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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2016
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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. |
format | Online Article Text |
id | pubmed-4839207 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
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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