Tetsuro Kobayashi1, Yoriko Nishida, Shoichiro Tanaka, Kaoru Aida. 1. Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan. tetsurou@yamanashi.ac.jp
Abstract
OBJECTIVE: The contribution of innate immunity responsible for beta-cell destruction in fulminant type 1 diabetes (FT1D) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) is unclear. RESEARCH DESIGN AND METHODS: Islet-cell expression of Toll-like receptors (TLRs) including TLR3 and TLR4, the cytoplasmic retinoic acid-inducible protein I (RIG-I)-like helicases, RIG-I, melanoma differentiation-associated gene-5 and laboratory of genetics and physiology 2 in the affected islets were studied immuno-histochemically on three pancreases obtained 2-5 days after the onset of FT1D and a pancreas from a patient with SPIDDM. RESULTS: Laboratory of genetics and physiology 2 and RIG-I strongly expressed in beta cells in all three FT1D pancreases infected with enterovirus (VP1 antigen). Melanoma differentiation-associated gene-5 was hyper-expressed in all subsets of islet cells including beta cells and alpha cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated to islets. IFN-alpha/beta was strongly expressed in islet cells. In contrast, pancreas of a patient with SPIDDM, enterovirus and expression of innate immune receptors including RIG-I, melanoma differentiation-associated gene-5, hyperexpression of laboratory of genetics and physiology 2 and mononuclear cells, which were positive for TLR3 and TLR4, and infiltration to the islets were not detected. CONCLUSIONS: These findings demonstrate that retinoic acid-inducible protein I (RIG-I)-like helicases and TLRs play a crucial role on beta-cell destruction in enterovirus-induced FT1D. The presence of distinct mechanism(s) of slowly progressive beta-cell failure in SPIDDM was suggested.
OBJECTIVE: The contribution of innate immunity responsible for beta-cell destruction in fulminant type 1 diabetes (FT1D) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) is unclear. RESEARCH DESIGN AND METHODS: Islet-cell expression of Toll-like receptors (TLRs) including TLR3 and TLR4, the cytoplasmic retinoic acid-inducible protein I (RIG-I)-like helicases, RIG-I, melanoma differentiation-associated gene-5 and laboratory of genetics and physiology 2 in the affected islets were studied immuno-histochemically on three pancreases obtained 2-5 days after the onset of FT1D and a pancreas from a patient with SPIDDM. RESULTS: Laboratory of genetics and physiology 2 and RIG-I strongly expressed in beta cells in all three FT1D pancreases infected with enterovirus (VP1 antigen). Melanoma differentiation-associated gene-5 was hyper-expressed in all subsets of islet cells including beta cells and alpha cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated to islets. IFN-alpha/beta was strongly expressed in islet cells. In contrast, pancreas of a patient with SPIDDM, enterovirus and expression of innate immune receptors including RIG-I, melanoma differentiation-associated gene-5, hyperexpression of laboratory of genetics and physiology 2 and mononuclear cells, which were positive for TLR3 and TLR4, and infiltration to the islets were not detected. CONCLUSIONS: These findings demonstrate that retinoic acid-inducible protein I (RIG-I)-like helicases and TLRs play a crucial role on beta-cell destruction in enterovirus-induced FT1D. The presence of distinct mechanism(s) of slowly progressive beta-cell failure in SPIDDM was suggested.
Authors: Jessica L Dunne; Sarah J Richardson; Mark A Atkinson; Maria E Craig; Knut Dahl-Jørgensen; Malin Flodström-Tullberg; Heikki Hyöty; Richard A Insel; Åke Lernmark; Richard E Lloyd; Noel G Morgan; Alberto Pugliese Journal: Diabetologia Date: 2019-01-23 Impact factor: 10.122