干扰素调节因子4（IRF4）异常与ITP患者Treg/Th17失衡的研究

Primary thrombocytopenia (ITP) is an immune-mediated disorder, characterized by platelet decrease. CD4+T cells dysfunction plays an important role in the pathogenesis. Treg and Th17 cells are two subtypes of CD4+T cells, playing opposite roles in immune tolerance maintenance while sharing common precursor cells in their differentiation process. Treg/Th17 balance is thus regarded as a key factor in immune homeostasis. Interferon regulatory factor 4 (IRF4) is a major regulator of both Treg and Th17 cells'differentiation and function. Studies showed that IRF4 deletion impaired Treg cells' inhibition on Th17 cells proliferation and IL-17 secretion, which might be related with down regulation of IL-10, the target gene of IRF4. We recently demonstrated that Treg/Th17 imbalance played a role in ITP as Treg/Th17 ratio was related to the disease activity. We also showed that IL-10 concentration in PBMCs culture supernatant was connected with ITP disease status in the preliminary study. So we presumed that IRF4 abnormality might cause IL-10 expression alteration, leading to Treg/Th17 imbalance, constituting to the pathogenesis of ITP. The present study is to prove that IRF4 defect contributes to the Treg/Th17 imbalance via IL-10 expression alteration. This study attempts to explore the underlying mechanisms of ITP, which is fundamental to find a new therapy.

原发性免疫性血小板减少症（ITP）是以血小板减少为主要表现的自身免疫性疾病，除体液免疫外，细胞免疫亦在ITP发病中起着重要作用。T调节细胞（Treg）和Th17细胞是CD4+T细胞两种亚群，分别发挥免疫调节和促炎作用。干扰素调节因子4（IRF4）是Treg及Th17细胞分化和功能共同的主要调控者。IL-10作为Treg抑制Th17增殖和分泌IL-17作用中的关键因素，其基因表达依赖于IRF4的调控。我们前期研究证实ITP患者Treg/Th17失衡，Treg/Th17比值与ITP疾病状态相关，并发现IL-10与ITP疾病状态可能相关。本课题旨在研究ITP患者Treg细胞IRF4功能异常；Treg细胞IRF4缺失可能导致其IL-10基因表达异常，分泌IL-10能力降低，抑制Th17细胞功能受损；Treg/Th17失衡可能由IRF4异常所致。本研究的完成将为ITP治疗研究提供新思路。

原发性免疫性血小板减少症（Primary immune thrombocytopenia，ITP）是一种异质性的自身免疫疾病，CD4+ T效应细胞过度激活（CD4+ T effector cell，Teff）以及调节性T细胞（regulatory T cells，Treg）受损都在ITP发病中发挥作用，以往多项研究表明Treg细胞对Teff细胞的抑制作用减弱，但其机制并不明确。白介素10（Interleukin-10，IL-10）是Treg细胞在炎症环境中发挥重要作用的的调节性细胞因子，在多种自身免疫性疾病中发现分泌IL-10的Treg细胞具有保护作用。我们随访ITP患者疗效和外周血IL-10+Treg细胞数量、以及体外试验证实：ITP患者Treg对Teff细胞的抑制作用主要来自于IL-10，其分泌IL-10异常是Treg细胞功能受损的机制之一。.Treg细胞异质性对Treg在自身免疫性疾病的研究造成一定的困难，按Treg细胞表型（CD45，Foxp3）和免疫功能分为静止期Treg（rTreg，Group I）、活动性Treg（aTreg，Group II）和无免疫抑制活性的Treg（Group III）。ITP患者免疫活性的Treg（rTreg+ aTreg）减少，治疗前aTreg增加提示糖皮质激素可获较好疗效。.干扰素调节因子4（interferon regulatory factor 4, IRF4）是IRF转录因子家族成员，在CD4+T细胞的成熟过程中发挥基础性作用，是维持Treg/Th17平衡的无法取代的转录因子。我们的初步试验结果提示：ITP患者的IRF4表达低于正常人；体外培养中，应用siRNA干扰正常人Treg细胞IRF4表达后，Th17细胞数量增加。IRF4表达异常是否引起Treg细胞IL-10表达异常、并由此干扰Treg/Th17细胞平衡有待进一步试验证实。