Bi-glandular and persistent enterovirus infection and distinct changes of the pancreas in slowly progressive type 1 diabetes mellitus

Tomoyasu Fukui; Tetsuro Kobayashi; Erika Jimbo; Kaoru Aida; Akira Shimada; Yoichi Oikawa; Yasumichi Mori; Takeshi Fujii; Rikako Koyama; Kazuhiko Kobayashi; Akira Takeshita; Soroku Yagihashi

doi:10.1038/s41598-023-33011-7

Bi-glandular and persistent enterovirus infection and distinct changes of the pancreas in slowly progressive type 1 diabetes mellitus

Sci Rep. 2023 Apr 28;13(1):6977. doi: 10.1038/s41598-023-33011-7.

Authors

Tomoyasu Fukui^{1

2}, Tetsuro Kobayashi^{3

4}, Erika Jimbo¹, Kaoru Aida⁵, Akira Shimada⁶, Yoichi Oikawa⁶, Yasumichi Mori⁷, Takeshi Fujii⁸, Rikako Koyama⁹, Kazuhiko Kobayashi¹⁰, Akira Takeshita⁷, Soroku Yagihashi¹¹

Affiliations

¹ Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
² Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
³ Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan. tetsurou@yamanashi.ac.jp.
⁴ Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. tetsurou@yamanashi.ac.jp.
⁵ Department of Diabetes and Endocrinology, Kanoiwa Hospital, Yamanashi, Japan.
⁶ Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan.
⁷ Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan.
⁸ Department of Pathology, Toranomon Hospital, Tokyo, Japan.
⁹ Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan.
¹⁰ Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
¹¹ Department of Exploratory Medicine on Nature, Life, and Man, Toho University of Medicine, Chiba, Japan.

Abstract

In slowly progressive type 1 diabetes mellitus (SPIDDM), the pancreas shows sustained islet inflammation, pancreatitis, pancreatic acinar cell metaplasia/dysplasia (ADM), and intraepithelial neoplasia (PanIN), a precancerous lesion. The mechanisms underlying these changes remain unclear. The presence of enterovirus (EV) encoded-capsid protein 1 (VP1) and -2A protease (2A^pro) and the innate immune responses of the pancreas were studied using immunohistochemistry and in situ hybridization in 12 SPIDDM and 19 non-diabetic control pancreases. VP1, 2A^pro, and EV-RNA were detected in islets and the exocrine pancreas in all SPIDDM pancreases. Innate immune receptor, melanoma differentiation-associated gene 5 (MDA5), and interferon (IFN)-beta1 were intensified in the islets of SPIDDM patients with short disease duration. However, expressions of MDA5 and IFN-beta1were suppressed in those with longer disease duration. CD3⁺ T cell infiltration was observed in the VP1- and insulin-positive islets (insulitis) and exocrine acinar cells. CD11c⁺ dendritic cells (DCs) in islets were scarce in long-term SPIDDM. This study showed the consistent presence of EV, suggesting an association with inflammatory changes in the endocrine and exocrine pancreas in SPIDDM. Suppressed expressions of MDA5 and IFN-beta1, as well as decreased numbers of DCs in the host cells, may contribute to persistent EV infection and induction of ADM/PanIN lesions, which may potentially provide a scaffold for pancreatic neoplasms.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Viral / metabolism
Diabetes Mellitus, Type 1* / metabolism
Enterovirus Infections* / metabolism
Enterovirus* / genetics
Humans
Islets of Langerhans* / metabolism
Pancreas / metabolism
Pancreas, Exocrine* / metabolism

Substances

Antigens, Viral