Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling

Limbach, Maia; Saare, Mario; Tserel, Liina; Kisand, Kai; Eglit, Triin; Sauer, Sascha; Axelsson, Tomas; Syvänen, Ann‐Christine; Metspalu, Andres; Milani, Lili; Peterson, Pärt

doi:10.1016/j.jaut.2015.09.006

Cited by 94 publications

(84 citation statements)

References 51 publications

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“…Several studies have shown that global DNA hypomethylation exists in AITD patients, which may cause the overexpression of some genes involved in immune function or the activation of immune cells and further result in autoimmune attack toward thyroid tissues (74, 75). We previously studied the genome-wide DNA methylation of GD patients and revealed more than 200 hypermethylated and hypomethylated genetic regions in GD patients, such as ICAM1, DNMT1 , and MECP2 genes (74).…”

Section: Epigenetics In Aitdmentioning

confidence: 99%

“…We previously studied the genome-wide DNA methylation of GD patients and revealed more than 200 hypermethylated and hypomethylated genetic regions in GD patients, such as ICAM1, DNMT1 , and MECP2 genes (74). Limbach et al investigated the genome-wide DNA methylation of CD4+ and CD8+ T cells of GD patients and found more than 300 differentially methylated sites in CD4+ T cells and more than 3,000 differentially methylated sites in CD8+ T cells, and many of those genes were from T cell signaling (75). Many of those DNA methylations were immune-related modifications, such as hypermethylated sites in ICAM1, CD247 , and CTLA4 (74, 75).…”

Section: Epigenetics In Aitdmentioning

confidence: 99%

“…In the past decade, epigenetics have been considered to have key roles in integrating genetic and environmental factors in human complex diseases including autoimmune diseases (64, 70, 71). In the past decade, increasing evidence has suggested the critical roles of epigenetics in the pathogenesis of AITD, and epigenetic modifications caused by environmental factors may drive genetically susceptibility individuals to develop AITD (42, 60, 72–75). The aim of this review is to provide an overview of recent advances in the epigenetic mechanisms of AITD, to highlight the epigenetic roles in the pathogenesis of AITD, and to discuss the potential clinical utility of epigenetic modifications in AITD.…”

Section: Introductionmentioning

confidence: 99%

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The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

et al. 2017

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Autoimmune thyroid diseases (AITD) are a group of both B cell- and T cell-mediated organ-specific autoimmune diseases. Graves’ disease and Hashimoto thyroiditis are the two main clinical presentations of AITD. Both genetic and environmental factors have important roles in the development of AITD. Epigenetics have been considered to exert key roles in integrating those genetic and environmental factors, and epigenetic modifications caused by environmental factors may drive genetically susceptibility individuals to develop AITD. Recent studies on the epigenetics of AITD have provided some novel insights into the pathogenesis of AITD. The aim of this review is to provide an overview of recent advances in the epigenetic mechanisms of AITD, such as DNA methylation, histone modifications, and non-coding RNAs. This review highlights the key roles of epigenetics in the pathogenesis of AITD and potential clinical utility. However, the epigenetic roles in AITD are still not fully elucidated, and more researches are needed to provide further deeper insights into the roles of epigenetics in AITD and to uncover new therapeutic targets. Although there are many studies assessing the epigenetic modifications in AITD patients, the clinical utility of epigenetics in AITD remains poorly defined. More studies are needed to identify the underlying epigenetic modifications that can contribute to accurate diagnosis of AITD, adequate choice of treatment approach, and precise prediction of treatment outcomes.

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Section: Epigenetics In Aitdmentioning

confidence: 99%

Section: Epigenetics In Aitdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

et al. 2017

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“…Recently, Limbach et al found hypermethylation of T-cell signaling genes and TSHR gene, suggesting dysregulation in T cell and TSHR signaling in GD patients (38). Stefan et al also reported a genetic–epigenetic interaction involving a non-coding SNP in the TSHR gene that controls thymic TSHR gene expression and promotes escape of TSHR-reactive T cells from central tolerance, triggering GD (39).…”

