Mikako Takita1,2, Erika Jimbo1, Tomoyasu Fukui1,3, Kaoru Aida4, Akira Shimada5, Yoichi Oikawa5, Soroku Yagihashi6, Junnosuke Miura2, Tetsuya Babazono2, Tetsuro Kobayashi1,7. 1. Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan. 2. Diabetes Center, Tokyo Woman's Medical University School of Medicine, Tokyo, Japan. 3. Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan. 4. Department of Diabetic Medicine, Kanoiwa General Hospital, Yamanashi, Japan. 5. Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Saitama, Japan. 6. Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan. 7. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan.
Abstract
CONTEXT: There are scant reports on the pathological changes of the exocrine and endocrine pancreas in fulminant type 1 diabetes mellitus (FT1DM). OBJECTIVE: To clarify the distinct pathological changes in the exocrine as well as the endocrine pancreas shortly after onset of diabetes in FT1DM. DESIGN: The exocrine and endocrine pancreases of 3 patients with FT1DM and 17 nondiabetic controls were immunohistochemically examined for islet and exocrine tissue inflammation, infiltrating mononuclear cell (MNC) CD subtype, enterovirus capsid protein 1 (VP1) localization, and CXC chemokine ligand 10 (CXCL10) and CXC chemokine receptor 3 (CXCR3) expressions. RESULTS: The median frequency of insulitis in the 3 FT1DM pancreases was 60%. In the nondiabetic control pancreases, no insulitis was observed. In the islets of FT1DM, the numbers of CD45+, CD3+, CD8+, CD68+, and CD11c+ MNCs were significantly higher than those of the control group. In the exocrine pancreas of FT1DM, the numbers of CD3+ T cells, CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were significantly higher than those of the control group. Infiltrating CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were observed around exocrine acinar cells in FT1DM. There was a close association between VP1 and CXCL10 expression in pancreatic exocrine ductal cells and acinar cells as well as islet cells in FT1DM. CXCL10+ exocrine cells were surrounded by CXCR3+ T cells. CONCLUSION: The pathological findings suggested that suppression of the activated CXCL10-CXCR3 axis in the exocrine as well as the endocrine pancreas is a novel therapeutic target in FT1DM and possibly in enterovirus-associated acute-onset type 1 diabetes.
CONTEXT: There are scant reports on the pathological changes of the exocrine and endocrine pancreas in fulminant type 1 diabetes mellitus (FT1DM). OBJECTIVE: To clarify the distinct pathological changes in the exocrine as well as the endocrine pancreas shortly after onset of diabetes in FT1DM. DESIGN: The exocrine and endocrine pancreases of 3 patients with FT1DM and 17 nondiabetic controls were immunohistochemically examined for islet and exocrine tissue inflammation, infiltrating mononuclear cell (MNC) CD subtype, enterovirus capsid protein 1 (VP1) localization, and CXC chemokine ligand 10 (CXCL10) and CXC chemokine receptor 3 (CXCR3) expressions. RESULTS: The median frequency of insulitis in the 3 FT1DM pancreases was 60%. In the nondiabetic control pancreases, no insulitis was observed. In the islets of FT1DM, the numbers of CD45+, CD3+, CD8+, CD68+, and CD11c+ MNCs were significantly higher than those of the control group. In the exocrine pancreas of FT1DM, the numbers of CD3+ T cells, CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were significantly higher than those of the control group. Infiltrating CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were observed around exocrine acinar cells in FT1DM. There was a close association between VP1 and CXCL10 expression in pancreatic exocrine ductal cells and acinar cells as well as islet cells in FT1DM. CXCL10+ exocrine cells were surrounded by CXCR3+ T cells. CONCLUSION: The pathological findings suggested that suppression of the activated CXCL10-CXCR3 axis in the exocrine as well as the endocrine pancreas is a novel therapeutic target in FT1DM and possibly in enterovirus-associated acute-onset type 1 diabetes.