端粒酶逆转录酶在ITP发病中的作用

Primary immune thrombocytopenia (ITP) is an acquired disorder characterized by autoantibody-mediated platelet destruction and insufficient platelet production. Humoral and cellular immunity are both implicated in ITP pathogenesis and playing important roles. Telomere/telomerase system has always been viewed as a focus in tumor research, however, it has gradually become a hotspot in several immune disorders resently, hTERT standed in central position and involved in numerous pathogenesis of numerous tumorous and autoimmune disorders. Till now, the role of hTERT in ITP etiology was not clear yet. We were the first to report telomerase activity increased and telomere length shortened in ITP patients comparing to healthy controls, and then found that the ratio of telomerase activity level of CD4+/CD8+ T cell had an association with the ratio of lymphocyte count of CD4+/CD8+ T cell. All these verified that this system were implicated in ITP. On the basis of those, we aim to research telomere/telomerase system in ITP further, and to clarify the regulatory mechanism of hTERT and the influences of hTERT on immune system in ITP. In addition, we will preliminary explore the alteration of hTERT in megakaryocytes. All these will provide a theoretial basis of new treatment strategy for the ITP patients.

原发免疫性血小板减少症（ITP）是一种由于自身免疫异常所致的以血小板破坏过多及生成不足为特点的出血性疾病，体液免疫和细胞免疫的异常均在该病发生中扮演重要角色。端粒/端粒酶系统一直以来是肿瘤疾病研究的焦点，近年来逐渐成为许多自身免疫病的关注热点，hTERT在该系统中占核心地位，参与了众多肿瘤及自身免疫病的发生。目前关于hTERT在ITP中的作用暂未见报道。我们率先报道了ITP患者端粒酶活性升高和端粒长度缩短的研究结果，随后又发现患者CD4+/CD8+淋巴细胞端粒酶活性的比值与体内CD4+/CD8+T淋巴细胞数的比值间有一定的相关性，进一步印证该系统参与了ITP的发生。在此基础上，本项目旨在深化该系统在ITP中的研究，阐明hTERT在ITP中的调控机制和hTERT对ITP患者免疫系统的影响，并初步探讨hTERT在患者骨髓巨核细胞中的变化，为新的治疗策略提供理论依据。

免疫性血小板减少症（ITP）属于自身免疫性疾病，原因尚不明确，患者体内发生的免疫反应导致血小板破坏过多超过骨髓的代偿能力，是以血小板减低为特点的出血性疾病。大多数患者体内的体液免疫和细胞免疫呈持续异常状态。端粒/端粒酶系统对这种异常应答状态的持续发挥着重要作用。目前关于hTERT在ITP中的作用暂未见报道。为进一步明确该系统在ITP中的发病机制，我们进行了以下研究。首先，明确 hTERT 是否受JAK-STAT信号通路调控。我们以IL-17a小分子刺激患者及正常人骨髓单个核细胞，检测端粒酶及端粒长度在两组间并无显著差异（端粒酶活性：P=0.058；端粒长度：P=0.321），同时对STAT的活性进行干预，测得端粒酶及端粒长度在两组间亦无统计学意义（端粒酶活性：P=0.397；端粒长度：P=0.126）。同法，我们换以IL-2对两组骨髓细胞进行刺激，发现端粒酶活性在患者组较正常明显升高（P=0.001），端粒长度两组间无差异。我们还检测了PI3K-Akt通路中AKt不同条件下的表达，结果表明患者体内hTERT受到T细胞活化生长因子IL-2影响，通过PI3k-Akt通路介导了hTERT的调控。其次，明确 hTERT对免疫系统的影响，我们对ITP 患者组及正常对照组的外周血细胞的端粒酶活性进行干预，检测在不同表达情况下免疫系统中各相关细胞因子及转录因子的表达情况，同时包括细胞增殖、细胞凋亡的检测，并结合临床资料进行回顾分析。发现细胞因子PAIgG、IL-2、IL-6、IFN-r在患者组的表达均显著高于正常对照组。由此阐明hTERT参与了ITP的发生，通过PI3K-Akt通路进行调控并改变免疫系统平衡状态，为新的治疗策略指明了方向。