KEGG   PATHWAY: pps04940
pps04940                    Pathway                                

Type I diabetes mellitus - Pan paniscus (bonobo)
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.
Human Diseases; Endocrine and metabolic disease
Pathway map
pps04940  Type I diabetes mellitus

Pan paniscus (bonobo) [GN:pps]
100969387  INS; insulin [KO:K04526]
100975263  GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:]
100992436  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:]
100968828  PTPRN; protein tyrosine phosphatase, receptor type N [KO:K07817] [EC:]
100978473  PTPRN2; protein tyrosine phosphatase, receptor type N2 [KO:K07817] [EC:]
100983801  CPE; carboxypeptidase E [KO:K01294] [EC:]
100981698  HSPD1; heat shock protein family D (Hsp60) member 1 [KO:K04077]
100979991  ICA1; islet cell autoantigen 1 [KO:K19863]
100986750  HLA class II histocompatibility antigen, DRB1-4 beta chain [KO:K06752]
100987433  HLA class II histocompatibility antigen, DRB1-10 beta chain-like [KO:K06752]
100987081  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
100967723  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
100972641  HLA class II histocompatibility antigen, DQ beta 2 chain [KO:K06752]
100967376  RLA class II histocompatibility antigen, DP alpha-1 chain-like [KO:K06752]
100979649  HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
100968989  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
100968410  MHC-DMB; HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
100995577  HLA class II histocompatibility antigen, DP alpha 1 chain [KO:K06752]
100995226  Papa-DPB1; HLA class II histocompatibility antigen, DP beta 1 chain [KO:K06752]
100970847  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
100973583  HLA class II histocompatibility antigen, DQ alpha 2 chain [KO:K06752]
100972994  HLA class II histocompatibility antigen, DQ beta 1 chain [KO:K06752]
100993847  HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
100993508  HLA class II histocompatibility antigen, DQ alpha 1 chain [KO:K06752]
100967832  CD80; CD80 molecule [KO:K05412]
100981251  CD86; CD86 molecule [KO:K05413]
100992093  CD28; CD28 molecule [KO:K06470]
100979574  IL12A; interleukin 12A [KO:K05406]
100989950  IL12B; interleukin 12B [KO:K05425]
100984780  IL2; interleukin 2 [KO:K05429]
100991779  IFNG; interferon gamma [KO:K04687]
100978457  MHC-F; patr class I histocompatibility antigen, CH28 alpha chain [KO:K06751]
100978112  Papa-A; patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
100979338  HLA-H; putative HLA class I histocompatibility antigen, alpha chain H [KO:K06751]
100978774  MHC-G; patr class I histocompatibility antigen, alpha chain G [KO:K06751]
100993452  HLA class I histocompatibility antigen, A-3 alpha chain-like [KO:K06751]
100977055  patr class I histocompatibility antigen, alpha chain E [KO:K06751]
100982294  Papa-C; class I histocompatibility antigen, Gogo-C*0202 alpha chain [KO:K06751]
100982859  PAPA-B; class I histocompatibility antigen, Gogo-B*0101 alpha chain [KO:K06751]
100975083  uncharacterized LOC100975083 [KO:K10785]
100985012  uncharacterized LOC100985012 [KO:K10785]
100988366  uncharacterized LOC100988366 [KO:K10785]
100982662  uncharacterized LOC100982662 [KO:K10785]
100983000  uncharacterized LOC100983000 [KO:K10785]
100995080  uncharacterized LOC100995080 [KO:K10785]
100988045  uncharacterized LOC100988045 [KO:K10785]
100970360  FASLG; Fas ligand [KO:K04389]
100988526  FAS; Fas cell surface death receptor [KO:K04390]
100979698  PRF1; perforin 1 [KO:K07818]
100987153  GZMB; granzyme B [KO:K01353] [EC:]
100979816  LTA; lymphotoxin alpha [KO:K05468]
100977674  TNF; tumor necrosis factor [KO:K03156]
100994286  IL1A; interleukin 1 alpha [KO:K04383]
100993613  IL1B; interleukin 1 beta [KO:K04519]
C00027  Hydrogen peroxide
C00533  Nitric oxide
C00704  Superoxide
Rabinovitch A, Suarez-Pinzon WL.
Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus.
Biochem Pharmacol 55:1139-49 (1998)
Cox NJ, Wapelhorst B, Morrison VA, Johnson L, Pinchuk L, Spielman RS, Todd JA, Concannon P
Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families.
Am J Hum Genet 69:820-30 (2001)
Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM, et al.
A genome-wide search for human type 1 diabetes susceptibility genes.
Nature 371:130-6 (1994)
Fujisawa T, Ikegami H, Kawaguchi Y, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Shima K, Ogihara T.
Class I HLA is associated with age-at-onset of IDDM, while class II HLA confers susceptibility to IDDM.
Diabetologia 38:1493-5 (1995)
Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H.
Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.
J Exp Med 197:1635-44 (2003)
Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS.
Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.
Nature 435:220-3 (2005)
Kent SC, Chen Y, Bregoli L, Clemmings SM, Kenyon NS, Ricordi C, Hering BJ, Hafler DA.
Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope.
Nature 435:224-8 (2005)
Lieberman SM, DiLorenzo TP.
A comprehensive guide to antibody and T-cell responses in type 1 diabetes.
Tissue Antigens 62:359-77 (2003)
Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC.
Granzyme B: a natural born killer.
Immunol Rev 193:31-8 (2003)
pps04210  Apoptosis
pps04660  T cell receptor signaling pathway
KO pathway

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