@article{2b2de1560157470c85bff3b0070d1812,
title = "Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms",
abstract = "Recognition of β-cell antigens by autoreactive T cells is a critical step in the initiation of autoimmune type1 diabetes. A complete protection from diabetes development in NOD mice harboring a point mutation in the insulin B-chain 9–23 epitope points to a dominant role of insulin in diabetogenesis. Generation of NOD mice lacking the chromogranin A protein (NOD.ChgA−/−) completely nullified the autoreactivity of the BDC2.5 T cell and conferred protection from diabetes onset. These results raised the issue concerning the dominant antigen that drives the autoimmune process. Here we revisited the NOD.ChgA−/− mice and found that their lack of diabetes development may not be solely explained by the absence of chromogranin A reactivity. NOD.ChgA−/− mice displayed reduced presentation of insulin peptides in the islets and periphery, which corresponded to impaired T-cell priming. Diabetes development in these mice was restored by antibody treatment targeting regulatory T cells or inhibiting transforming growth factor-β and programmed death-1 pathways. Therefore, the global deficiency of chromogranin A impairs recognition of the major diabetogenic antigen insulin, leading to broadly impaired autoimmune responses controlled by multiple regulatory mechanisms.",
author = "Neetu Srivastava and Hao Hu and Vomund, {Anthony N.} and Peterson, {Orion J.} and Baker, {Rocky L.} and Kathryn Haskins and Luc Teyton and Xiaoxiao Wan and Unanue, {Emil R.}",
note = "Funding Information: this project. The authors appreciate the help of Katherine Fredericks (Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO) for the maintenance of the mouse colony and Pavel Zakharov (Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO) for his assistance in some experiments. Funding. This study is supported by grants from the National Institutes of Health (DK058177 and AI114551), Juvenile Diabetes Research Foundation, and Kilo Diabetes and Vascular Research Foundation. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. N.S., X.W., and E.R.U. designed the study, analyzed the data, and wrote and edited the manuscript. N.S., H.H., A.N.V., and O.J.P. performed all the experiments. R.L.B., K.H., and L.T. critically reviewed the manuscript. K.H. provided NOD.ChgA−/− mice. L.T. provided Ins12–20 tetramers. N.S., X.W., and E.R.U. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2021, American Diabetes Association Inc.. All rights reserved.",
year = "2021",
month = dec,
doi = "10.2337/db21-0513",
language = "English",
volume = "70",
pages = "2860--2870",
journal = "Diabetes",
issn = "0012-1797",
number = "12",
}