A Histological Study of Fulminant Type 1 Diabetes Mellitus Related to Human Cytomegalovirus Reactivation

• Published in: The journal of clinical endocrinology and metabolism Vol. 102; no. 7; pp. 2394 - 2400
• Main Authors: Yoneda, Sho, Imagawa, Akihisa, Fukui, Kenji, Uno, Sae, Kozawa, Junji, Sakai, Makoto, Yumioka, Toshiki, Iwahashi, Hiromi, Shimomura, Iichiro
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.07.2017; Copyright Oxford University Press; Oxford University Press
• Subjects: Activation; Aged; Autopsies; Autopsy; Biopsy, Needle; Case-Control Studies; CD4 antigen; CD8 antigen; Cell injury; Cells, Cultured; Cytomegalovirus; Cytomegalovirus - pathogenicity; Cytomegalovirus Infections - physiopathology; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - physiopathology; DNA structure; DNA-Binding Proteins - metabolism; Epstein-Barr virus; Glucose tolerance; Humans; Hypersensitivity; Immunohistochemistry; Immunological tolerance; Infections; Inflammation; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - virology; Interferon; Interferon regulatory factor; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - metabolism; Localization; Lymphocytes; Lymphocytes T; Macrophages; Male; Pancreas; Reference Values; Retinoic acid; Severity of Illness Index; Statistics, Nonparametric; Virus Activation; Viruses
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2016-4029

Abstract Context: Fulminant type 1 diabetes mellitus (T1DM) is thought to be partly caused by virus infection. Objective: This study investigated the mechanism of β cell destruction in fulminant T1DM after drug-induced hypersensitivity syndrome (DIHS). Methods: We determined the localization of human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV) and the expression of interferon regulatory factor 3 (IRF3) and viral receptors of Z-DNA binding protein 1 (ZBP1) and retinoic acid-inducible gene I (RIG-I), together with inflammatory cells, by immunohistochemistry of the autopsy pancreas of a patient with fulminant T1DM with DIHS and in seven subjects with normal glucose tolerance who underwent pancreatectomy. Results: HCMV-positive cells were detected in islets and exocrine areas in the patient with fulminant T1DM. Greater numbers of macrophages and CD4+ and CD8+ T lymphocytes had infiltrated into HCMV-positive islets than into HCMV-negative islets, and 52.6% of HCMV-positive cells were also positive for IRF3. α Cells expressed IRF3, ZBP1, or RIG-I. No HCMV-positive cells were detected in the control subjects. HHV-6−positive, but not EBV-positive, cells were present in the patient and the control subjects. Conclusions: These findings indicate that the immunoresponse caused by HCMV infection was associated with β cell injury. In a patient who developed fulminant T1DM after DIHS, HCMV-positive cells were detected in islets, into which increased numbers of macrophages and CD4+ and CD8+ T lymphocytes had infiltrated.