Aire is a transcriptional regulator that controls immunological tolerance by driving the expression of a large repertoire of gene transcripts encoding peripheral-tissue self-antigens in thymic medullary epithelial cells (MECs), thereby promoting the clonal deletion of thymocytes capable of recognizing these self-antigens. Mutations in the AIRE gene underlie a rare multi-organ autoimmune disease called APECED or APS-1, and abnormalities in the Aire-pathway have also been implicated in certain of the more common autoimmune disorders, notably type-1 diabetes and myasthenia gravis. The project proposed herein will focus on the novel, very surprising, finding that Aire's impact on immunological tolerance has an intriguing temporal window: its expression during the perinatal period is necessary and sufficient to avoid the multi-organ autoimmune disease typical of aire-knockout mice. Hence, the project's overall goal is to understand why Aire must be expressed in perinatal mice to guard against autoimmunity, but is dispensable in adults.
Its Specific Aims are: 1. To compare the repertoires of Aire-dependent MEC transcripts from adult and perinatal mice;2. To assess the effect of aire gene shutdown in adults versus perinates on emerging self-reactive effector T cells;and 3. To evaluate the influence of aire turnoff in adult vs. perinatal mice on the emerging repertoire of regulatory T cells. Results from these studies will not only elucidate the nature of the temporal window of Aire's impact on immunological tolerance but, more generally, should yield new insights into neonatal tolerance, which has fascinated immunologists for decades. In addition, it may be worth emphasizing the wealth of entirely novel data that will come from the RNAseq studies under Aim 1, independent of whether or not they also reveal differences in the repertories of adult and perinatal MEC transcripts. For example, we will learn, for the first time, whether Aire has an impact on microRNA expression in MECs and to what extent it also influences transcript splicing. Autoimmune diseases afflict 7-10% of Americans, and are increasing in incidence. It is imperative to learn how to re-establish immunological tolerance in individuals with autoimmune disorders - understanding tolerance mechanisms will undoubtedly advance this goal.
This study focuses on the cellular mechanisms of Aire, the protein encoded by the gene mutated in individuals with APECED (or APS-1), a primary immunodeficiency disease characterized by multi-organ autoimmunity. While APECED patients are rather rare, the supposition is that, as is often the case, insights into its molecular etiology will be applicable to more common diseases;indeed, genetic studies on several human autoimmune disorders, notably type-1 diabetes and myasthenia gravis, have revealed that they also, at least partially, reflect defects in the Aire-dependent pathway of immunological tolerance. Targeting of new cellular and molecular interactions and pathways highlighted in this study may have therapeutic potential;in addition, we should also learn about the optimum points for intervening in disease course.
|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|