组蛋白乙酰化诱导FcγRIIb表达纠正ITP单核巨噬细胞亚群失衡的机制研究

原发免疫性血小板减少症（ITP）是临床最常见的出血性疾病，发病机制尚未完全阐明。最新研究发现，单核巨噬细胞表面Fcγ受体亚群失衡、免疫耐受异常，在ITP发病机制中发挥重要作用。申请者发现，低剂量组蛋白去乙酰化酶抑制剂西达本胺可改善被动ITP模型血小板减少（Zhao HY, et al. Blood 2019 133:730-742），然而具体机制尚不明确；我们预实验结果提示，低剂量西达本胺体外可诱导单核细胞表面抑制性受体FcγRIIb表达，纠正单核巨噬细胞亚群失衡，抑制单核巨噬细胞对抗体包被血小板的吞噬作用。基于此，我们提出 “组蛋白乙酰化可诱导单核巨噬细胞表面FcγRIIb表达，调控单核/巨噬系统亚群平衡，恢复ITP免疫耐受” 的假说。本研究拟从组蛋白乙酰化等水平探讨FcγRIIb基因组蛋白乙酰化对单核/巨噬系统亚群的调控作用，以解析ITP的发病机制，为ITP治疗提供新的手段。

Primary immune thrombocytopenia (ITP) is the most common bleeding disease in clinic. The pathogenesis of ITP has not been fully elucidated. Recent studies have found that the imbalance of Fcγ receptor subsets on the surface of monocyte macrophages and the abnormal immune tolerance play an important role in the pathogenesis of ITP. The applicant found that the low-dose histone deacetylase inhibitor chidamide could improve the thrombocytopenia (Zhao HY, et al. Blood 2019 133:730-742), however, the specific mechanism is not completely clear; our preliminary results suggest that low-dose chidamide can induce the expression of monocyte surface inhibitory receptor FcγRIIb in vitro, correct the imbalance of monocyte macrophage subpopulation, and inhibit the phagocytosis of monocyte/ macrophages against the antibody coated platelets. Based on this, we propose the hypothesis that histone acetylation can induce the expression of FcγRIIb on the surface of monocyte/macrophages, regulate the balance of monocyte/macrophage system subpopulation, and restore the immune tolerance of ITP. The aim of this study is to explore the regulatory effect of FcγRIIb gene histone acetylation on mononuclear/macrophage system subpopulation, so as to analyze the pathogenesis of ITP and provide a new means for ITP treatment.