Chromogranin A Deficiency Confers Protection from Autoimmune Diabetes Via Multiple Mechanisms
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posted on 2021-09-08, 22:01 authored by Neetu Srivastava, Hao Hu, Anthony N. Vomund, Orion J. Peterson, Rocky L. Baker, Kathryn Haskins, Luc Teyton, Xiaoxiao Wan, Emil R. UnanueRecognition 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.