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Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms

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....

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Autores principales: Srivastava, Neetu, Hu, Hao, Vomund, Anthony N., Peterson, Orion J., Baker, Rocky L., Haskins, Kathryn, Teyton, Luc, Wan, Xiaoxiao, Unanue, Emil R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660984/
https://www.ncbi.nlm.nih.gov/pubmed/34497137
http://dx.doi.org/10.2337/db21-0513
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author Srivastava, Neetu
Hu, Hao
Vomund, Anthony N.
Peterson, Orion J.
Baker, Rocky L.
Haskins, Kathryn
Teyton, Luc
Wan, Xiaoxiao
Unanue, Emil R.
author_facet Srivastava, Neetu
Hu, Hao
Vomund, Anthony N.
Peterson, Orion J.
Baker, Rocky L.
Haskins, Kathryn
Teyton, Luc
Wan, Xiaoxiao
Unanue, Emil R.
author_sort Srivastava, Neetu
collection PubMed
description 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.
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spelling pubmed-86609842021-12-27 Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms Srivastava, Neetu Hu, Hao Vomund, Anthony N. Peterson, Orion J. Baker, Rocky L. Haskins, Kathryn Teyton, Luc Wan, Xiaoxiao Unanue, Emil R. Diabetes Immunology and Transplantation 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. American Diabetes Association 2021-12 2021-09-08 /pmc/articles/PMC8660984/ /pubmed/34497137 http://dx.doi.org/10.2337/db21-0513 Text en © 2021 by the American Diabetes Association https://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.
spellingShingle Immunology and Transplantation
Srivastava, Neetu
Hu, Hao
Vomund, Anthony N.
Peterson, Orion J.
Baker, Rocky L.
Haskins, Kathryn
Teyton, Luc
Wan, Xiaoxiao
Unanue, Emil R.
Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms
title Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms
title_full Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms
title_fullStr Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms
title_full_unstemmed Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms
title_short Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms
title_sort chromogranin a deficiency confers protection from autoimmune diabetes via multiple mechanisms
topic Immunology and Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660984/
https://www.ncbi.nlm.nih.gov/pubmed/34497137
http://dx.doi.org/10.2337/db21-0513
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