KEGG   PATHWAY: hsa04940Help
Entry
hsa04940                    Pathway                                

Name
Type I diabetes mellitus - Homo sapiens (human)
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 diseases
BRITE hierarchy
Pathway map
Type I diabetes mellitus
hsa04940

All organismsOrtholog table
Disease
H00408  
Type I diabetes mellitus
Drug
D04748  
Lisofylline (USAN/INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3630  
INS; insulin [KO:K04526]
2571  
GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
2572  
GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
5798  
PTPRN; protein tyrosine phosphatase, receptor type N [KO:K07817] [EC:3.1.3.48]
5799  
PTPRN2; protein tyrosine phosphatase, receptor type N2 [KO:K07817] [EC:3.1.3.48]
1363  
CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
3329  
HSPD1; heat shock protein family D (Hsp60) member 1 [KO:K04077]
3382  
ICA1; islet cell autoantigen 1 [KO:K19863]
3108  
HLA-DMA; major histocompatibility complex, class II, DM alpha [KO:K06752]
3109  
HLA-DMB; major histocompatibility complex, class II, DM beta [KO:K06752]
3111  
HLA-DOA; major histocompatibility complex, class II, DO alpha [KO:K06752]
3112  
HLA-DOB; major histocompatibility complex, class II, DO beta [KO:K06752]
3113  
HLA-DPA1; major histocompatibility complex, class II, DP alpha 1 [KO:K06752]
3115  
HLA-DPB1; major histocompatibility complex, class II, DP beta 1 [KO:K06752]
3117  
HLA-DQA1; major histocompatibility complex, class II, DQ alpha 1 [KO:K06752]
3118  
HLA-DQA2; major histocompatibility complex, class II, DQ alpha 2 [KO:K06752]
3119  
HLA-DQB1; major histocompatibility complex, class II, DQ beta 1 [KO:K06752]
3122  
HLA-DRA; major histocompatibility complex, class II, DR alpha [KO:K06752]
3123  
HLA-DRB1; major histocompatibility complex, class II, DR beta 1 [KO:K06752]
3125  
HLA-DRB3; major histocompatibility complex, class II, DR beta 3 [KO:K06752]
3126  
HLA-DRB4; major histocompatibility complex, class II, DR beta 4 [KO:K06752]
3127  
HLA-DRB5; major histocompatibility complex, class II, DR beta 5 [KO:K06752]
941  
CD80; CD80 molecule [KO:K05412]
942  
CD86; CD86 molecule [KO:K05413]
940  
CD28; CD28 molecule [KO:K06470]
3592  
IL12A; interleukin 12A [KO:K05406]
3593  
IL12B; interleukin 12B [KO:K05425]
3558  
IL2; interleukin 2 [KO:K05429]
3458  
IFNG; interferon gamma [KO:K04687]
3105  
HLA-A; major histocompatibility complex, class I, A [KO:K06751]
3106  
HLA-B; major histocompatibility complex, class I, B [KO:K06751]
3107  
HLA-C; major histocompatibility complex, class I, C [KO:K06751]
3134  
HLA-F; major histocompatibility complex, class I, F [KO:K06751]
3135  
HLA-G; major histocompatibility complex, class I, G [KO:K06751]
3133  
HLA-E; major histocompatibility complex, class I, E [KO:K06751]
356  
FASLG; Fas ligand [KO:K04389]
355  
FAS; Fas cell surface death receptor [KO:K04390]
5551  
PRF1; perforin 1 [KO:K07818]
3002  
GZMB; granzyme B [KO:K01353] [EC:3.4.21.79]
4049  
LTA; lymphotoxin alpha [KO:K05468]
7124  
TNF; tumor necrosis factor [KO:K03156]
3552  
IL1A; interleukin 1 alpha [KO:K04383]
3553  
IL1B; interleukin 1 beta [KO:K04519]
Compound
C00027  
Hydrogen peroxide
C00533  
Nitric oxide
C00704  
O2.-
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)
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)
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)
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)
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)
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)
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)
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)
Reference
  Authors
Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC.
  Title
Granzyme B: a natural born killer.
  Journal
Immunol Rev 193:31-8 (2003)
KO pathway
 

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