
101347585  T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
101343092  T-cell-specific surface glycoprotein CD28 isoform X1 [KO:K06470]
101353752  interleukin-12 subunit alpha [KO:K05406]
101344352  interleukin-12 subunit beta [KO:K05425]
101360180  interleukin-2 [KO:K05429]
101346429  interferon gamma [KO:K04687]
101359320  HLA class I histocompatibility antigen, A-80 alpha chain-like [KO:K06751]
101345748  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X3 [KO:K06751]
101346884  HLA class I histocompatibility antigen, A-80 alpha chain-like [KO:K06751]
101347138  HLA class I histocompatibility antigen, B-40 alpha chain-like isoform X1 [KO:K06751]
101345854  class I histocompatibility antigen, Gogo-B*0101 alpha chain-like isoform X1 [KO:K06751]
101350180  patr class I histocompatibility antigen, B-1 alpha chain-like isoform X1 [KO:K06751]
101346109  class I histocompatibility antigen, Gogo-B*0102 alpha chain-like isoform X1 [KO:K06751]
101346365  class I histocompatibility antigen, Gogo-B*0103 alpha chain-like [KO:K06751]
101340887  saoe class I histocompatibility antigen, A alpha chain-like [KO:K06751]
101349740  HLA class I histocompatibility antigen, Cw-12 alpha chain-like [KO:K06751]
111819117  uncharacterized protein LOC111819117 [KO:K10784]
101361451  LOW QUALITY PROTEIN: uncharacterized protein LOC101361451 [KO:K10785]
105756611  uncharacterized protein LOC105756611 [KO:K10785]
101342429  uncharacterized protein LOC101342429 [KO:K10785]
101344408  tumor necrosis factor ligand superfamily member 6 isoform X1 [KO:K04389]
101346704  tumor necrosis factor receptor superfamily member 6 isoform X1 [KO:K04390]
101349286  granzyme B [KO:K01353] [EC:3.4.21.79]
101350051  granzyme-like protein 2 [KO:K01353] [EC:3.4.21.79]
105756280  granzyme B-like [KO:K01353] [EC:3.4.21.79]
101342393  lymphotoxin-alpha [KO:K05468]
101342656  TNF; tumor necrosis factor [KO:K03156]
101359155  interleukin-1 alpha isoform X1 [KO:K04383]
101359415  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
tmu04210  Apoptosis
tmu04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

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