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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Sex Bias in CNS Autoimmune Disease Mediated by Androgen Control of Autoimmune Regulator

ABSTRACT: Male gender is protective against multiple sclerosis and other T cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well-understood. Autoimmune Regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here, we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared to females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity. RNA-seq comparison of male vs. female expression in mTEC cells. Pools of 10 mice each were used for each replicate (two for male and two for female)

ORGANISM(S): Mus musculus

SUBMITTER: Joshua Starmer

PROVIDER: E-GEOD-79014 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Similar Datasets

Sex Bias in CNS Autoimmune Disease Mediated by Androgen Control of Autoimmune Regulator

Project description:Male gender is protective against multiple sclerosis and other T cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well-understood. Autoimmune Regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here, we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared to females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity.

2016-03-09 | GSE79014 | GEO

Identification of a novel Aire-regulating cis-regulatory element using H3K27ac ChIP-seq

Project description:Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. We used sequence conservation analysis and ChIP-seq against the enhancer-associated histone mark H3K27ac to identify a candidate Aire cis-regulatory element. There is enrichment of H3K27ac near this element, ACNS1, in mTECs and the element also has characteristics of being NF-ÎºB-responsive. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance. Two experimental groups (GFP neg mTECs and GFP pos mTECs), each with three samples, and one control sample (D10 Th2 cells).

2015-10-23 | E-GEOD-74257 | biostudies-arrayexpress

The role of Autoimmune regulator (Aire) gene in the control of adhesion between medullary thymic epithelial cells and thymocytes

Project description:The crosstalk between thymocytes and thymic epithelial cells is critical for T cell development and establishment of central tolerance. Although the role of Autoimmune Regulator (Aire) gene in the induction of central tolerance is well known, the precise cellular and molecular mechanisms by which Aire controls the ectopic expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (mTECS) remain unclear. In this study we performed a functional assay with fresh thymocytes dissociated from a normal mouse thymus co-cultured with a Mus musculus mTEC cell line - named 3.10 mTEC line - , in which we had previously knocked-down Aire gene by means of siRNA transfection. Agilent Mouse Gene Expression microarrays were used to determine the large scale transcriptional expression profiles of control and Aire-knockdown 3.10 mTECs co-cultured with thymocytes.

2016-06-27 | E-MTAB-4595 | biostudies-arrayexpress

Sirt1 is essential for Aire-mediated induction of central immunological tolerance

Project description:Autoimmune regulator (Aire) is a unique transcriptional regulator that induces promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for induction of immunological self-tolerance. Although several recent studies provided very important molecular insights into how Aire operates, a more comprehensive understanding of this process still remains elusive. Here we demonstrate that a lysine deacetylase Sirtuin-1 (Sirt1) is predominantly expressed in mature Aire+ mTECs, where it is required for expression of Aire-dependent TRA genes and a subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and uncovers a unique functional role for Sirt1 in preventing organ-specific autoimmunity. ~100ng of total RNA isolated by Trizol extraction from MHC-II low and high mTECs (pool of 3 mice) was used to generate poly-A-selected transcriptome libraries using the non-directionnal TruSeq V3 RNA Sample Prep Kit (without additional pre-amplification) following the manufacturer's protocols. Enrichment of DNA fragment with adapter molecules on both ends was done using 15 cycles of PCR amplification using the Illumina PCR mix and primer cocktail. Paired-end (2 × 100 bp) sequencing was performed using the Illumina HiSeq2000 machine.

2015-05-25 | E-GEOD-68190 | biostudies-arrayexpress

Identification of a novel Aire-regulating cis-regulatory element using H3K27ac ChIP-seq

Project description:Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. We used sequence conservation analysis and ChIP-seq against the enhancer-associated histone mark H3K27ac to identify a candidate Aire cis-regulatory element. There is enrichment of H3K27ac near this element, ACNS1, in mTECs and the element also has characteristics of being NF-κB-responsive. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.

2015-10-23 | GSE74257 | GEO

RNA-sequencing of bulk CD19+ Thymic B cells from young (3 month - 4 year) and old (42 - 61 years) humans

Project description:Thymic B cells have been recently shown the ability to be licensed to express Aire, a critical transcription factor involved in the expression of self-antigens in the thymus which are critical for clonal deletion of autoreactive T cells and maintenance of self-tolerance. Mutations in AIRE cause systemic autoimmunity in humans and autoimmunity with varying degrees of severity in different mouse strains. Thymic B cells have been studied in young animals, but studies of this population with age are lacking. Given the thymus undergoes age-associated atrophy in its stromal compartment, we hypothesized that aged thymic B cells may under go changes with age which may impact their ability to mediate clonal deletion of autoreactive T cells and may contribute to age-associated increases in autoimmune prevalence. By comparing the transcriptome of young and aged thymic B cells we find that Aire and transcriptional activators of Aire are signficantly decreased with age.

2018-01-30 | GSE107111 | GEO

RNA-sequencing of bulk CD19+ Thymic B cells from young (5 week) and aged (10-24 month) mice

2018-01-30 | GSE107110 | GEO

mRNA expression profile of medullary thymic epithelial cells-mTECs- of BALBc mice

Project description:The medullary thymic epithelial cells (mTECs) express virtually all autoantigens of the body. This phenomenon was then termed promiscuous gene expression (PGE). A large set of autoantigen genes (but not all) is controlled by the transcriptional modulator Autoimmune regulator (Aire) in mTECs. These autoantigens represent all tissues and organs in the thymus and it is implicated in the negative selection of autoreactive thymocytes, and consequantly preventing autoreactive autoimmune reactions and autoimmune diseases (e.g. type 1 diabetes mellitus, systemic lupus erythematosus). Thus, we are looking at gene expression in thse cells because it is very important to better understand the molecular basis of central immune tolerance to normal tissues and organs. The aim of this study is to evaluate the possible link between the expression of the transcriptional regulator Aire, the genetic background of mouse strains and the promiscuous gene expression in mTECs.

2014-04-18 | E-MEXP-3881 | biostudies-arrayexpress

Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance [Ikaros scATAC-seq]

Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.

2023-10-25 | GSE238149 | GEO

Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance [Pou2f3 RNA-seq]

2023-10-25 | GSE238148 | GEO

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