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1.
Cell Rep ; 43(10): 114810, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39388354

RESUMO

CD4+ T cells play a crucial role in adaptive immune responses and have been implicated in the pathogenesis of autoimmune diseases (ADs). Despite numerous studies, the molecular mechanisms underlying T cell dysregulation in ADs remain incompletely understood. Here, we used chromatin immunoprecipitation (ChIP)-sequencing of active chromatin and transcriptomic data from CD4+ T cells of healthy donors and patients with systemic lupus erythematosus (SLE), psoriasis, juvenile idiopathic arthritis (JIA), and Graves' disease to investigate the role of enhancers in AD pathogenesis. By generating enhancer-based gene regulatory networks (eGRNs), we identified disease-specific dysregulated pathways and potential downstream target genes of enhancers harboring AD-associated single-nucleotide polymorphisms (SNPs), which we also validated using chromatin-capture (HiC) data and CRISPR interference (CRISPRi) in primary CD4+ T cells. Our results suggest that alterations in the regulatory landscapes of CD4+ T cells, including enhancers, contribute to the development of ADs and provide a basis for developing new therapeutic approaches.


Assuntos
Linfócitos T CD4-Positivos , Cromatina , Elementos Facilitadores Genéticos , Humanos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Elementos Facilitadores Genéticos/genética , Cromatina/metabolismo , Polimorfismo de Nucleotídeo Único , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Redes Reguladoras de Genes , Montagem e Desmontagem da Cromatina , Autoimunidade/genética
2.
Front Immunol ; 11: 838, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32477345

RESUMO

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by recessive mutations in the AIRE gene. The hallmark of the disease is the production of highly neutralizing autoantibodies against type I interferons and IL-22. Considering the importance of IL-22 in maintaining mucosal barrier integrity and shaping its microbial community, we sought to study potential changes in the oral cavity in this model of human IL-22 paucity. We found that besides known Th22 cell deficiency, APECED patients have significantly fewer circulating MAIT cells with potential IL-22 secreting capacity. Saliva samples from APECED patients revealed local inflammation, the presence of autoantibodies against IFN-α and IL-22, and alterations in the oral microbiota. Moreover, gene expression data of buccal biopsy samples suggested impaired antimicrobial response and cell proliferation, both of which are processes regulated by IL-22. Our data complement the knowledge gained from mouse models and support the concept of IL-22 being a critical homeostatic cytokine in human mucosal sites.


Assuntos
Interleucinas/deficiência , Interleucinas/imunologia , Microbiota/imunologia , Boca/imunologia , Boca/microbiologia , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Adulto , Autoanticorpos/imunologia , Biópsia , Criança , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Inflamação , Interferon-alfa/imunologia , Masculino , Boca/patologia , Mutação , Saliva/imunologia , Adulto Jovem , Interleucina 22
3.
Eur J Immunol ; 49(5): 790-800, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30801692

RESUMO

STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.


Assuntos
Epigênese Genética , Mutação com Ganho de Função , Predisposição Genética para Doença , Interferons/metabolismo , Fator de Transcrição STAT1/genética , Candidíase Mucocutânea Crônica/etiologia , Candidíase Mucocutânea Crônica/metabolismo , Candidíase Mucocutânea Crônica/patologia , Estudos de Casos e Controles , Sequenciamento de Cromatina por Imunoprecipitação , Regulação da Expressão Gênica , Humanos , Fosforilação , Ligação Proteica , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
4.
Front Immunol ; 9: 2707, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30515176

RESUMO

Vitiligo is a chronic multifactorial depigmentation disorder characterized by the destruction and functional loss of melanocytes. Although a direct cytotoxic T cell attack is thought to be responsible for melanocyte damage, the events leading to the loss of self-tolerance toward melanocytic antigens are not understood. This research aimed to identify novel cellular and molecular factors that participate in vitiligo pathogenesis through the application of gene expression and immunofluorescence analysis of skin biopsy samples along with immunophenotyping of circulating cells. Our study provides insights into the mechanisms involved in melanocyte destruction. The upregulation of stress-ligand MICA/MICB, recognized by activating receptors on innate and innate-like T cells, imply involvement of lymphoid stress surveillance responses in vitiligo lesions. A simultaneous increase in the expression of transcription factor EOMES that is characteristic for innate-like virtual memory T cells, suggest a similar scenario. Local lymphoid stress surveillance has been previously associated with the amplification of systemic humoral responses that were mirrored in our study by increased T follicular helper cells and switched memory B cell proportions in patients with active vitiligo. In addition, microtubule-associated protein light chain 3 staining was compatible with the activation of autophagy in keratinocytes and in the remaining melanocytes of vitiligo lesional skin.


Assuntos
Linfócitos B/imunologia , Imunidade Humoral , Estresse Fisiológico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vitiligo/imunologia , Adulto , Autofagia/imunologia , Linfócitos B/patologia , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Queratinócitos/imunologia , Queratinócitos/patologia , Masculino , Melanócitos/imunologia , Melanócitos/patologia , Pessoa de Meia-Idade , Proteínas com Domínio T/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Vitiligo/patologia
5.
Cytometry A ; 93(11): 1150-1156, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30343519

RESUMO

B cells with regulatory properties have been recently identified and described in different immune disorders, including autoimmunity, infection, cancer, and allergy. in vitro studies of regulatory B cells are usually performed following prolonged cell culture and stimulation in order to obtain B cells capable of IL-10 secretion. We describe the isolation of viable IL-10-positive B cells directly from ex vivo unstimulated samples using the IL-10 secretion assay from Miltenyi Biotec, which was originally designed for IL-10-positive T cell analysis and isolation. IL-10-positive B cells from unstimulated samples represented approximately 2% of all B cells in healthy individuals, suppressed T cell proliferation and were enriched for surface markers of B cell activation. This tool has a potential to boost functional studies of IL-10-secreting B cells in health and disease. © 2018 International Society for Advancement of Cytometry.


Assuntos
Linfócitos B Reguladores/imunologia , Interleucina-10/imunologia , Ativação Linfocitária/imunologia , Proliferação de Células/fisiologia , Citometria de Fluxo/métodos , Humanos , Fenótipo , Linfócitos T/imunologia
7.
PLoS Genet ; 13(3): e1006643, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28248954

RESUMO

Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13.2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases.


Assuntos
Doenças Autoimunes/genética , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Locos de Características Quantitativas/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Mapeamento Cromossômico/métodos , Diabetes Mellitus Tipo 1/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Células HEK293 , Humanos , Fator Regulador 1 de Interferon/genética , Interleucina-27/genética , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas Ribossômicas/genética , Fator de Transcrição STAT1/genética
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