Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity.

Cornacchia, Elizabeth; Golbus, Joseph; Maybaum, Jonathan; Strahler, John R.; Hanash, Samir M.; Richardson, Bruce C.

doi:10.4049/jimmunol.140.7.2197

Cited by 367 publications

(17 citation statements)

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“…Polymorphisms in DNMT1 are also associated with SLE [ 52 ] and the gene is reportedly expressed at lower levels in SLE immune cells than in healthy controls [ 53 ]. Reduced genomic methylation can also be caused by certain drugs, such as hydralazine and procainamide, which are known to induce SLE (so-called ‘drug-induced lupus’)[ 54 ]. Another well-known trigger of lupus flares, ultraviolet-B light [ 55 ], also induces genomic hypomethylation [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of L1 retrotransposons in granulocytes from patients with active systemic lupus erythematosus

Ukadike

Najjar

et al. 2023

Mobile DNA

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Background Patients with systemic lupus erythematosus (SLE) have autoantibodies against the L1-encoded open-reading frame 1 protein (ORF1p). Here, we report (i) which immune cells ORF1p emanates from, (ii) which L1 loci are transcriptionally active, (iii) whether the cells express L1-dependent interferon and interferon-stimulated genes, and (iv) the effect of inhibition of L1 ORF2p by reverse transcriptase inhibitors. Results L1 ORF1p was detected by flow cytometry primarily in SLE CD66b+CD15+ regular and low-density granulocytes, but much less in other immune cell lineages. The amount of ORF1p was higher in neutrophils from patients with SLE disease activity index (SLEDAI) > 6 (p = 0.011) compared to patients with inactive disease, SLEDAI < 4. Patient neutrophils transcribed seven to twelve human-specific L1 loci (L1Hs), but only 3 that are full-length and with an intact ORF1. Besides serving as a source of detectable ORF1p, the most abundant transcript encoded a truncated ORF2p reverse transcriptase predicted to remain cytosolic, while the two other encoded an intact full-length ORF2p. A number of genes encoding proteins that influence L1 transcription positively or negatively were altered in patients, particularly those with active disease, compared to healthy controls. Components of nucleic acid sensing and interferon induction were also altered. SLE neutrophils also expressed type I interferon-inducible genes and interferon β, which were substantially reduced after treatment of the cells with drugs known to inhibit ORF2p reverse transcriptase activity. Conclusions We identified L1Hs loci that are transcriptionally active in SLE neutrophils, and a reduction in the epigenetic silencing mechanisms that normally counteract L1 transcription. SLE neutrophils contained L1-encoded ORF1p protein, as well as activation of the type I interferon system, which was inhibited by treatment with reverse transcriptase inhibitors. Our findings will enable a deeper analysis of L1 dysregulation and its potential role in SLE pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Expression of L1 retrotransposons in granulocytes from patients with active systemic lupus erythematosus

Ukadike

Najjar

et al. 2023

Mobile DNA

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“…However, these drugs, including azacytidine and decitabine, are DNA methyltransferase inhibitors, and they function in a nonspecific manner to reduce genomic DNA methylation, which could be counterproductive for the treatment of pSS, given that pSS-associated genes tend to be hypomethylated. Indeed, the drugs hydralazine and procainamide, which inhibit DNA methylation 201 , have long been known to confer a high risk of triggering drug-induced SLE 202 . To date, epigenetic modifiers have not been tested in pSS but constitute an interesting future treatment approach.…”

Section: Targeting Dna Methylationmentioning

confidence: 99%

Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies

2023

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In primary Sjögren syndrome (pSS), chronic inflammation of exocrine glands results in tissue destruction and sicca symptoms, primarily of the mouth and eyes. Fatigue, arthralgia and myalgia are also common symptoms, whereas extraglandular manifestations that involve the respiratory, nervous and vascular systems occur in a subset of patients. The disease predominantly affects women, with an estimated female to male ratio of 14 to 1. The aetiology of pSS, however, remains incompletely understood, and effective treatment is lacking. Largescale genetic and epigenetic investigations have revealed associations between pSS and genes in both innate and adaptive immune pathways. The genetic variants mediate context-dependent effects, and both sex and environmental factors can influence the outcome. As such, genetic and epigenetic studies can provide insight into the dysregulated molecular mechanisms, which in turn might reveal new therapeutic possibilities. This Review discusses the genetic and epigenetic features that have been robustly connected with pSS, putting them into the context of cellular function, carrier sex and environmental challenges. In all, the observations point to several novel opportunities for early detection, treatment development and the pathway towards personalized medicine. Key points• Advances in the past few years provide new insight into the genetic and epigenetic basis of primary Sjögren syndrome (pSS), and how environmental factors and carrier sex might interact with risk-associated loci.• Immunomodulatory treatments that affect disease progression and activity have not been identified for pSS and remain unmet clinical needs.• Data from genetic and epigenetic studies point to Toll-like receptor and interferon signalling, lymphocyte regulation, antigen presentation and target tissue maintenance as the most relevant processes for therapeutic targeting.• Of the implicated pathogenic processes, Toll-like receptor and interferon signalling, as well as lymphocyte regulation, contain targets of various treatments in development or in clinical trials.• Novel treatment approaches for pSS could include modification of epigenetic signatures, interference with antigen presentation pathways and antigen-specific immunotherapy.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author selfarchiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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“…Procaine ( 12 ) has been used as an anesthetic for years, and it was not known that procainamide could inhibit DNA methylation until 1988 ( Cornacchia et al, 1988 ). Inspired by this, researchers turned to procaine, which has a similar structure to procainamide.…”

Section: Dna Methyltransferase Inhibitorsmentioning

confidence: 99%

Recent progress in DNA methyltransferase inhibitors as anticancer agents

Zhang

Wang

et al. 2022

Front. Pharmacol.

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DNA methylation mediated by DNA methyltransferase is an important epigenetic process that regulates gene expression in mammals, which plays a key role in silencing certain genes, such as tumor suppressor genes, in cancer, and it has become a promising therapeutic target for cancer treatment. Similar to other epigenetic targets, DNA methyltransferase can also be modulated by chemical agents. Four agents have already been approved to treat hematological cancers. In order to promote the development of a DNA methyltransferase inhibitor as an anti-tumor agent, in the current review, we discuss the relationship between DNA methylation and tumor, the anti-tumor mechanism, the research progress and pharmacological properties of DNA methyltransferase inhibitors, and the future research trend of DNA methyltransferase inhibitors.

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Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity.

Cited by 367 publications

References 0 publications

Expression of L1 retrotransposons in granulocytes from patients with active systemic lupus erythematosus

Expression of L1 retrotransposons in granulocytes from patients with active systemic lupus erythematosus

Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies

Recent progress in DNA methyltransferase inhibitors as anticancer agents

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