RNA编辑酶ADAR1在体液免疫反应中的作用及机制研究

体液免疫是由抗体介导的细胞间质中抗原的清除过程，属于机体免疫系统的重要组成部分。在体液免疫反应中B细胞被抗原激活并分化为浆细胞和记忆B细胞。浆细胞具有独特的细胞结构，可大量合成并分泌抗体，抗体将介导病原体的清除过程。记忆B细胞长期存在于体内，当机体再次遭遇同种抗原时被迅速激活并对抗原做出快速高效的响应。当B细胞激活和分化发生异常时会导致免疫缺陷、自身免疫疾病以及淋巴瘤的发生，因此，在体液免疫反应中B细胞的激活和分化受到严格的调控。研究B细胞活化和分化调控机制对于病原体感染和自身免疫疾病的治疗以及疫苗设计具有重要的指导意义。RNA腺苷脱氨酶1（ADAR1）是主要的对双链RNA上腺苷进行脱氨基修饰的酶，近年来大量研究报道了ADAR1在细胞天然免疫反应、B细胞和T细胞等免疫细胞的发育过程中发挥了重要调控作用。然而ADAR1在B细胞活化及体液免疫反应过程中的作用及机制还需要进一步研究。

为了探究ADAR1在B细胞活化和免疫反应过程中的功能，本文利用Cre-loxP基因条件性敲除系统构建了在小鼠B细胞中特异性敲除ADAR1的转基因小鼠。ADAR1的敲除导致小鼠生发中心反应减弱，进而导致生发中心反应下游记忆B细胞和发生免疫球蛋白基因类别转换重组的抗体分泌细胞分化受阻。然而ADAR1的敲除却增强了小鼠免疫反应早期浆母细胞的分化。因此，ADAR1在活化B细胞向生发中心B细胞和浆母细胞分化过程中发挥了重要的调控作用。

已有研究表明ADAR1通过作用于细胞内源RNA而抑制MDA5、PKR和RNase L的异常激活，为了确定MDA5、PKR和RNase L通路在ADAR1条件性敲除小鼠免疫反应中的作用，本文构建了在B细胞中条件性敲除ADAR1并分别敲除MDA5、PKR和RNase L的转基因小鼠。结果显示MDA5的敲除可以部分回补ADAR1条件性敲除小鼠生发中心B细胞减少的表型，但是不能回补记忆B细胞和浆细胞分化减弱的表型，而且MDA5的敲除也不能回补ADAR1条件性敲除小鼠浆母细胞分化增强的表型，PKR和RNase L的敲除对ADAR1敲除小鼠免疫反应的表型没有回补作用。表明ADAR1在体液免疫反应中的作用不依赖PKR和RNase L，在调控生发中心B细胞形成过程中部分依赖MDA5。

ADAR1蛋白主要存在两个变体—ADAR1 p150和ADAR1 p110，ADAR1 p150主要分布在细胞质中而ADAR1 p110主要分布在细胞核中。研究表明两个变体在小鼠不同的组织器官发育中具有不同的功能。为了探究ADAR1 p150和ADAR1 p110在体液免疫反应中的功能，本文利用Cre-loxP系统构建了ADAR1条件性敲除并且同时条件性敲入ADAR1 p150或ADAR1 p110变体的转基因小鼠。结果显示ADAR1 p150的敲入可以完全回补ADAR1敲除小鼠体液免疫反应的表型，而ADAR1 p110的敲入不能回补ADAR1敲除小鼠体液免疫反应的表型。表明ADAR1 p150变体在体液免疫反应中发挥了主导功能。

为了探究ADAR1 p150调控小鼠生发中心反应的机制，本文通过小鼠骨髓细胞重构和移植方法，在ADAR1条件性敲除小鼠骨髓细胞中分别高表达ADAR1 p150 Zα结构域、双链RNA结合结构域和催化脱氨基结构域突变的3种突变基因以及N端带有核输出信号的ADAR1 p110融合基因。通过检测不同ADAR1突变体在生发中心反应中的功能发现ADAR1 p150 Zα结构域和双链RNA结合结构域的突变使ADAR1 p150蛋白在小鼠生发中心反应中丧失功能，而且核输出型ADAR1 p110在小鼠生发中心反应中依然没有功能。结果表明ADAR1 p150在生发中心反应中发挥功能依赖Zα结构域和双链RNA结合结构域，同时Zα结构域和双链RNA结合结构域在功能上具有协同作用。

通过转录组测序分析发现ADAR1的缺失导致活化B细胞中与细胞分化相关的基因表达异常，包括调控B细胞分化的核心转录因子Blimp-1、IRF4、Pax5、Bach2、Bcl6等。进一步实验结果表明ADAR1的缺失导致B细胞受体信号通路上游Syk和BLNK等关键信号分子的过度激活，以及下游MEK-ERK通路的过度激活。表明ADAR1在B细胞受体信号通路的激活过程中发挥了重要的负调控作用。

综上所述，本文揭示了RNA编辑酶ADAR1在体液免疫反应中的功能，阐明了ADAR1 p150变体在体液免疫反应中发挥主导作用，揭示了ADAR1在活化B细胞分化命运选择过程中发挥了重要的调控作用，提出了ADAR1通过参与B细胞受体信号通路调控活化B细胞分化途径的分子机制。

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