Unique pathological changes in the pancreas of fulminant type 1 diabetes
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MINI-REVIEW
Unique pathological changes in the pancreas of fulminant type 1 diabetes Tetsuro Kobayashi1,2 · Shoichiro Tanaka3 · Kaoru Aida4 Received: 6 August 2020 / Accepted: 18 August 2020 © The Japan Diabetes Society 2020
Abstract Distinct features of the pancreas of fulminant type 1 diabetes (FT1DM) include (1) enterovirus infection of the islets and exocrine acinar tissue. (2) Activated innate immune responses: MDA5 and RIG-I expression and TLR4 and TLR9 expression in the islets of FT1DM. (3) Combined activation of the STAT/JNK and NFkB pathways, resulting in Type I interferon (IFN) and proinflammatory cytokine (i.e., IFNγ) expression in islet beta cells and MHC class I hyper-expression. (4) Activation of dendritic cells followed by effector cell infiltration of C D8+ T cells and C D68+ macrophages, resulting in apoptosis and neurosis of islet cells and exocrine acinar cells. (5) Many chemo-attractants (i.e., CXCL10) and chemotactic activators (i.e., l-plastin) were induced by a viral infection. (6) Mutual stimulating effect of cytokines expressed in beta cells in autocrine and paracrine mechanisms may enhance beta-cell destruction through the STA1-caspase pathway. (7) Proteomics analysis using laser capture microdissection followed by mass spectrometry found 38 molecules in inflamed islets of FT1DM, which were not highlighted before. Our pathologically verified model of beta-cell destruction in FT1DM will contribute to antivirus therapy of type 1 diabetes in the near future. Keywords Fulminant type 1 diabetes · Enterovirus · Innate immunity · MDA5 · RIG-I · Toll-like receptor · Insulitis · Pancreatitis
Introduction The term “fulminant type 1 diabetes (FT1DM)” is derived from the characteristic symptoms documented as “an abrupt onset of diabetic symptoms, thirst and weakness, and the point at which symptoms first developed can be easily determined” [1–3]. At admission to hospital, such patients usually show normal HbA1 levels and the extent of their hyperglycemia and ketosis is more severe than in acute-onset type 1 diabetes [1–3]. Recent pathological analysis demonstrated * Tetsuro Kobayashi [email protected] 1
Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, 2‑2‑2 Toranomon, Minato‑ku, Tokyo 105‑8470, Japan
2
Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
3
Ai Home Clinic Toshima, 4th Floor, INS Building, 2‑32‑2 Minamiotsuka, Toshima‑ku, Tokyo 170‑0005, Japan
4
Department of Diabetes Medicine, Kanoiwa Hospital, Kamijinnai River 1309, Yamanashi, Yamanashi, Japan
that the destructive process progresses rapidly through virusinduced innate and adaptive immune processes and specific host immunogenetic backgrounds [1–9] in addition to many molecules not highlighted in type 1 diabetes previously [10, 11].
Pathogenic virus The virus that causes FT1DM is an acutely cytolytic virus that exhibits tropism mainly to islets and occasionally to exocrine acinar cells [12, 13]. It generally assumed that the causati
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