AIF-1介导日本血吸虫感染小鼠Th2反应极化中的作用

In the first weeks of schistosoma infection, a Th1 type immune response is observed when the host is exposed to schistosomula and semi-mature schistosomes. After 5-6 weeks with the onset of egg deposition, a pronounced Th2 immune response comes up. The granuloma formation induced by soluble egg antigens and subsequent fibrosis owing to Th2 polarization are the main pathologic manifestations. However, the molecular mechanism of Th2 polarization is not clear. Allograft inflammatory factor 1 (AIF-1) was an important factor involved in many inflammatory diseases and autoimmune diseases. It can function as an immune regulator through inhibiting Th1 type response or promoting Th2 type response. In our previous study, it was observed that the expression of AIF-1 was enhanced in mice infected with Schistosoma japonicum, and the tendency of its expression was consistent with that of Th2 response. It suggested that AIF-1 could function in the development of inflammatory reaction in schistosomiasis by regulating the balance of Th1/Th2. Based on above information, we would like to elucidate its effect through neutralizing AIF-1 by anti-AIF-1 monoantibodies, and giving exogenous AIF-1 to mice infected with Schistosoma japonicum respectively. Then we could demonstrate the mechamism of AIF-1 in immune regulation by observing the pathologic manifestation in liver and polarization of Th1/Th2 response. Based on this research, we will know more about the immunological mechanism of schistosomiasis and this may offer alternative strategies for prevention of granuloma formation and liver fibrosis in schistosomiasis.

血吸虫感染早期刺激机体产生Th1型反应,自成虫产卵开始免疫反应向Th2型偏向并导致肝脏的虫卵肉芽肿及纤维化反应，但具体分子机制尚不明确。研究发现同种异体移植物炎症因子1（AIF-1）作为一种重要的炎症因子可参与多种炎症反应性病变，并抑制机体Th1型反应，促进免疫反应向Th2型偏向。本课题组前期实验发现日本血吸虫感染的小鼠体内AIF-1表达升高且其变化趋势与Th2反应变化一致，提示AIF-1在血吸虫感染所致肝脏炎症反应中可能通过介导Th2反应极化而参与病变的发展。基于以上资料，本研究拟通过外源性给予抗AIF-1单克隆抗体中和AIF-1以及给予AIF-1后分别观察日本血吸虫感染小鼠的急慢性期肝脏病变情况以及机体Th1/Th2反应偏向情况，以明确AIF-1在血吸虫感染中的免疫调节作用，从而阐明血吸虫病免疫调节的分子机制，为控制血吸虫病肉芽肿和纤维化病变提供参考。

日本血吸虫病是严重危害人群健康的第二大热带病，作为一种免疫性疾病，其诱导机体Th1/Th2反应极化的分子机制仍不清楚。近来发现的同种异体移植物炎症因子1（AIF-1）主要是由巨噬细胞和淋巴细胞等免疫细胞表达的一种重要炎症因子，并且可以参与多种炎症、肿瘤、神经系统损伤及自身免疫性疾病等免疫反应性过程。课题组在前期研究中发现AIF-1在日本血吸虫感染急性期的小鼠体内表达升高，表明其参与了血吸虫感染的过程，但具体机制不明确。本研究通过外源性给予AIF-1多肽处理和构建AIF-1稳定高表达的转基因小鼠，观察其对血吸虫感染小鼠肝脏病变和机体Th1/Th2反应的影响。通过AIF-1多肽干预感染小鼠，发现干预组小鼠在感染后肝脏坏死和纤维化病变均减轻，感染14周纤维化减轻最明显，但细胞因子变化不明显。AIF-1基因高表达小鼠相对于非转基因小鼠，在血吸虫感染后早期促进Th1反应，慢性期促进Th2反应。以上研究表明，AIF-1作为一种重要的炎性因子参与了血吸虫感染的病变过程。