KEGG PATHWAY: opi04940

KEGG

PATHWAY: opi04940

Entry

opi04940                    Pathway

Name

Type I diabetes mellitus - Ochotona princeps (American pika)

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

Type I diabetes mellitus

Organism

Ochotona princeps (American pika) [GN:opi]

Gene

insulin isoform X2 [KO:K04526]

GAD1; glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]

GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]

PTPRN; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]

PTPRN2; receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]

CPE; carboxypeptidase E isoform X2 [KO:K01294] [EC:3.4.17.10]

HSPD1; 60 kDa heat shock protein, mitochondrial isoform X1 [KO:K04077] [EC:5.6.1.7]

60 kDa heat shock protein, mitochondrial-like [KO:K04077] [EC:5.6.1.7]

ICA1; islet cell autoantigen 1 [KO:K19863]

mamu class II histocompatibility antigen, DR alpha chain [KO:K06752]

RLA class II histocompatibility antigen, DP alpha-1 chain [KO:K06752]

HLA class II histocompatibility antigen, DR beta 3 chain-like [KO:K06752]

H-2 class II histocompatibility antigen, E-S beta chain-like [KO:K06752]

HLA class II histocompatibility antigen, DM beta chain [KO:K06752]

HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]

HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]

HLA class II histocompatibility antigen, DP alpha 1 chain-like [KO:K06752]

LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DRB1 beta chain-like [KO:K06752]

HLA class II histocompatibility antigen, DO beta chain [KO:K06752]

HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]

SLA class II histocompatibility antigen, DQ haplotype D alpha chain [KO:K06752]

HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]

H-2 class II histocompatibility antigen, E-S beta chain-like [KO:K06752]

CD80; T-lymphocyte activation antigen CD80 [KO:K05412]

CD86; T-lymphocyte activation antigen CD86 [KO:K05413]

CD28; T-cell-specific surface glycoprotein CD28 [KO:K06470]

IL12A; interleukin-12 subunit alpha [KO:K05406]

interleukin-12 subunit beta-like [KO:K05425]

IL12B; interleukin-12 subunit beta [KO:K05425]

IL2; interleukin-2 [KO:K05429]

IFNG; interferon gamma [KO:K04687]

H-2 class I histocompatibility antigen, Q10 alpha chain-like [KO:K06751]

class I histocompatibility antigen, Gogo-B*0103 alpha chain-like isoform X2 [KO:K06751]

RLA class I histocompatibility antigen, alpha chain 11/11-like [KO:K06751]

HLA class I histocompatibility antigen, B alpha chain-like [KO:K06751]

putative HLA class I histocompatibility antigen, alpha chain H [KO:K06751]

patr class I histocompatibility antigen, B-2 alpha chain-like [KO:K06751]

RLA class I histocompatibility antigen, alpha chain 11/11-like [KO:K06751]

HLA class I histocompatibility antigen, alpha chain G-like [KO:K06751]

HLA class I histocompatibility antigen, B alpha chain-like [KO:K06751]

HLA class I histocompatibility antigen, B alpha chain-like isoform X1 [KO:K06751]

HLA class I histocompatibility antigen, A alpha chain-like isoform X1 [KO:K06751]

H-2 class I histocompatibility antigen, Q9 alpha chain-like [KO:K06751]

H-2 class I histocompatibility antigen, Q9 alpha chain-like [KO:K06751]

patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]

class I histocompatibility antigen, Gogo-B*0103 alpha chain-like isoform X1 [KO:K06751]

class I histocompatibility antigen, Gogo-B*0103 alpha chain-like [KO:K06751]

HLA class I histocompatibility antigen, A alpha chain-like [KO:K06751]

class I histocompatibility antigen, Gogo-B*0101 alpha chain-like isoform X1 [KO:K06751]

HLA class I histocompatibility antigen, A alpha chain-like [KO:K06751]

LOW QUALITY PROTEIN: putative HLA class I histocompatibility antigen, alpha chain H [KO:K06751]

FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]

FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]

PRF1; perforin-1 [KO:K07818]

LOW QUALITY PROTEIN: granzyme B(G,H) [KO:K01353] [EC:3.4.21.79]

LTA; lymphotoxin-alpha [KO:K05468]

TNF; tumor necrosis factor isoform X2 [KO:K03156]

IL1A; interleukin-1 alpha [KO:K04383]

IL1B; interleukin-1 beta [KO:K04519]

Compound

Hydrogen peroxide

Nitric oxide

Superoxide

Reference

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

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

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

Apoptosis

T cell receptor signaling pathway

KO pathway

LinkDB

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