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.
Highlights
Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease in children and an important cause of short- and long-term disability [1, 2]
Cells from the innate immune system play an essential role in the pathogenesis of Oligo-articular JIA (oJIA) and poly-articular JIA (pJIA) as well, it is generally thought that activation of autoreactive CD4+ T cells, leading to a T cell-driven immune response is a key manifestation in the pathogenesis of oJIA and pJIA
Therapy with disease modifying anti-rheumatic drugs (DMARDs) and biologicals has proven to be very successful in inducing remission in JIA, there is a high percentage of patients that relapse after tapering and stop of maintenance immunosuppressive treatment
Summary
Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease in children and an important cause of short- and long-term disability [1, 2]. Higher numbers of Treg and lower numbers of Teff cells (Th17 and Th1) at the site of inflammation have been correlated to a more favorable course and outcome in JIA [16, 20,21,22] These observations support the concept that treatment may be aimed to restore the immunological imbalance between effector mechanisms and regulatory mechanism in children with JIA. In the context of autoimmune disease, HDAC inhibition proved to influence both the innate immune system and Teff cell and Treg cell function, potentially restoring immunological tolerance. We here provide an overview and focus on the role of the different types of HDACs in CD4+ Teff cells and Treg cells, and explore the potential of specific HDACi as a therapeutic strategy for the treatment of autoimmune diseases, in specific oJIA and pJIA
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