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Expression-Based Genome-Wide Association Study Links Vitamin D–Binding Protein With Autoantigenicity in Type 1 Diabetes

Type 1 diabetes (T1D) is caused by autoreactive T cells that recognize pancreatic islet antigens and destroy insulin-producing β-cells. This attack results from a breakdown in tolerance for self-antigens, which is controlled by ectopic antigen expression in the thymus and pancreatic lymph nodes (PLN...

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Autores principales: Kodama, Keiichi, Zhao, Zhiyuan, Toda, Kyoko, Yip, Linda, Fuhlbrigge, Rebecca, Miao, Dongmei, Fathman, C. Garrison, Yamada, Satoru, Butte, Atul J., Yu, Liping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839207/
https://www.ncbi.nlm.nih.gov/pubmed/26983959
http://dx.doi.org/10.2337/db15-1308
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author Kodama, Keiichi
Zhao, Zhiyuan
Toda, Kyoko
Yip, Linda
Fuhlbrigge, Rebecca
Miao, Dongmei
Fathman, C. Garrison
Yamada, Satoru
Butte, Atul J.
Yu, Liping
author_facet Kodama, Keiichi
Zhao, Zhiyuan
Toda, Kyoko
Yip, Linda
Fuhlbrigge, Rebecca
Miao, Dongmei
Fathman, C. Garrison
Yamada, Satoru
Butte, Atul J.
Yu, Liping
author_sort Kodama, Keiichi
collection PubMed
description Type 1 diabetes (T1D) is caused by autoreactive T cells that recognize pancreatic islet antigens and destroy insulin-producing β-cells. This attack results from a breakdown in tolerance for self-antigens, which is controlled by ectopic antigen expression in the thymus and pancreatic lymph nodes (PLNs). The autoantigens known to be involved include a set of islet proteins, such as insulin, GAD65, IA-2, and ZnT8. In an attempt to identify additional antigenic proteins, we performed an expression-based genome-wide association study using microarray data from 118 arrays of the thymus and PLNs of T1D mice. We ranked all 16,089 protein-coding genes by the likelihood of finding repeated differential expression and the degree of tissue specificity for pancreatic islets. The top autoantigen candidate was vitamin D–binding protein (VDBP). T-cell proliferation assays showed stronger T-cell reactivity to VDBP compared with control stimulations. Higher levels and frequencies of serum anti-VDBP autoantibodies (VDBP-Abs) were identified in patients with T1D (n = 331) than in healthy control subjects (n = 77). Serum vitamin D levels were negatively correlated with VDBP-Ab levels in patients in whom T1D developed during the winter. Immunohistochemical localization revealed that VDBP was specifically expressed in α-cells of pancreatic islets. We propose that VDBP could be an autoantigen in T1D.
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spelling pubmed-48392072017-05-01 Expression-Based Genome-Wide Association Study Links Vitamin D–Binding Protein With Autoantigenicity in Type 1 Diabetes Kodama, Keiichi Zhao, Zhiyuan Toda, Kyoko Yip, Linda Fuhlbrigge, Rebecca Miao, Dongmei Fathman, C. Garrison Yamada, Satoru Butte, Atul J. Yu, Liping Diabetes Immunology and Transplantation Type 1 diabetes (T1D) is caused by autoreactive T cells that recognize pancreatic islet antigens and destroy insulin-producing β-cells. This attack results from a breakdown in tolerance for self-antigens, which is controlled by ectopic antigen expression in the thymus and pancreatic lymph nodes (PLNs). The autoantigens known to be involved include a set of islet proteins, such as insulin, GAD65, IA-2, and ZnT8. In an attempt to identify additional antigenic proteins, we performed an expression-based genome-wide association study using microarray data from 118 arrays of the thymus and PLNs of T1D mice. We ranked all 16,089 protein-coding genes by the likelihood of finding repeated differential expression and the degree of tissue specificity for pancreatic islets. The top autoantigen candidate was vitamin D–binding protein (VDBP). T-cell proliferation assays showed stronger T-cell reactivity to VDBP compared with control stimulations. Higher levels and frequencies of serum anti-VDBP autoantibodies (VDBP-Abs) were identified in patients with T1D (n = 331) than in healthy control subjects (n = 77). Serum vitamin D levels were negatively correlated with VDBP-Ab levels in patients in whom T1D developed during the winter. Immunohistochemical localization revealed that VDBP was specifically expressed in α-cells of pancreatic islets. We propose that VDBP could be an autoantigen in T1D. American Diabetes Association 2016-05 2016-03-16 /pmc/articles/PMC4839207/ /pubmed/26983959 http://dx.doi.org/10.2337/db15-1308 Text en © 2016 by the American Diabetes Association. Readers 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.
spellingShingle Immunology and Transplantation
Kodama, Keiichi
Zhao, Zhiyuan
Toda, Kyoko
Yip, Linda
Fuhlbrigge, Rebecca
Miao, Dongmei
Fathman, C. Garrison
Yamada, Satoru
Butte, Atul J.
Yu, Liping
Expression-Based Genome-Wide Association Study Links Vitamin D–Binding Protein With Autoantigenicity in Type 1 Diabetes
title Expression-Based Genome-Wide Association Study Links Vitamin D–Binding Protein With Autoantigenicity in Type 1 Diabetes
title_full Expression-Based Genome-Wide Association Study Links Vitamin D–Binding Protein With Autoantigenicity in Type 1 Diabetes
title_fullStr Expression-Based Genome-Wide Association Study Links Vitamin D–Binding Protein With Autoantigenicity in Type 1 Diabetes
title_full_unstemmed Expression-Based Genome-Wide Association Study Links Vitamin D–Binding Protein With Autoantigenicity in Type 1 Diabetes
title_short Expression-Based Genome-Wide Association Study Links Vitamin D–Binding Protein With Autoantigenicity in Type 1 Diabetes
title_sort expression-based genome-wide association study links vitamin d–binding protein with autoantigenicity in type 1 diabetes
topic Immunology and Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839207/
https://www.ncbi.nlm.nih.gov/pubmed/26983959
http://dx.doi.org/10.2337/db15-1308
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