日本血吸虫虫源抗原与抗原递呈细胞的相互作用的（体外）实验研究
发布时间：2018-11-05 16:15
【摘要】： 日本血吸虫病(schistosomiasis japonica)迄今仍然是我国主要公共卫生问题之一。依据疾病传播的生态学原理确定的综合防治措施虽然有效,但效果难以巩固。鉴于疫苗在许多传染病控制中无可比拟的作用,试图发展血吸虫病疫苗是二十世纪六十年代以来世界各国有关科学家为之奋斗的目标。但经过长期努力,迄今尚未能成功研制出有效的抗血吸虫感染的疫苗,其原因在于对血吸虫感染中存在的一些免疫现象及其分子机制的认识还比较模糊,因而极大地限制了我们明确选择日本血吸虫病疫苗发展。 辐照致弱尾蚴疫苗免疫可以诱导相对高水平的保护力。由于现实的条件和伦理的原因,不能以辐照致弱尾蚴直接免疫人。关于辐照尾蚴免疫诱导高保护力的机制,现有的主要观点是:辐照诱导了尾蚴成分的改变并因此更加有效地诱导了免疫活化;另一种观点认为辐照致弱尾蚴不能发育为成虫产卵,从而避免了虫卵沉积和虫卵抗原释放对宿主免疫应答的下调和抑制作用,从而可以使机体内存在的,已经被辐照致弱尾蚴抗原(attenuated cercaria antigen, ACA)活化的免疫细胞,对再次接触到的来自正常尾蚴的抗原发生有效的活化并发挥有效的攻击和杀伤效应。以往研究多以体内实验对获得性免疫应答的免疫效应进行观察和分析,或者对正常尾蚴抗原(normal cercaria antigen, NCA)与ACA组分进行比较分析。这些研究结果为理解辐照致弱尾蚴诱导保护力的分子机制提供了诸多支持。 基于先天免疫在启动和调节免疫应答中的重要作用,观察和比较日本血吸虫NCA和/或ACA以及可溶性虫卵抗原(soluble egg antigen, SEA)对抗原递呈细胞(antigen presenting cells, APCs)的作用也具有重要意义,可为解释辐照致弱尾蚴诱导保护力的分子机制提供新的视角。一方面,APCs摄取病原体成分并降解为小分子抗原肽,通过主要组织相容性复合体Ⅱ类分子(major histocompatibility complexⅡ, MHCⅡ)递呈给T细胞受体(T cell receptor, TCR)识别;另一方面,APCs通过模式识别受体(pattern recognition receptors, PRRs)识别病原体相关的分子模式(pathogen-associated molecular pattern,.PAMP),启动信号转导和基因表达,分泌各种细胞因子对免疫应答起重要的调节作用。本研究基于APCs在启动和调节免疫应答中的关键作用,着眼于血吸虫抗原对MHCⅡ表达的调节,着重观察了血吸虫感染早期和晚期阶段涉及的两种重要抗原,即NCA、ACA和SEA对小鼠巨噬细胞模型细胞系RAW264.7的免疫调节。 本研究结果证实,日本血吸虫SEA可以显著抑制IFN-γ诱导的巨噬细胞MHCⅡ的表达;IFN-γ可以促进SEA诱导巨噬细胞分泌IL-10和IL-6;IL-10对介导SEA诱导的MHCⅡ下调起重要作用,SEA也通过诱导IL-6抑制MHCⅡ表达;在IFN-γ存在条件下,SEA诱导巨噬细胞分泌TGF-β的过程受到抑制并且未显示TGF-β对MHCⅡ的抑制作用; SEA通过TLR4识别下调巨噬细胞MHCⅡ表达。 本研究结果显示,NCA与ACA不同地调节巨噬细胞MHCⅡ分子表达,NCA可以显著下调IFN-γ诱导巨噬细胞表达MHCⅡ,而ACA对IFN-γ诱导巨噬细胞表达MHCⅡ不具有明显影响;NCA在IFN-γ存在条件下诱导巨噬细胞产生的IL-10、IL-6和PGE2均显著高于ACA刺激组。这些结果提示正常尾蚴可能通过诱导APCs分泌抑制性因子下调MHCⅡ表达实现免疫逃避,而辐照则可能由于导致尾蚴成分变化而废除或者抑制了其中抑制MHCⅡ表达的因素,从而有效地致敏和活化了T细胞。 总之,本研究从日本血吸虫尾蚴和虫卵抗原对MHCⅡ表达的调节的角度,为血吸虫感染后期免疫应答的下调和抑制以及正常尾蚴感染与辐照尾蚴免疫诱导的免疫应答活化和效应的差异提供了合理的解释,其中的相关分子机制值得进一步探讨。
[Abstract]:The schistosomiasis japonica is still one of the main public health problems in China. The comprehensive prevention and control measures based on the ecology principle of disease transmission are effective, but the effect is difficult to consolidate. In view of the unparalleled role of vaccines in many infectious diseases control, attempts to develop schistosomiasis vaccines have been the goal of the world's scientists in the 1960s. However, after long-term efforts, effective vaccines against schistosome infection have not been successfully developed so far, and the reason is that some immune phenomena and their molecular mechanisms exist in the infection of schistosome, Therefore, we have greatly restricted the development of schistosomiasis vaccine in Japan. Induction of relatively high levels of immune responses induced by radiation-induced weak immune vaccine Due to the actual conditions and the ethical reasons, it cannot be directly irradiated by irradiation. The main point of view is that irradiation induces a change in the cytoskeleton component and thus more effectively induces immune activation; another view is that radiation-induced weakness does not develop as The adult oviposition, so as to avoid the down regulation and the inhibition of the egg deposition and egg antigen release on the host immune response, so that the existing antibody which is present in the organism, which has been activated by the irradiated weak nuclear antigen (ACA), can be caused to exist in the organism. immune cells that effectively activate and play an effective attack on antigens from normal cells that are again in contact, The effects of anti-killing effect on immune response in vivo were observed and analyzed, or normal cercasia antigen (NCA) and ACA component were analyzed. The results of these studies provide the molecular mechanism for understanding the protective force induced by irradiation. Many support. Based on the important role of innate immunity in the initiation and regulation of immune response, the antigen presenting cells (APCs) of Schistosoma japonicum NCA and/ or ACA and soluble egg antigen (SEA) were