KEGG   PATHWAY: lww04940
Entry
lww04940                    Pathway                                
Name
Type I diabetes mellitus - Leptonychotes weddellii (Weddell seal)
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
lww04940  Type I diabetes mellitus
lww04940

Organism
Leptonychotes weddellii (Weddell seal) [GN:lww]
Gene
102747637  INS; insulin [KO:K04526]
102731758  glutamate decarboxylase 1-like [KO:K01580] [EC:4.1.1.15]
102726082  GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
102730178  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
102732891  PTPRN; receptor-type tyrosine-protein phosphatase-like N [KO:K07817] [EC:3.1.3.48]
102748596  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
102731829  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
102727518  ICA1; islet cell autoantigen 1 isoform X1 [KO:K19863]
102733188  HLA class II histocompatibility antigen, DP alpha 1 chain-like isoform X1 [KO:K06752]
102748173  H-2 class II histocompatibility antigen, E-S beta chain-like [KO:K06752]
102747192  HLA class II histocompatibility antigen, DQ alpha 1 chain-like [KO:K06752]
102734456  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
102740784  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
102741082  DLA class II histocompatibility antigen, DR-1 beta chain isoform X1 [KO:K06752]
102747485  HLA class II histocompatibility antigen, DQ beta 2 chain isoform X1 [KO:K06752]
102748462  HLA class II histocompatibility antigen, DO beta chain isoform X2 [KO:K06752]
102750166  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
102750454  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
102742353  CD80; T-lymphocyte activation antigen CD80 isoform X1 [KO:K05412]
102729117  CD86; T-lymphocyte activation antigen CD86 [KO:K05413]
102736415  CD28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
102738603  IL12A; interleukin-12 subunit alpha [KO:K05406]
102740807  IL12B; interleukin-12 subunit beta [KO:K05425]
102742200  IL2; interleukin-2 [KO:K05429]
102733689  IFNG; interferon gamma [KO:K04687]
102749162  LOW QUALITY PROTEIN: HLA class I histocompatibility antigen, alpha chain G-like [KO:K06751]
102735909  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
102746195  DLA class I histocompatibility antigen, A9/A9 alpha chain-like [KO:K06751]
102730025  HLA class I histocompatibility antigen, A-24 alpha chain-like [KO:K06751]
102736667  patr class I histocompatibility antigen, A-2 alpha chain [KO:K06751]
102745146  tumor necrosis factor ligand superfamily member 6-like [KO:K04389]
102738718  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
102739242  PRF1; perforin-1 [KO:K07818]
102749524  LOW QUALITY PROTEIN: mast cell protease 1A-like [KO:K01353] [EC:3.4.21.79]
102749815  granzyme B [KO:K01353] [EC:3.4.21.79]
102743202  LTA; lymphotoxin-alpha [KO:K05468]
102743506  TNF; tumor necrosis factor [KO:K03156]
102740423  IL1A; interleukin-1 alpha isoform X1 [KO:K04383]
102739919  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
lww04210  Apoptosis
lww04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

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