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Expression data from WT and Aire deficient mTECs

ABSTRACT: Aire is an important transcription regulator that mediates a role in central tolerance via promoting the promiscuous expression of tissue-specific antigens in the thymus. Although several mouse models of Aire-deficiency have been described, none has analysed the phenotype induced by a mutation that emulates the common 13bp deletion in human APECED by disrupting the first PHD domain in exon 8. Aire-deficient mice with a corresponding mutation showed some disturbance of the medullary epithelial compartment, but at the phenotypic level their T cell compartment appeared relatively normal in the thymus and periphery. An increase in the number of activated T cells was evident, and autoantibodies against several organs were detected. At the histological level, lymphocytic infiltration of several organs indicated the development of autoimmunity, though symptoms were mild and quality of life for Aire-deficient mice appeared equivalent to wild-type littermates, with the exception of male infertility. Vbeta and CDR3 length analysis suggested that each Aire-deficient mouse developed it own polyclonal autoimmune repertoire. Finally, given the prevalence of candidiasis in APECED patients, we examined the control of infection with Candida albicans in Aire-deficient mice. No increase in disease susceptibility was found for either oral or systematic infection. These observations support the view that additional genetic and/or environmental factors contribute substantially to the overt nature of autoimmunity associated with Aire mutations, even for mutations identical to those found in humans with APECED. Keywords: Gene expression comparison between genotypes

ORGANISM(S): Mus musculus

PROVIDER: GSE14365 | GEO | 2009/03/15

SECONDARY ACCESSION(S): PRJNA111403

REPOSITORIES: GEO

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Expression data from WT and Aire deficient mTECs

Project description:Aire is an important transcription regulator that mediates a role in central tolerance via promoting the promiscuous expression of tissue-specific antigens in the thymus. Although several mouse models of Aire-deficiency have been described, none has analysed the phenotype induced by a mutation that emulates the common 13bp deletion in human APECED by disrupting the first PHD domain in exon 8. Aire-deficient mice with a corresponding mutation showed some disturbance of the medullary epithelial compartment, but at the phenotypic level their T cell compartment appeared relatively normal in the thymus and periphery. An increase in the number of activated T cells was evident, and autoantibodies against several organs were detected. At the histological level, lymphocytic infiltration of several organs indicated the development of autoimmunity, though symptoms were mild and quality of life for Aire-deficient mice appeared equivalent to wild-type littermates, with the exception of male infertility. Vbeta and CDR3 length analysis suggested that each Aire-deficient mouse developed it own polyclonal autoimmune repertoire. Finally, given the prevalence of candidiasis in APECED patients, we examined the control of infection with Candida albicans in Aire-deficient mice. No increase in disease susceptibility was found for either oral or systematic infection. These observations support the view that additional genetic and/or environmental factors contribute substantially to the overt nature of autoimmunity associated with Aire mutations, even for mutations identical to those found in humans with APECED. Keywords: Gene expression comparison between genotypes In this experiment there are 5 samples altogether which consist of two biological replicates of Aire knock-out mTECs and 3 biological replicates of wild type mTECs.

2009-03-15 | E-GEOD-14365 | biostudies-arrayexpress

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

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. 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)

2016-03-09 | E-GEOD-79014 | biostudies-arrayexpress

Protein microarray (Protoarray, Invitrogen) screening with APECED patient, healthy relative and healthy control serum samples

Project description:APECED is a monogenic autoimmune disease caused by defects in Autoimmune Regulator (AIRE) gene that promotes the expression of self-antigens in the thymus. The autoimmune phenotype in APECED is variable, and multiple proteins are targeted by autoantibodies. This study used human protein arrays to screen autoantibody targets in APECED and to identify novel autoimmune targets. Altogether 100 sera samples from 82 individual APECED patients were profiled using Protoarray antibody specificity service at Invitrogen as well as samples from 12 healthy controls and 8 healthy relatives. The protein arrays (ProtoArray v5.1) were probed as described in Invitrogenâs protocol for Immune Response BioMarker Profiling using detection reagent (Alexa Fluor 647 Goat Anti-Human IgG A21445, Invitrogen) and blocking buffer (Blocking Buffer Kit PA055, Invitrogen). Arrays were scanned using a GenePix 4000B fluorescent scanner, and the data was acquired with GenePixÂ® Pro software. The arrays were probed with sera at a dilution of 1:500.