observed and compared. It also plays an important role in explaining the distribution of protective force induced by irradiation induced by irradiation. Submechanism provides a new perspective. On the one hand, APCs ingest pathogen components and degrade to small molecular antigenic peptides, which are presented to T cell receptors (TCR) by major histocompatibility complex II molecules (MHC II). On the other hand, APCs are identified by pattern recognition receptors. receptors, prrs) identification of pathogen-related molecular patterns (pathogen-associated molecula r pattern,. PAMP), activate signal transduction and gene expression, secrete various cytokines to immunize This study is based on the key role of APCs in the initiation and regulation of immune responses, focusing on the regulation of the expression of MHC 鈪，
本文编号：2312606
[Abstract]:The schistosomiasis japonica is still one of the main public health problems in China. The comprehensive prevention and control measures based on the ecology principle of disease transmission are effective, but the effect is difficult to consolidate. In view of the unparalleled role of vaccines in many infectious diseases control, attempts to develop schistosomiasis vaccines have been the goal of the world's scientists in the 1960s. However, after long-term efforts, effective vaccines against schistosome infection have not been successfully developed so far, and the reason is that some immune phenomena and their molecular mechanisms exist in the infection of schistosome, Therefore, we have greatly restricted the development of schistosomiasis vaccine in Japan. Induction of relatively high levels of immune responses induced by radiation-induced weak immune vaccine Due to the actual conditions and the ethical reasons, it cannot be directly irradiated by irradiation. The main point of view is that irradiation induces a change in the cytoskeleton component and thus more effectively induces immune activation; another view is that radiation-induced weakness does not develop as The adult oviposition, so as to avoid the down regulation and the inhibition of the egg deposition and egg antigen release on the host immune response, so that the existing antibody which is present in the organism, which has been activated by the irradiated weak nuclear antigen (ACA), can be caused to exist in the organism. immune cells that effectively activate and play an effective attack on antigens from normal cells that are again in contact, The effects of anti-killing effect on immune response in vivo were observed and analyzed, or normal cercasia antigen (NCA) and ACA component were analyzed. The results of these studies provide the molecular mechanism for understanding the protective force induced by irradiation. Many support. Based on the important role of innate immunity in the initiation and regulation of immune response, the antigen presenting cells (APCs) of Schistosoma japonicum NCA and/ or ACA and soluble egg antigen (SEA) were observed and compared. It also plays an important role in explaining the distribution of protective force induced by irradiation induced by irradiation. Submechanism provides a new perspective. On the one hand, APCs ingest pathogen components and degrade to small molecular antigenic peptides, which are presented to T cell receptors (TCR) by major histocompatibility complex II molecules (MHC II). On the other hand, APCs are identified by pattern recognition receptors. receptors, prrs) identification of pathogen-related molecular patterns (pathogen-associated molecula r pattern,. PAMP), activate signal transduction and gene expression, secrete various cytokines to immunize This study is based on the key role of APCs in the initiation and regulation of immune responses, focusing on the regulation of the expression of MHC 鈪，
本文编号：2312606
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