Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms

Neetu Srivastava, Hao Hu, Anthony N. Vomund, Orion J. Peterson, Rocky L. Baker, Kathryn Haskins, Luc Teyton, Xiaoxiao Wan, Emil R. Unanue

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2860-2870
Number of pages11
JournalDiabetes
Volume70
Issue number12
DOIs
StatePublished - Dec 2021

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