DNA Methylation of T Lymphocytes as a Therapeutic Target: Implications for Rheumatoid Arthritis Etiology

Zhao, Jianan; Wei, Kai; Chang, Cen; Xu, Lingxia; Jiang, Ping; Guo, Shicheng; Schrodi, Steven J.; He, Dongyi

doi:10.3389/fimmu.2022.863703

Cited by 15 publications

(13 citation statements)

References 157 publications

(127 reference statements)

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“…The inhibition of epigenetic regulators may also be skillfully used to obtain the desired functional profile of T cells suitable for treatment of endometriosis. Inhibitors of DNA methyltransferase (e.g., 5′-azacytidine), histone deacetylase (e.g., valproic acid), histone methyltransferase (e.g., BIX-01294), and histone demethylase (e.g., tranylcypromine) should be considered (343,344). Remarkable developments in the basic understanding and tools for reprogramming have begun to show the clinical impact of cellular reprogramming.…”

Section: Overview Of T-cell Reprogrammingmentioning

confidence: 99%

Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity

Szukiewicz

2022

Front. Immunol.

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Endometriosis is defined as the presence of endometrial-like glands and stroma located outside the uterine cavity. This common, estrogen dependent, inflammatory condition affects up to 15% of reproductive-aged women and is a well-recognized cause of chronic pelvic pain and infertility. Despite the still unknown etiology of endometriosis, much evidence suggests the participation of epigenetic mechanisms in the disease etiopathogenesis. The main rationale is based on the fact that heritable phenotype changes that do not involve alterations in the DNA sequence are common triggers for hormonal, immunological, and inflammatory disorders, which play a key role in the formation of endometriotic foci. Epigenetic mechanisms regulating T-cell responses, including DNA methylation and posttranslational histone modifications, deserve attention because tissue-resident T lymphocytes work in concert with organ structural cells to generate appropriate immune responses and are functionally shaped by organ-specific environmental conditions. Thus, a failure to precisely regulate immune cell transcription may result in compromised immunological integrity of the organ with an increased risk of inflammatory disorders. The coexistence of endometriosis and autoimmunity is a well-known occurrence. Recent research results indicate regulatory T-cell (Treg) alterations in endometriosis, and an increased number of highly active Tregs and macrophages have been found in peritoneal fluid from women with endometriosis. Elimination of the regulatory function of T cells and an imbalance between T helper cells of the Th1 and Th2 types have been reported in the endometria of women with endometriosis-associated infertility. This review aims to present the state of the art in recognition epigenetic reprogramming of T cells as the key factor in the pathophysiology of endometriosis in the context of T-cell-related autoimmunity. The new potential therapeutic approaches based on epigenetic modulation and/or adoptive transfer of T cells will also be outlined.

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Section: Overview Of T-cell Reprogrammingmentioning

confidence: 99%

Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity

Szukiewicz

2022

Front. Immunol.

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“…Increased DNA methylation in CD4 + T cells is also found in RA, associated with their autoimmune responses. Methotrexate (MTX), a first-line drug for RA treatment through antagonizing folate metabolism, affects one-carbon metabolism to disrupt the methyl transfer process of CpG methylation [ 212 ]. In addition, the inhibition of histone methyltransferase Ezh2 is currently under evaluation for the therapy of SLE.…”

Section: Epigenetic Therapeutics Of Sjsmentioning

confidence: 99%

Abnormal Epigenetic Regulations in the Immunocytes of Sjögren’s Syndrome Patients and Therapeutic Potentials

Han

Zhao

Ren

et al. 2022

Cells

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Sjögren’s syndrome (SjS), characterized by keratoconjunctivitis sicca and dry mouth, is a common autoimmune disease, especially in middle-aged women. The immunopathogenesis of SjS is caused by the sequential infiltration of T and B cells into exocrine glands, including salivary and lacrimal glands. Effector cytokines produced by these immunocytes, such as interferons (IFNs), IL-17, IL-22, IL-21, IL-4, TNF-α, BAFF and APRIL, play critical roles in promoting autoimmune responses and inducing tissue damages. Epigenetic regulations, including DNA methylation, histone modification and non-coding RNAs, have recently been comprehensively studied during the activation of various immunocytes. The deficiency of key epigenetic enzymes usually leads to aberrant immune activation. Epigenetic modifications in T and B cells are usually found to be altered during the immunopathogenesis of SjS, and they are closely correlated with autoimmune responses. In particular, the important role of methylation in activating IFN pathways during SjS progression has been revealed. Thus, according to the involvement of epigenetic regulations in SjS, target therapies to reverse the altered epigenetic modifications in auto-responsive T and B cells are worthy of being considered as a potential therapeutic strategy for SjS.

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“…Epigenetic mechanisms ( 4 ), such as deoxyribonucleic acid (DNA) methylation, participate in many important life activities ( 5 ), including cell differentiation and proliferation, organism aging ( 6 ), and tumorigenesis ( 7 ), and play an important role in the regulation of gene expression ( 8 ). In recent years, the potential role of DNA methylation in RA development has attracted the attention of researchers ( 9 , 10 ). DNA methylation affects different aspects of RA and modulates epigenetic silencing of genes and cellular behavior, especially in fibroblast-like synoviocytes (FLS), whose abnormal proliferation promotes persistent inflammation and joint damage ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

DNA methylation change of HIPK3 in Chinese rheumatoid arthritis and its effect on inflammation

Jiang

Wei

et al. 2023

Front. Immunol.

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IntroductionHomeodomain-interacting protein kinase 3 (HIPK3) plays an important role in cell proliferation, apoptosis, and inflammation. Over-expression of HIPK3 in immune cells in rheumatoid arthritis (RA) has been reported. In this study, we investigated blood methylation levels and clinical characteristics of RA in a Chinese population.MethodsA total of 235 patients with RA, 30 with osteoarthritis (OA), and 30 matched healthy controls were recruited. The methylation status of seven CpGs in the differentially methylated region of HIPK3 (cg05501357) was measured using targeted methylation-sequencing technology. The association between methylation haplotypes and the overall methylation status of HIPK3 with clinical characteristics was assessed using generalized linear regression.ResultsAll seven CpGs showed hypomethylation status in RA blood compared with OA and normal individuals (overall p= 1.143×10-8 and FDR= 2.799×10-7), which is consistent with the previously reported high expression of HIPK3 in RA immune cells. Among all seven CpGs, 33286785 showed the highest predictive power with an area under the curve (AUC) of 0.829; we received a higher AUC=0.864 when we combined HIPK3 with anti-citrullinated protein antibodies (ACPA -) and rheumatoid factor (RF +) in the prediction model, indicating that when a patient’s ACPA is negative, HIPK3 can assist RF as a new clinical index for the diagnosis of RA. We also found that HIPK3 methylation levels were negatively correlated with C-reactive protein (CRP; r= -0.16, p= 0.01). Methylation haplotypes were analyzed, and the full methylation haplotype (FMH; r= 0.16, p= 0.01) and full non-methylation haplotype (FNH; r= 0.18, p= 0.0061) were negatively correlated with CRP.ConclusionCirculating blood methylation levels in the protein region of HIPK3 can be utilized as a supportive diagnostic biomarker and CRP level indicator for RA.

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DNA Methylation of T Lymphocytes as a Therapeutic Target: Implications for Rheumatoid Arthritis Etiology

Cited by 15 publications

References 157 publications

Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity

Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity

Abnormal Epigenetic Regulations in the Immunocytes of Sjögren’s Syndrome Patients and Therapeutic Potentials

DNA methylation change of HIPK3 in Chinese rheumatoid arthritis and its effect on inflammation

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