Restoring T Cell Tolerance, Exploring the Potential of Histone Deacetylase Inhibitors for the Treatment of Juvenile Idiopathic Arthritis

Abstract

Juvenile Idiopathic Arthritis (JIA) is characterized by a loss of immune tolerance. Here, the balance between the activity of effector T (Teff) cells and regulatory T (Treg) cells is disturbed resulting in chronic inflammation in the joints. Presently, therapeutic strategies are predominantly aimed at suppressing immune activation and pro-inflammatory effector mechanisms, ignoring the opportunity to also promote tolerance by boosting the regulatory side of the immune balance. Histone deacetylases (HDACs) can deacetylate both histone and non-histone proteins and have been demonstrated to modulate epigenetic regulation as well as cellular signaling in various cell types. Importantly, HDACs are potent regulators of both Teff cell and Treg cell function and can thus be regarded as attractive therapeutic targets in chronic inflammatory arthritis. HDAC inhibitors (HDACi) have proven therapeutic potential in the cancer field, and are presently being explored for their potential in the treatment of autoimmune diseases. Specific HDACi have already been demonstrated to reduce the secretion of pro-inflammatory cytokines by Teff cells, and promote Treg numbers and suppressive capacity in vitro and in vivo. In this review, we outline the role of the different classes of HDACs in both Teff cell and Treg cell function. Furthermore, we will review the effect of different HDACi on T cell tolerance and explore their potential as a therapeutic strategy for the treatment of oligoarticular and polyarticular JIA.

The Multi-Omics Architecture of Juvenile Idiopathic Arthritis

“…Histone deacetylases (HDACs) are acetylation ‘erasers’ that can deacetylate both histone and non-histone proteins. HDACs are involved in cellular signaling, epigenetic regulation, and important in regulating the function of Teff cells and Treg cells [ 125 ]. Besides the above mentioned HLA class II molecules related sJIA that may be suitable to use abatacept, studies showed the epigenetic effects of HDAC9 in regulating critical innate immune processes through deacetylation of histone proteins [ 126 , 127 ].…”

Pathways and microRNAs bioinformatics analyses identifying possible existing therapeutics for COVID-19 treatment

“…HDACs are enzymes that remove the acetyl group from nuclei histone proteins, in this way the DNA is less accessible to transcription factors. HDAC inhibitors (HDACi) are a recent class of therapeutic targets in autoimmune and neoplastic diseases39,40 . These enzymes are able to epigenetically modulate signi cant cellular functions, altering transcription and also modulating alternative post-translational lysine modi cations like methylation, ubiquitination, and sumoylation, by removing acetyl groups from proteins ε-amino lysines41 .…”

An In Vitro Study Determining the anti-inflammatory activities of sinapinic acid-containing extracts generated from Irish rapeseed meal

“…Many pro-inflammatory cytokines are regulated at the epigenetic level, particularly via histone deacetylases 14 . This has made them attractive for potentially targeting cancer 15 , but also within the sphere of other pro-inflammatory conditions [16][17][18] . Natural products with epigenetic targeting activity therefore represent novel potential…”