MiR-146a in myasthenia gravis thymus: from uncontrolled innate immunity to B cell-mediated autoimmunity

P. Cavalcante, M. Tarasco, Nicola Iacomino, C. Antozzi, R. Mantegazza
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Abstract

The thymus is the main site of autoimmunity development in myasthenia gravis (MG) associated with anti-acetylcholine receptor (AChR) autoantibodies, a prototypic autoimmune disease affecting neuromuscular junction. Most MG patients with early-onset disease presents follicular hyperplastic changes of the thymus, that are critically implicated in the initiation and perpetuation of the autoimmune response against the AChR. Uncontrolled activation of Toll-like receptor (TLR)-mediated innate immune responses, chronic inflammation and ectopic germinal center (GC) formation are key pathological features of hyperplastic thymus in MG, indicating that a close link between innate immunity and B cell-mediated autoimmunity underlies the intra-thymic pathogenesis of MG. MiR-146a, an “immune-miR” acting as key modulator of both innate and adaptive immunity, is a potent inhibitor of TLR signaling pathways, able to prevent and avoid an overstimulation of the inflammatory response by targeting the NF-κB signaling transducers IRAK1 and TRAF6. At the same time, miR-146a modulates the expression of c-REL, ICOS and ICOSL, which are crucial regulators of B cell function and GC response. Dysregulation of miR-146a expression is a common molecular event in several autoimmune disorders. Our recent findings revealed defective expression of miR-146a, associated with over-expression of its TLR- and B cell-related target genes, in follicular hyperplastic MG thymuses, indicating that loss of regulatory functions of this miRNA may significantly contribute to the immunopathological steps leading to MG. Of note, corticosteroids were found to increase the miR-146a expression levels, thus suggesting the miRNA capacity to mediate the effects of these drugs in inducing immunosuppression and autoimmunity control.  In this review, we discuss the role of miR-146a as a molecular bridge between innate and adaptive immunity, and summarize the current knowledge on the miRNA contribution to the pathogenesis of MG. Based on our and literature data, we highlight the miR-146a potential as biomarker for therapeutic monitoring, as well as target of future advanced RNA-based therapies to modulate the immune system and counteract the autoimmune response in MG.
MiR-146a在重症肌无力胸腺中的作用:从不受控制的先天免疫到B细胞介导的自身免疫
胸腺是重症肌无力(MG)自身免疫发展的主要部位,与抗乙酰胆碱受体(AChR)自身抗体相关,是一种影响神经肌肉交界处的典型自身免疫性疾病。大多数MG患者早发性疾病表现为胸腺滤泡增生性改变,这与针对AChR的自身免疫反应的开始和持续存在密切相关。toll样受体(TLR)介导的先天免疫反应失控激活、慢性炎症和异位生发中心(GC)形成是MG胸腺增生性的关键病理特征,表明先天免疫和B细胞介导的自身免疫之间的密切联系是MG胸腺内发病机制的基础。MiR-146a是一种“免疫mir”,作为先天免疫和适应性免疫的关键调节剂,是TLR信号通路的有效抑制剂,能够通过靶向NF-κB信号转导器IRAK1和TRAF6来预防和避免炎症反应的过度刺激。同时,miR-146a调节c-REL、ICOS和ICOSL的表达,这是B细胞功能和GC应答的重要调节因子。miR-146a表达失调是几种自身免疫性疾病中常见的分子事件。我们最近的研究发现,在滤泡性增生性MG胸腺中,miR-146a的表达缺陷与其TLR-和B细胞相关靶基因的过度表达有关,这表明该miRNA调节功能的丧失可能在导致MG的免疫病理步骤中起着重要作用。值得注意的是,皮质类固醇被发现可以增加miR-146a的表达水平,从而表明miRNA有能力介导这些药物诱导免疫抑制和自身免疫控制的作用。在这篇综述中,我们讨论了miR-146a作为先天免疫和适应性免疫之间的分子桥梁的作用,并总结了目前关于miRNA在MG发病机制中的作用的知识。基于我们和文献数据,我们强调了miR-146a作为治疗监测的生物标志物的潜力,以及未来先进的基于rna的治疗靶标,以调节免疫系统并抵消MG中的自身免疫反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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