滤泡调节性T（Tfr）细胞在产科抗磷脂综合征中的免疫调节机制及治疗潜能研究

Obstetric antiphospholipid syndrome (OAPS) is a systemic autoimmune disease that is characterized clinically by a variety of obstetric manifestations (fetal death and recurrent abortions) and serologically by the presence of antiphospholipid antibodies (aPLs). As a systemic autoimmune disease, less attention has been given to the factors that initiate and sustain immune cell activation and the continuous secretion of aPLs in OAPS. As 30% of women continue to have pregnancy complications after the current treatment of regular heparin and aspirin, effective treatment options are still needed to explore. Follicular regulatory T (Tfr) cells were defined as a specialized population of Tregs that are primarily located in germinal centers (GC) and suppress the GC reaction and B cells differentiation to produce high-affinity antibodies and thus play an opposing role with Tfh cells in the regulation of humoral immunity. The immunomodulatory mechanisms of Tfr cells involved in the occurrence and continuous development of OAPS are still not elucidated. In this project, we aim to study the phenotype and function of Tfr cells, potential regulatory mechanisms of Tfr-mediated Tfh cell and B cell activations and functions in OAPS so as to improve the understanding of Tfr cells’ roles in the immunopathogenesis of OAPS. Moreover, this study will also provide theoretical basis for exploring novel immune-associated intervention strategies aimed at ameliorating high-affinity aPLs produced by B cells through targeting and improving the Tfr cells functions in OAPS subjects.

产科抗磷脂综合征(OAPS)是以一种反复病态妊娠(胎死宫内和复发性流产)为主要表现，同时伴有抗磷脂抗体(aPLs)阳性的系统性自身免疫病，而启动和维持OAPS免疫细胞激活和aPLs持续分泌的免疫机制鲜有关注。且仍有30%的OAPS患者经过正规肝素联合阿司匹林治疗后仍出现流产等不良妊娠事件，亟待更好的治疗手段。滤泡调节性T细胞(Tfr细胞)是一类定位于淋巴滤泡的新型Treg细胞，在功能上抑制生发中心形成，B细胞分化以及高亲和力抗体的形成，起到免疫调节作用。Tfr细胞是否参与了OAPS疾病发生和持续发展的机制还尚未明确。本项目将通过研究Tfr细胞表型和功能特征及其对自身抗体生成的关键细胞群Tfh细胞和B细胞的功能影响以及潜在分子机制，揭示Tfr细胞在OAPS自身免疫发病中作用和机制，并期待找到基于干预Tfr细胞功能从而影响B细胞分泌aPLs的治疗靶点，为OAPS新型免疫治疗策略提供理论依据。

产科抗磷脂综合征(OAPS)是一种以反复病态妊娠为主要表现，同时伴有抗磷脂抗体阳性的系统性自身免疫病。本项目系统阐释了外周血广泛性的免疫细胞表型和功能异常参与了抗磷脂综合征这一复杂系统性自身免疫病的病理机制。尤其是对于Tfh细胞、Tfr细胞以及NK细胞亚群比例失调以及受体表达异常，且与临床指标密切相关的现象的揭示，均属首次阐释了上述细胞参与OAPS自身免疫病机制，提示靶向上述免疫细胞，改善免疫系统紊乱机制可以作为靶向难治性OAPS治疗的新型策略和手段。迁移体是一种可介导细胞内物质迁移性胞吐的新型细胞外囊泡。本项目相关研究发现在OAPS患者血清迁移体中包含有大量的IgG、IgM,提示迁移体中包含大量的自身抗体。提示靶向迁移体等细胞外囊泡也是OAPS针对自身抗体诊断和治疗的重要方向。本项目在OAPS患者血清及血清迁移体筛选并验证了OAPS特异性高表达蛋白血浆激肽蛋白酶，提示该高表达蛋白作为潜在OAPS诊断标志物的可能性。而机制研究发现胎盘发育中最重要的也是最具有侵袭性的细胞绒毛外滋养层细胞（EVT）也产生迁移体，具有迁移体的标志物integrin α5和HLA-G标记，并且迁移体里富含趋化因子CXCL12。迁移体发生缺陷的小鼠也存在一定程度的生殖缺陷。推测迁移体可能参与并介导了妊娠母胎界面免疫稳态的机制。本研究深入发掘参与OAPS发病的重要机制和信号通路，为诊断和治疗OAPS疾病提供新的思路。

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