KEGG   PATHWAY: mlf04940
Entry
mlf04940                    Pathway                                
Name
Type I diabetes mellitus - Myotis lucifugus (little brown bat)
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
mlf04940  Type I diabetes mellitus
mlf04940

Organism
Myotis lucifugus (little brown bat) [GN:mlf]
Gene
102430737  INS; insulin [KO:K04526]
102434026  GAD1; glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]
102443023  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
102431628  PTPRN; LOW QUALITY PROTEIN: receptor-type tyrosine-protein phosphatase-like N [KO:K07817] [EC:3.1.3.48]
102429035  CPE; LOW QUALITY PROTEIN: carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
102429538  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
102424371  LOW QUALITY PROTEIN: 60 kDa heat shock protein, mitochondrial-like [KO:K04077] [EC:5.6.1.7]
102422538  ICA1; islet cell autoantigen 1 isoform X2 [KO:K19863]
102433442  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
111822996  HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
111823581  HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
102424361  HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
102424046  boLa class II histocompatibility antigen, DQB*0101 beta chain-like [KO:K06752]
102426046  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102417581  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102417899  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102418225  HLA class II histocompatibility antigen, DRB1-4 beta chain-like [KO:K06752]
102416953  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
102421254  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
102423761  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102441293  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
102418131  HLA class II histocompatibility antigen, DR alpha chain-like [KO:K06752]
102434058  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102434372  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
111824054  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102443188  HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
102431574  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102431885  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102417382  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
102431149  HLA class II histocompatibility antigen, DRB1-9 beta chain-like [KO:K06752]
102417268  HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
102439327  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
106694679  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
102426241  HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
102423747  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102433751  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
106695222  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102422459  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
102419180  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
102441506  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102428157  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
102431769  HLA class II histocompatibility antigen, DRB1-4 beta chain-like [KO:K06752]
102418553  SLA class II histocompatibility antigen, DQ haplotype C beta chain-like [KO:K06752]
102419081  RLA class II histocompatibility antigen, DP alpha-1 chain-like [KO:K06752]
102423684  HLA class II histocompatibility antigen, DP beta 1 chain-like isoform X1 [KO:K06752]
102429593  H-2 class II histocompatibility antigen, E-S beta chain-like [KO:K06752]
102423144  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like isoform X2 [KO:K06752]
102423440  boLa class II histocompatibility antigen, DQB*0101 beta chain-like [KO:K06752]
102423734  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
102425725  HLA class II histocompatibility antigen, DR alpha chain-like [KO:K06752]
102426355  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
102424057  DLA class II histocompatibility antigen, DR-1 beta chain-like isoform X1 [KO:K06752]
102424373  HLA class II histocompatibility antigen, DR beta 5 chain-like [KO:K06752]
102417504  CD80; T-lymphocyte activation antigen CD80 isoform X1 [KO:K05412]
102436777  CD86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
102438564  CD28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
102431058  IL12A; interleukin-12 subunit alpha [KO:K05406]
102435627  IL12B; interleukin-12 subunit beta [KO:K05425]
102433200  IL2; interleukin-2 [KO:K05429]
102438946  IFNG; interferon gamma [KO:K04687]
102440675  HLA class I histocompatibility antigen, B-46 alpha chain-like isoform X10 [KO:K06751]
102442541  HLA class I histocompatibility antigen, B-15 alpha chain-like [KO:K06751]
102433344  HLA class I histocompatibility antigen, B-67 alpha chain-like isoform X2 [KO:K06751]
102438185  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X2 [KO:K06751]
102435002  HLA class I histocompatibility antigen, B-67 alpha chain-like isoform X3 [KO:K06751]
102429481  HLA class I histocompatibility antigen, B-67 alpha chain-like isoform X12 [KO:K06751]
111822980  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X3 [KO:K06751]
111822961  HLA class I histocompatibility antigen, B-15 alpha chain-like [KO:K06751]
102432715  patr class I histocompatibility antigen, B-2 alpha chain-like isoform X6 [KO:K06751]
102429581  saoe class I histocompatibility antigen, A alpha chain-like isoform X1 [KO:K06751]
102417058  HLA class I histocompatibility antigen, A-11 alpha chain-like [KO:K06751]
102435927  HLA class I histocompatibility antigen, B-67 alpha chain-like isoform X1 [KO:K06751]
102431662  HLA class I histocompatibility antigen, B-18 alpha chain-like isoform X1 [KO:K06751]
102428684  HLA class I histocompatibility antigen, B-57 alpha chain-like [KO:K06751]
102418243  class I histocompatibility antigen, Gogo-B*0103 alpha chain-like isoform X1 [KO:K06751]
102424088  H-2 class I histocompatibility antigen, alpha chain-like isoform X1 [KO:K06751]
102440606  HLA class I histocompatibility antigen, B-54 alpha chain-like isoform X1 [KO:K06751]
102416963  patr class I histocompatibility antigen, B-1 alpha chain-like [KO:K06751]
111823006  saoe class I histocompatibility antigen, A alpha chain-like [KO:K06751]
102431053  HLA class I histocompatibility antigen, B-82 alpha chain-like [KO:K06751]
102442224  HLA class I histocompatibility antigen, B-14 alpha chain-like [KO:K06751]
102438496  patr class I histocompatibility antigen, A-126 alpha chain-like isoform X1 [KO:K06751]
102441816  patr class I histocompatibility antigen, A-108 alpha chain-like isoform X1 [KO:K06751]
102418018  class I histocompatibility antigen, Gogo-B*0103 alpha chain-like [KO:K06751]
102422972  HLA class I histocompatibility antigen, B-57 alpha chain-like [KO:K06751]
102424815  HLA class I histocompatibility antigen, B-45 alpha chain-like isoform X3 [KO:K06751]
102422085  class I histocompatibility antigen, Gogo-B*0102 alpha chain-like [KO:K06751]
102424768  HLA class I histocompatibility antigen, B-15 alpha chain-like [KO:K06751]
102417991  BOLA class I histocompatibility antigen, alpha chain BL3-7-like [KO:K06751]
102439228  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
102433075  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
102435988  PRF1; perforin-1 [KO:K07818]
102440283  granzyme H-like [KO:K01353] [EC:3.4.21.79]
102440598  LOW QUALITY PROTEIN: granzyme H-like [KO:K01353] [EC:3.4.21.79]
102441463  granzyme B-like [KO:K01353] [EC:3.4.21.79]
102441778  granzyme B-like [KO:K01353] [EC:3.4.21.79]
102435479  granzyme H-like isoform X4 [KO:K01353] [EC:3.4.21.79]
102434869  granzyme B-like [KO:K01353] [EC:3.4.21.79]
102442096  LOW QUALITY PROTEIN: granzyme B-like [KO:K01353] [EC:3.4.21.79]
111823008  LOW QUALITY PROTEIN: granzyme H-like [KO:K01353] [EC:3.4.21.79]
102435171  granzyme B [KO:K01353] [EC:3.4.21.79]
111822966  LTA; lymphotoxin-alpha isoform X2 [KO:K05468]
102437558  TNF; tumor necrosis factor isoform X1 [KO:K03156]
102426867  IL1A; interleukin-1 alpha [KO:K04383]
102427189  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
PMID:11507694
  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
PMID:12796471
  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
PMID:15889095
  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
PMID:15889096
  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
PMID:14617043
  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
PMID:12752668
  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
mlf04210  Apoptosis
mlf04660  T cell receptor signaling pathway
KO pathway
ko04940   
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