2017-10-01 | E-MTAB-5369 | biostudies-arrayexpress

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

2016-03-09 | GSE79014 | GEO

Aberrant type 1 immunity drives mucosal fungal infection susceptibility

Project description:The objective of this study was to understand the impact of autoimmune regulator (AIRE) on immunity against oral Candida albicans infection. Previous work indicated that autoantibodies against IL-17 and IL-22 may contribute to host susceptibility; however, there is not a 100% correlation between autoantibodies and mucosal candidiasis in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) patients, indicating that other pathways may be affected. Using a mouse model that very closely mimics what is seen in APECED patients, oral epithelial cells were sorted and RNA extracted from them to perform RNA-seq analysis to determine what other pathways may be involved. These data show that the type II interferon pathway is highly upregulated in Aire-deficient mice, while the IL-17R pathway is intact.

2021-08-11 | GSE133603 | GEO

In vitro monocyte-differentiated dendritic cells (moDCs) obtained from APECED patients and healthy controls.

2008-10-01 | GSE11309 | GEO

Transcription profiling by array of human APECED patients in vitro monocyte-differentiated dendritic cells vs. healthy controls

Project description:Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the AIRE gene. AIRE functions as a transcriptional regulator and it has a central role in the development of immunological tolerance. AIRE regulates the expression of ectopic antigens in epithelial cells of the thymic medulla and has been shown to participate in the development of peripheral tolerance. However, the mechanism of action of AIRE has remained elusive. To further investigate the role of AIRE in host immune functions, using microarray technology, we studied the properties and transcript profiles in in vitro monocyte-differentiated dendritic cells (moDCs) obtained from APECED patients and healthy controls. Experiment Overall Design: This study includes three female APECED patients between the ages of 26 and 51 years and all patients carried the homozygote FinnMajor mutation (R257X) in the AIRE gene. As controls, we used buffy coats from helathy voluntary blood donors obtained from the Finnish Red Cross Transfusion Service (Helsinki, Finland). The controls were sex- and age-matched. Peripheral blood mononuclear cells (PBMC) were isolated from these subjects. The PBMCs were stimulated to differentiate into mature moDCs. RNA harvested from these cells was labeled and hybridized into microarrays. Part of the cells were treated with candida albicans. RNA from these cells was similarly labeled and studied with mocroarrays.

2008-10-26 | E-GEOD-11309 | biostudies-arrayexpress

Aire+ Cell Depletioin Results in Expansion of Activated T Cells in Pregnant Mice

Project description:We explored the role of the autoimmune regulator (Aire) gene in supporting fetal tolerance during pregnancy with transgenic diphtheria toxin receptor (Aire-DTR) mice, in which Aire-expressing populations can be deleted by injection of diptheria toxins (DT). Aire-expressing cell depletion was found to cause intruterine growth restriction (IUGR) in both allogenic and syngeneic pregnancies. This phenotype is immune-mediated, as IUGR is rescued in Rag1-deficient mice, and involves a memory response, as demonstrated by severe IUGR in second pregnancies. We further explored this phenotype through single-cell RNA sequencing of leukocytes obtained from the secondary lymphoid organs (uterine and non-uterine-draining lymph nodes) of wild-type (WT) and Aire-DTR pregnant dams during allogeneic pregnancy. Transciptomic data reveals a shift in population distributions from naïve to effector CD4+ and CD8+ T cells in Aire-DTR mice. Within the effector CD4+ compartment, there was a significant shift away from Tregs and toward mature T effectors, most notably T follicular helper (Tfh) and Th17 cells. These findings support the idea that Aire is essential in maintaining immune homeostasis.

2021-05-18 | GSE174521 | GEO

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