RIG-I– and MDA5-Initiated Innate Immunity Linked With Adaptive Immunity Accelerates β-Cell Death in Fulminant Type 1 Diabetes
| Autor: | Hiroki Shimura, Masahiro Kaneshige, Masako Suzuki, Hideki Fujii, Kaoru Aida, Akio Kawaguchi, Soichi Takizawa, Daiichiro Akiyama, Shoichiro Tanaka, Masashi Ichijo, Takuya Awata, Tetsuro Kobayashi, Taro Maruyama, Yoriko Nishida, Jun Itakura, Toyoshi Endo, Fumihiko Furuya, Akira Shimada |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Adult
Male endocrine system Interferon-Induced Helicase IFIH1 Adolescent Endocrinology Diabetes and Metabolism Biology Adaptive Immunity Major histocompatibility complex DEAD-box RNA Helicases Interferon-gamma Immune system Immunity Interferon Insulin-Secreting Cells Internal Medicine medicine Enterovirus Infections Humans Receptors Immunologic Aged geography Analysis of Variance Innate immune system geography.geographical_feature_category Cell Death Toll-Like Receptors Histocompatibility Antigens Class II Interleukin-18 Interferon-beta Middle Aged Acquired immune system Islet Immunohistochemistry Immunity Innate Diabetes Mellitus Type 1 TLR3 Immunology biology.protein DEAD Box Protein 58 Female Immunology and Transplantation medicine.drug |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE The contribution of innate immunity responsible for aggressive β-cell destruction in human fulminant type 1 diabetes is unclear. RESEARCH DESIGN AND METHODS Islet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid–inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes. RESULTS RIG-I was strongly expressed in β-cells in all three pancreata infected with enterovirus. Melanoma differentiation–associated gene-5 was hyperexpressed in islet cells, including β- and α-cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated islets. Interferon (IFN)-α and IFN-β were strongly expressed in islet cells. Major histocompatibility complex (MHC)-class I, IFN-γ, interleukin-18, and CXC motif ligand 10 were expressed and colocalized in affected islets. CD11c+ MHC-class II+ dendritic cells and macrophage subsets infiltrated most islets and showed remarkable features of phagocytosis of islet cell debris. CD4+ forkhead box P3+ regulatory T cells were not observed in and around the affected islets. Mononuclear cells expressed the Fas ligand and infiltrated most Fas-expressing islets. Retinoic acid–receptor responder 3 and activated caspases 8, 9, and 3 were preferentially expressed in β-cells. Serum levels of IFN-γ were markedly increased in patients with fulminant type 1 diabetes. CONCLUSIONS These findings demonstrate the presence of specific innate immune responses to enterovirus infection connected with enhanced adoptive immune pathways responsible for aggressive β-cell toxicity in fulminant type 1 diabetes. |
| Databáze: | OpenAIRE |
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