title: Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes.
abstract: Fulminant type 1 diabetes is characterized by a rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetic complications. This review summarizes new findings related to the pathophysiology of accelerated β-cell failure in fulminant type 1 diabetes. Immunohistological examination revealed the presence of enterovirus in pancreatic islet cells and exocrine tissues and hyperexpression of pattern recognition receptors (PRRs) including melanoma differentiation-associated antigen 5 (MDA5), retinoic acid-inducible gene-I (RIG-I), Toll-like receptor (TLR)3 and TLR4, essential sensors of innate immunity, in islet cells and mononuclear cells (MNCs) infiltrating islets. Interferon (IFN)-α and IFN-β, products of PRR cascades, were expressed in both islet cells and infiltrating MNCs. Phenotypes of infiltrating cells around and/or into islets were mainly dendritic cells, macrophages and CD8+ T cells. Islet β-cells simultaneously expressed CXC chemokine ligand 10 (CXCL10), IFN-γ and interleukin-18, indicating that these chemokines/ cytotoxic cytokines mutually amplify their cytoplasmic expression in the islet cells. These positive feedback systems might enhance adaptive immunity, leading to rapid and complete loss of β-cells in fulminant type 1 diabetes. In innate and adaptive/autoimmune immune processes, the mechanisms behind bystander activation/killing might further amplify β-cell destruction. In addition to intrinsic pathway of cell apoptosis, the Fas and Fas ligand pathway are also involved as an extrinsic pathway of cell apoptosis. A high prevalence of anti-amylase autoantibodies was recognized in patients with fulminant type 1 diabetes, which suggests that Th2 T-cell reactive immunity against amylase might contribute to β-cell destruction in fulminant type 1 diabetes.
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo 409-3898, Japan. tanakas@yamanashi.ac.jp
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Tanaka
authors.forename: Kaoru
authors.initials: K
authors.lastname: Aida
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Nishida
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D016923:Cell Death; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004770:Enterovirus / Q000502:physiology; D006801:Humans; D007372:Interferons / Q000502:physiology; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology / Q000502:physiology* / Q000821:virology; D017254:Leukemic Infiltration / Q000503:physiopathology; D010179:Pancreas / Q000502:physiology / Q000821:virology; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000378:metabolism
chemical_list: D051192:Receptors, Pattern Recognition; D007372:Interferons