Anti-CD45RC mAb controls APECED disease
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ABSTRACT:
PROVIDER: PRJEB43753 | ENA |
REPOSITORIES: ENA
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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. Keywords: patient vs. healthy control comparative analysis
2008-10-01 | GSE11309 | GEO
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
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
Project description:Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX to those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multi-omic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs lost their phenotypic and functional markers including CD25 and often also FOXP3. Functional experiments with CRISPR/Cas9-mediated FOXP3 knock-out Treg and Tregs from patients with IPEX indicated that the patients’ Tregs gain a Th2 skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation, indicated that Tregs expressing non-mutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. Collectively, we describe Treg instability and Teff autoreactivity in patients with IPEX. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.
2023-12-20 | GSE247274 | GEO
Project description:Down syndrome (DS) patients frequently develop organ-specific autoimmune disorders, particularly endocrinopathies and coeliac disease, as well as an increased susceptibility to mucosal candidiasis. These clinical features resemble APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy), a monogenic condition due to mutations in the AIRE gene, located on 21q22.3 and already described as down-regulated in 21 trisomy. Here we investigated AIRE expression and global gene expression profiles in surgically removed thymuses from 14 DS infants and children with congenital heart defects and from 42 age-matched individuals with cardiac defect as an isolated malformation. Immunohistochemistry revealed significantly reduced AIRE expression in DS thymuses (70.48M-BM-149.59 positive cells/mm2 in DS X 154.70M-BM-161.16 in controls, p<0.0001). qPCR confirmed the lower expression of AIRE in DS thymuses. Global thymic RNA profiles from DS patients and controls revealed 407 genes significantly hypoexpressed in DS. Network transcriptional analysis showed that hypoexpressed genes are related to biological processes such as antigen processing and presentation of endogenous antigen (ERAP2, CD1D), negative (PRDX2) and positive (CD3D, CD74) thymic T-cell selection and homeostasis of number of cells (PRDX2). Altogether these findings may explain the high prevalence of autoimmune phenomena in DS patients. Moreover, our data are in accordance with previous findings of thymic abnormal development in DS patients, characterized by lymphocyte depletion, diminution of the cortex, and loss of corticomedullary demarcation. Global gene profiles indicate that in DS patients, the trisomic imbalance probably leads to thymic hypofunction. In conclusion, lower AIRE expression and the impairment of other crucial pathways for central tolerance could well explain the high prevalence of organ-specific autoimmune disorders in DS. Among the 14 DS infants and 42 age-matched individuals with cardiac defect, only 4 from each group provided enough biological material (thymus fragments) for isolation of high-quality RNA to perform array analysis. Eight thymic samples were analyzed: C1, C2, C3 and C4 are controls, and D1, D2, D3 and D4 are from patients with Down syndrome.
2011-11-28 | E-GEOD-23910 | biostudies-arrayexpress
Project description:The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T-cells by promoting the ectopic expression of tissue-specific genes in thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA-seq, we found that the inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by topoisomerase 1 (TOP1) inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional upregulation to co-occur with the chromatin structural changes within the genomic cluster of carcino-embryonic antigen-like cellular adhesion molecule (CEACAM) genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes.
2017-03-13 | GSE76240 | GEO
Project description:The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T-cells by promoting the ectopic expression of tissue-specific genes in thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA-seq, we found that the inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by topoisomerase 1 (TOP1) inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional upregulation to co-occur with the chromatin structural changes within the genomic cluster of carcino-embryonic antigen-like cellular adhesion molecule (CEACAM) genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes.
2017-03-13 | GSE89892 | GEO
Project description:Down syndrome (DS) patients frequently develop organ-specific autoimmune disorders, particularly endocrinopathies and coeliac disease, as well as an increased susceptibility to mucosal candidiasis. These clinical features resemble APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy), a monogenic condition due to mutations in the AIRE gene, located on 21q22.3 and already described as down-regulated in 21 trisomy. Here we investigated AIRE expression and global gene expression profiles in surgically removed thymuses from 14 DS infants and children with congenital heart defects and from 42 age-matched individuals with cardiac defect as an isolated malformation. Immunohistochemistry revealed significantly reduced AIRE expression in DS thymuses (70.48±49.59 positive cells/mm2 in DS X 154.70±61.16 in controls, p<0.0001). qPCR confirmed the lower expression of AIRE in DS thymuses. Global thymic RNA profiles from DS patients and controls revealed 407 genes significantly hypoexpressed in DS. Network transcriptional analysis showed that hypoexpressed genes are related to biological processes such as antigen processing and presentation of endogenous antigen (ERAP2, CD1D), negative (PRDX2) and positive (CD3D, CD74) thymic T-cell selection and homeostasis of number of cells (PRDX2). Altogether these findings may explain the high prevalence of autoimmune phenomena in DS patients. Moreover, our data are in accordance with previous findings of thymic abnormal development in DS patients, characterized by lymphocyte depletion, diminution of the cortex, and loss of corticomedullary demarcation. Global gene profiles indicate that in DS patients, the trisomic imbalance probably leads to thymic hypofunction. In conclusion, lower AIRE expression and the impairment of other crucial pathways for central tolerance could well explain the high prevalence of organ-specific autoimmune disorders in DS.
2011-11-28 | GSE23910 | GEO
Project description:CD25 monoclonal antibody binding to the alpha-chain of the Interleukin-2 (IL-2) receptor, blocks high affinity IL-2 binding thereby preventing complete T cell activation and being of ample importance in transplantation medicine and potentially the treatment of autoimmune disease. However, CD25 antibodies do not only block T cell activation but also prevent activation induced cell death (AICD) attributing a dual function to IL-2. In this study, the modulation of the genomic expression profile of human peripheral blood mononuclear cells (PBMC) with therapeutic concentrations of humanized anti-CD25 mAb was investigated. PBMC were stimulated with CD3 antibody OKT-3 together with recombinant IL-2 in the absence or presence of anti-CD25 mAb. RNA was extracted and subjected to microarray analysis on U133A microarrays (Affymetrix). The expression profile revealed the up-regulation of 62 genes and down-regulation of 38 genes by anti-CD25 mAb, respectively. Experiment Overall Design: Peripheral blood mononuclear cells (PBMC) were stimulated for 8 or 16 hrs with 100 ng/ml OKT-3 together with 100 U/ml recombinant human interleukin-2 (rhIL-2) in the absence or presence of 30 µg/ml anti-CD25 antibody. RNA from cells under such treatment was isolated with Trizol and subjected to microarray analysis onto human U133A microarray following the Affymetrix protocol.
2009-05-11 | E-GEOD-15928 | biostudies-arrayexpress