Enterovirus Infection, CXC Chemokine Ligand 10 (CXCL10), and CXCR3 Circuit: A Mechanism of Accelerated β-Cell Failure in Fulminant Type 1 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 10; pp. 2285 - 2291
• Main Authors: TANAKA, Shoichiro, NISHIDA, Yoriko, ARAI-YAMASHITA, Sayaka, FURUYA, Fumihiko, KAWAGUCHI, Akio, KANESHIGE, Masahiro, KATOH, Ryohei, ENDO, Toyoshi, KOBAYASHI, Tetsuro, AIDA, Kaoru, MARUYAMA, Taro, SHIMADA, Akira, SUZUKI, Masako, SHIMURA, Hiroki, TAKIZAWA, Soichi, TAKAHASHI, Masashi, AKIYAMA, Daiichiro
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2009
• Subjects: Adult; Aged; Autopsy; Biological and medical sciences; Capsid Proteins - genetics; Care and treatment; Chemokine CXCL10 - blood; Chemokine CXCL10 - genetics; Chemokines; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes. Impaired glucose tolerance; Diabetic Ketoacidosis - genetics; Diabetic Ketoacidosis - pathology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enterovirus diseases; Enterovirus infections; Enterovirus Infections - blood; Enterovirus Infections - complications; Enterovirus Infections - immunology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatal Outcome; Female; Genetic aspects; Health aspects; Histocompatibility Antigens Class I - genetics; HLA-D Antigens - genetics; Humans; Insulin-Secreting Cells - pathology; Male; Medical sciences; Middle Aged; Original; Pancreatic beta cells; Physiological aspects; Receptors, CXCR3 - genetics; Risk factors; RNA, Viral - genetics; RNA, Viral - isolation & purification; T cells; Type 1 diabetes; Japan; Endocrinopathy; Immunopathology; Picornaviridae; Ligand; Langerhans islet; Autoimmune disease; Enterovirus; Virus; Chemokine; Infection; Type 1 diabetes; β Cell; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db09-0091

Fulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated beta-cell failure are unclear. Subjects comprised three autopsied patients who died from diabetic ketoacidosis within 2-5 days after onset of fulminant type 1 diabetes. We examined islet cell status, including the presence of enterovirus and chemokine/cytokine/major histocompatibility complex (MHC) expressions in the pancreata using immunohistochemical analyses and RT-PCR. Immunohistochemical analysis revealed the presence of enterovirus-capsid protein in all three affected pancreata. Extensive infiltration of CXCR3 receptor-bearing T-cells and macrophages into islets was observed. Dendritic cells were stained in and around the islets. Specifically, interferon-gamma and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including beta-cells and alpha-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyperexpression of MHC class I was observed in some islet cells. These results strongly suggest the presence of a circuit for the destruction of beta-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates coexpression of interferon-gamma and CXCL10 in beta-cells. CXCL10 secreted from beta-cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-gamma in the islets, not only damaging beta-cells but also accelerating CXCL10 generation in residual beta-cells and thus further activating cell-mediated autoimmunity until all beta-cells have been destroyed.