腺苷A2a受体偏移介导子痫前期母体IgG产生机制研究

Pregnancy is a process of chronic stress, but the pregnant body can evade effectively the damage from the immunoreaction and inflammation by the compensatory mechanism of high-expression of adenosine /adenosine receptors. The fact that the high expression of adenosine receptor A2a is involved in the chronic stress injury is confusing. We hypothesized that sub-stimulation induced excess hydrogen sulfide and adenosine. The inhibition of excess hydrogen sulphide on the adenylate cyclase played the important role of inhibiting from adenosine activating the adenylate cyclase by A2a receptor and resulting in the decrease of cAMP in B lymphocyte.The high expression of the A2a receptor is opposite to the generation of cAMP, that is, the shift of A2a receptor. We proposed the hypothesis that "the shift of A2a receptor" may mediate the production of PE autoantibodies. In order to verify the hypothesis, this subject induced the PE model by trace LPS to Confirm the excess adenosine and hydrogen sulfide mediating the generation of IgG,confirm that the shift of A2a receptor of B cells lead to decreasing of intracellular cAMP generation was the key point of production of IgG and clear the mechanism of generation of IgG by reduction of cAMP. The aim of this study was to elucidate the pathogenesis of PE autoantibodies, and provide a new clue for the development of PE .

妊娠是一慢性应激过程，母体通过高表达腺苷/腺苷受体等代偿机制有效地逃避了免疫和炎症反应所致损伤。而新近发现腺苷受体A2a高表达参与慢性应激性损伤之事实正为人们所困惑。我们推测亚刺激激发母体硫化氢(H2S)和腺苷产生异常增加，过高的H2S通过抑制B细胞膜上腺苷酸环化酶(AC)而拮抗A2a受体信号对AC激活作用，而致B细胞内环磷酸腺苷（cAMP）生成减少。这种A2a受体高表达与cAMP生成背离，即为“A2a受体偏移”。本课题提出“A2a受体偏移”可能介导PE自身抗体产生之假说。为此，拟采用微量LPS复制PE模型，从整体和离体层面阐明H2S高表达引发B细胞A2a偏移，并介导IgG产生之机制；证实B细胞A2a受体偏移导致B细胞胞内cAMP减少系IgG产生关键所在；明确cAMP减少引发IgG产生之分子机制。旨在阐明PE自身抗体产生之发病机制，为PE防治策略制定提供新的线索。

妊娠是一慢性应激过程，母体通过高表达腺苷/腺苷受体等代偿机制有效地逃避了免疫和炎症反应所致损伤。研究发现腺苷受体A2a高表达参与慢性应激性损伤之事实正为人们所困惑。我们通过研究发现亚刺激激发母体硫化氢(H2S)和腺苷产生异常增加，过高的H2S通过抑制B细胞膜上腺苷酸环化酶(AC)而拮抗A2a受体信号对AC激活作用，而致B细胞内环磷酸腺苷（cAMP）生成减少。这种A2a受体高表达与cAMP生成背离，即为“A2a受体偏移”。本课题提出“A2a受体偏移”可能介导PE自身抗体产生之假说。复制PE动物模型，从整体和离体层面阐明H2S高表达引发B细胞A2a偏移，并介导IgG产生之机制；证实B细胞A2a受体偏移导致B细胞胞内cAMP减少系IgG产生关键所在；明确cAMP减少引发IgG产生之分子机制。本项目得出以下结论：1.腺苷受体A2A通过刺激G蛋白亚基(Gs)诱导腺苷酸环化酶（AC）从而诱导细胞内第二信使分子cAMP水平。2.激活腺苷A2A可刺激磷脂酰肌醇3-激酶(PI3K)/AKT通路，从而诱导ROS,EETs,PGI2和NO的释放，我们特别重要发现激活单核巨噬细胞、 Th2细胞、血管内皮细胞、成纤维细胞A2A受体可激活白介素IL-6释放。后者是决定参与间充质干细胞功能的关键分子。3.尽管各种应激源的刺激可上调腺苷A2A受体，但未发生本课题所预期腺苷A2A受体偏移现象。但我们确定过强应激源可刺激ATP经连接蛋白或泛连接蛋白通道使细胞内ATP释放之细胞外，细胞损伤也是细胞外ATP增加的重要因素。我们认为细胞外ATP的水平是左右腺苷受体功能的关键所在。4.结合我们先前的工作我们相关，我们认为胚胎即为应激源，正常妊娠系因胎盘-胎儿发育正常，妊娠相关激素，如雌激素促进胎盘干细胞正常发育，后者豁免胚胎的不良刺激，从而维系妊娠正常进行。倘若妊娠相关激素不足胎盘源性干细胞发育不良，势必导致其免疫调控功能不足从而引发PE。本项目旨在阐明PE自身抗体产生之发病机制，为PE防治策略制定提供新的线索。