KEGG   PATHWAY: mlx04940
Entry
mlx04940                    Pathway                                
Name
Type I diabetes mellitus - Mirounga leonina (Southern elephant 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
mlx04940  Type I diabetes mellitus
mlx04940

Organism
Mirounga leonina (Southern elephant seal) [GN:mlx]
Gene
118015656  INS; insulin [KO:K04526]
118004722  LOW QUALITY PROTEIN: glutamate decarboxylase 1-like [KO:K01580] [EC:4.1.1.15]
118011811  GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
118026564  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
118011744  PTPRN; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
118026798  PTPRN2; receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]
118022179  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
118012180  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
118020802  ICA1; islet cell autoantigen 1 isoform X1 [KO:K19863]
118000598  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP alpha 1 chain [KO:K06752]
118000703  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
118000882  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
118001122  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
118001151  HLA class II histocompatibility antigen, DO alpha chain isoform X1 [KO:K06752]
118001168  HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
118001169  DLA class II histocompatibility antigen, DR-1 beta chain isoform X1 [KO:K06752]
118001171  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
118001172  HLA class II histocompatibility antigen, DR alpha chain isoform X1 [KO:K06752]
118007066  CD80; T-lymphocyte activation antigen CD80 [KO:K05412]
118007039  CD86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
118012117  CD28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
118005789  IL12A; interleukin-12 subunit alpha [KO:K05406]
118016150  IL12B; interleukin-12 subunit beta [KO:K05425]
118022354  IL2; interleukin-2 [KO:K05429]
118008418  IFNG; interferon gamma [KO:K04687]
118000898  putative HLA class I histocompatibility antigen, alpha chain H [KO:K06751]
118026501  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
118026743  DLA class I histocompatibility antigen, A9/A9 alpha chain-like [KO:K06751]
118027349  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
118027378  LOW QUALITY PROTEIN: HLA class I histocompatibility antigen, alpha chain G [KO:K06751]
118014469  FASLG; LOW QUALITY PROTEIN: tumor necrosis factor ligand superfamily member 6 [KO:K04389]
118012958  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
118018380  perforin-1-like isoform X1 [KO:K07818]
118019135  perforin-1-like isoform X1 [KO:K07818]
118003297  granzyme B-like [KO:K01353] [EC:3.4.21.79]
118003491  LOW QUALITY PROTEIN: mast cell protease 1A-like [KO:K01353] [EC:3.4.21.79]
118027256  LTA; lymphotoxin-alpha [KO:K05468]
118027255  TNF; tumor necrosis factor [KO:K03156]
118007866  IL1A; interleukin-1 alpha isoform X1 [KO:K04383]
118007867  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
mlx04210  Apoptosis
mlx04660  T cell receptor signaling pathway
KO pathway
ko04940   
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