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Chromogranin A Deficiency Confers Protection from Autoimmune Diabetes Via Multiple Mechanisms

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posted on 08.09.2021, 22:01 by Neetu Srivastava, Hao Hu, Anthony N. Vomund, Orion J. Peterson, Rocky L. Baker, Kathryn Haskins, Luc Teyton, Xiaoxiao Wan, Emil R. Unanue
Recognition of beta-cell antigens by autoreactive T cells is a critical step in the initiation of autoimmune Type1 diabetes (T1D). A complete protection from diabetes development in non-obese diabetic (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 TGFb and PD-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.

Funding

This study is supported by grants from NIH (DK058177 and AI114551), Juvenile Diabetes Research Foundation, and Kilo Diabetes and Vascular Research Foundation.

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