Humans with the polyendocrine autoimmune disease APECED (or APS-1) harbor mutations in the AIRE gene, which encodes a protein with the structural and functional features of a transcriptional regulatory factor. Mice carrying an engineered null mutation of the a/re locus also develop multi- organ autoimmune disease. Mechanistic studies performed on these mice during the last funding cycle of R01 DK60027 established that aire protects an organism from autoimmunity by promoting the negative selection of differentiating thymocytes. It operates primarily by inducing the expression of transcripts encoding peripheral-tissue antigens, or PTTs, specifically in thymic medullary epithelial cells (MECs). Secondly, it enhances the capacity of MECs to present antigens to T cells and to clonally delete self-reactive thymocytes - via a currently unknown mechanism dissociable from PTT induction. This competitive renewal application proposes to further elucidate these two aspects of aire's mode of action - specifically, we intend: i) to gauge the plasticity of the MEC PTT repertoire; ii) to generalize and localize the antigen-presentation defect exhibited by aire-null MECs; iii) to assess the relevance of aire's role as an E3 ubiquitin ligase. Results from these studies should elucidate critical mechanistic elements of centrally (i.e. thymically) mediated immunological tolerance, potentially improving prospects for preventive or curative therapy for autoimmune diseases such as type-1 diabetes and multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060027-10
Application #
7761708
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Spain, Lisa M
Project Start
2002-03-01
Project End
2011-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
10
Fiscal Year
2010
Total Cost
$327,343
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Bansal, Kushagra; Yoshida, Hideyuki; Benoist, Christophe et al. (2017) The transcriptional regulator Aire binds to and activates super-enhancers. Nat Immunol 18:263-273
Mathis, Diane; Benoist, Christophe (2016) Promiscuity Promotes Tolerance. J Immunol 196:2913-4
Yang, Siyoung; Fujikado, Noriyuki; Kolodin, Dmitriy et al. (2015) Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348:589-94
Yoshida, Hideyuki; Bansal, Kushagra; Schaefer, Uwe et al. (2015) Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells. Proc Natl Acad Sci U S A 112:E4448-57
Meredith, Matthew; Zemmour, David; Mathis, Diane et al. (2015) Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat Immunol 16:942-9
Giraud, Matthieu; Jmari, Nada; Du, Lina et al. (2014) An RNAi screen for Aire cofactors reveals a role for Hnrnpl in polymerase release and Aire-activated ectopic transcription. Proc Natl Acad Sci U S A 111:1491-6
Giraud, Matthieu; Yoshida, Hideyuki; Abramson, Jakub et al. (2012) Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc Natl Acad Sci U S A 109:535-40
Mathis, Diane; Benoist, Christophe (2010) Levees of immunological tolerance. Nat Immunol 11:3-6
Koh, Andrew S; Kingston, Robert E; Benoist, Christophe et al. (2010) Global relevance of Aire binding to hypomethylated lysine-4 of histone-3. Proc Natl Acad Sci U S A 107:13016-21
Guerau-de-Arellano, Mireia; Martinic, Marianne; Benoist, Christophe et al. (2009) Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity. J Exp Med 206:1245-52

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