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Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes
OBJECTIVE: Tissue-specific self-antigens are ectopically expressed within the thymus and play an important role in the induction of central tolerance. Insulin is expressed in both pancreatic islets and the thymus and is considered to be the primary antigen for type 1 diabetes. Here, we report the ro...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279543/ https://www.ncbi.nlm.nih.gov/pubmed/20682694 http://dx.doi.org/10.2337/db10-0476 |
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author | Noso, Shinsuke Kataoka, Kohsuke Kawabata, Yumiko Babaya, Naru Hiromine, Yoshihisa Yamaji, Kaori Fujisawa, Tomomi Aramata, Shinsaku Kudo, Takashi Takahashi, Satoru Ikegami, Hiroshi |
author_facet | Noso, Shinsuke Kataoka, Kohsuke Kawabata, Yumiko Babaya, Naru Hiromine, Yoshihisa Yamaji, Kaori Fujisawa, Tomomi Aramata, Shinsaku Kudo, Takashi Takahashi, Satoru Ikegami, Hiroshi |
author_sort | Noso, Shinsuke |
collection | PubMed |
description | OBJECTIVE: Tissue-specific self-antigens are ectopically expressed within the thymus and play an important role in the induction of central tolerance. Insulin is expressed in both pancreatic islets and the thymus and is considered to be the primary antigen for type 1 diabetes. Here, we report the role of the insulin transactivator MafA in the expression of insulin in the thymus and susceptibility to type 1 diabetes. RESEARCH DESIGN AND METHODS: The expression profiles of transcriptional factors (Pdx1, NeuroD, Mafa, and Aire) in pancreatic islets and the thymus were examined in nonobese diabetic (NOD) and control mice. Thymic Ins2 expression and serum autoantibodies were examined in Mafa knockout mice. Luciferase reporter assay was performed for newly identified polymorphisms of mouse Mafa and human MAFA. A case-control study was applied for human MAFA polymorphisms. RESULTS: Mafa, Ins2, and Aire expression was detected in the thymus. Mafa expression was lower in NOD thymus than in the control and was correlated with Ins2 expression. Targeted disruption of MafA reduced thymic Ins2 expression and induced autoantibodies against pancreatic islets. Functional polymorphisms of MafA were newly identified in NOD mice and humans, and polymorphisms of human MAFA were associated with susceptibility to type 1 diabetes but not to autoimmune thyroid disease. CONCLUSIONS: These data indicate that functional polymorphisms of MafA are associated with reduced expression of insulin in the thymus and susceptibility to type 1 diabetes in the NOD mouse as well as human type 1 diabetes. |
format | Online Article Text |
id | pubmed-3279543 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-32795432012-02-16 Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes Noso, Shinsuke Kataoka, Kohsuke Kawabata, Yumiko Babaya, Naru Hiromine, Yoshihisa Yamaji, Kaori Fujisawa, Tomomi Aramata, Shinsaku Kudo, Takashi Takahashi, Satoru Ikegami, Hiroshi Diabetes Immunology and Transplantation OBJECTIVE: Tissue-specific self-antigens are ectopically expressed within the thymus and play an important role in the induction of central tolerance. Insulin is expressed in both pancreatic islets and the thymus and is considered to be the primary antigen for type 1 diabetes. Here, we report the role of the insulin transactivator MafA in the expression of insulin in the thymus and susceptibility to type 1 diabetes. RESEARCH DESIGN AND METHODS: The expression profiles of transcriptional factors (Pdx1, NeuroD, Mafa, and Aire) in pancreatic islets and the thymus were examined in nonobese diabetic (NOD) and control mice. Thymic Ins2 expression and serum autoantibodies were examined in Mafa knockout mice. Luciferase reporter assay was performed for newly identified polymorphisms of mouse Mafa and human MAFA. A case-control study was applied for human MAFA polymorphisms. RESULTS: Mafa, Ins2, and Aire expression was detected in the thymus. Mafa expression was lower in NOD thymus than in the control and was correlated with Ins2 expression. Targeted disruption of MafA reduced thymic Ins2 expression and induced autoantibodies against pancreatic islets. Functional polymorphisms of MafA were newly identified in NOD mice and humans, and polymorphisms of human MAFA were associated with susceptibility to type 1 diabetes but not to autoimmune thyroid disease. CONCLUSIONS: These data indicate that functional polymorphisms of MafA are associated with reduced expression of insulin in the thymus and susceptibility to type 1 diabetes in the NOD mouse as well as human type 1 diabetes. American Diabetes Association 2010-10 2010-08-03 /pmc/articles/PMC3279543/ /pubmed/20682694 http://dx.doi.org/10.2337/db10-0476 Text en © 2010 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. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Immunology and Transplantation Noso, Shinsuke Kataoka, Kohsuke Kawabata, Yumiko Babaya, Naru Hiromine, Yoshihisa Yamaji, Kaori Fujisawa, Tomomi Aramata, Shinsaku Kudo, Takashi Takahashi, Satoru Ikegami, Hiroshi Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes |
title | Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes |
title_full | Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes |
title_fullStr | Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes |
title_full_unstemmed | Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes |
title_short | Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes |
title_sort | insulin transactivator mafa regulates intrathymic expression of insulin and affects susceptibility to type 1 diabetes |
topic | Immunology and Transplantation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279543/ https://www.ncbi.nlm.nih.gov/pubmed/20682694 http://dx.doi.org/10.2337/db10-0476 |
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