Section: Genetic Factors In Gdmentioning

confidence: 99%

Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves’ Disease

2016

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Graves’ disease (GD) is an organ-specific autoimmune disease, and thyrotropin (TSH) receptor (TSHR) is a major autoantigen in this condition. Since the extracellular domain of human TSHR (TSHR-ECD) is shed into the circulation, TSHR-ECD is a preferentially immunogenic portion of TSHR. Both genetic factors and environmental factors contribute to development of GD. Inheritance of human leukocyte antigen (HLA) genes, especially HLA-DR3, is associated with GD. TSHR-ECD protein is endocytosed into antigen-presenting cells (APCs), and processed to TSHR-ECD peptides. These peptide epitopes bind to HLA-class II molecules, and subsequently the complex of HLA-class II and TSHR-ECD epitope is presented to CD4+ T cells. The activated CD4+ T cells secrete cytokines/chemokines that stimulate B-cells to produce TSAb, and in turn hyperthyroidism occurs. Numerous studies have been done to identify T- and B-cell epitopes in TSHR-ECD, including (1) in silico, (2) in vitro, (3) in vivo, and (4) clinical experiments. Murine models of GD and HLA-transgenic mice have played a pivotal role in elucidating the immunological mechanisms. To date, linear or conformational epitopes of TSHR-ECD, as well as the molecular structure of the epitope-binding groove in HLA-DR, were reported to be related to the pathogenesis in GD. Dysfunction of central tolerance in the thymus, or in peripheral tolerance, such as regulatory T cells, could allow development of GD. Novel treatments using TSHR antagonists or mutated TSHR peptides have been reported to be effective. We review and update the role of immunogenic TSHR epitopes and HLA in GD, and offer perspectives on TSHR epitope specific treatments.

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“…A Doença de Graves é o protótipo de tal condição: anormalidade autoimune que se origina da produção pelos linfócitos B de anticorpos contra o TSHR (TRAb)6. Perda de peso, agitação, insônia, fadiga, intolerância ao calor, tremores e palpitações são os sintomas mais comuns 7 .…”

Section: Introductionunclassified

Síndrome de Cornélia de Lange e Doença de Graves: uma associação rara

Ferreira¹,

Rebelo

Kahwage

et al. 2018

J Health Biol Sci.

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ResumoIntrodução: A síndrome de Cornelia de Lange (SCdL) corresponde a uma condição rara caracterizada por mutações nos genes responsáveis pelas proteínas estruturais e reguladoras do complexo da coesina, levando o paciente à distrofia facial e aos atrasos no crescimento e desenvolvimento. Seu diagnóstico é baseado nos achados clínicos e/ou a identificação da heterozigose patogênica variante em N1PBL, RAD21, ou SMC3 ou homozigose patogênica variante em HDAC8 ou SMC1A. Essa síndrome possui um amplo espectro de manifestações que incluem anormalidades neurológicas, endocrinológicas, musculoesqueléticas e cutâneas. A Doença de Graves, por sua vez, representa o expoente mais comum de hipertireodismo, possui origem autoimune e resulta de uma complexa interação entre fatores genéticos e ambientais. Relato de caso: Este artigo tem por objetivo relatar um caso de uma paciente de 22 anos com diagnóstico de SCdL, a qual abriu o quadro de hipertireoidismo por Doença de Graves, apresentando insônia, irritabilidade e agitação, com melhora após tratamento medicamentoso. Palavras-chave:Hipertireoidismo. Síndrome de Cornélia de Lange. Doença de Graves. AbstractIntroduction: The Cornelia de Lange syndrome is a rare condition characterized by mutations in genes responsible for structural and regulatory proteins of the coesin complex, causing facial dystrophy, delays in development and growth. Your Diagnosis is based on clinical findings and/or the identification of a heterozygous pathogenic variant in NIPBL, RAD21 and SMC3 or a hemizyous pathogenic variant in HDAC8 or SMC1A. This syndrome has a wide spectrum of manifestations that includes neurological, endocrinological, muscle-skeletal and cutaneous abnormalities. Graves' disease, in turn, represents the most common etiology of hyperthyroidism; it has an autoimmune origin and results from a complex interaction between genetic and environmental factors. Case report: Therefore, the current study aims to report a case of a 22-year-old female with diagnosis of Graves' disease, presenting insomnia, irritability and restlessness with improvement after drug treatment.

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Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling

Cited by 94 publications

References 51 publications

The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves’ Disease

Síndrome de Cornélia de Lange e Doença de Graves: uma associação rara

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