【摘要】： 日本血吸蟲病(schistosomiasis japonica)迄今仍然是我國主要公共衛(wèi)生問題之一。依據(jù)疾病傳播的生態(tài)學原理確定的綜合防治措施雖然有效,但效果難以鞏固。鑒于疫苗在許多傳染病控制中無可比擬的作用,試圖發(fā)展血吸蟲病疫苗是二十世紀六十年代以來世界各國有關科學家為之奮斗的目標。但經(jīng)過長期努力,迄今尚未能成功研制出有效的抗血吸蟲感染的疫苗,其原因在于對血吸蟲感染中存在的一些免疫現(xiàn)象及其分子機制的認識還比較模糊,因而極大地限制了我們明確選擇日本血吸蟲病疫苗發(fā)展。 輻照致弱尾蚴疫苗免疫可以誘導相對高水平的保護力。由于現(xiàn)實的條件和倫理的原因,不能以輻照致弱尾蚴直接免疫人。關于輻照尾蚴免疫誘導高保護力的機制,現(xiàn)有的主要觀點是:輻照誘導了尾蚴成分的改變并因此更加有效地誘導了免疫活化;另一種觀點認為輻照致弱尾蚴不能發(fā)育為成蟲產(chǎn)卵,從而避免了蟲卵沉積和蟲卵抗原釋放對宿主免疫應答的下調和抑制作用,從而可以使機體內存在的,已經(jīng)被輻照致弱尾蚴抗原(attenuated cercaria antigen, ACA)活化的免疫細胞,對再次接觸到的來自正常尾蚴的抗原發(fā)生有效的活化并發(fā)揮有效的攻擊和殺傷效應。以往研究多以體內實驗對獲得性免疫應答的免疫效應進行觀察和分析,或者對正常尾蚴抗原(normal cercaria antigen, NCA)與ACA組分進行比較分析。這些研究結果為理解輻照致弱尾蚴誘導保護力的分子機制提供了諸多支持。 基于先天免疫在啟動和調節(jié)免疫應答中的重要作用,觀察和比較日本血吸蟲NCA和/或ACA以及可溶性蟲卵抗原(soluble egg antigen, SEA)對抗原遞呈細胞(antigen presenting cells, APCs)的作用也具有重要意義,可為解釋輻照致弱尾蚴誘導保護力的分子機制提供新的視角。一方面,APCs攝取病原體成分并降解為小分子抗原肽,通過主要組織相容性復合體Ⅱ類分子(major histocompatibility complexⅡ, MHCⅡ)遞呈給T細胞受體(T cell receptor, TCR)識別;另一方面,APCs通過模式識別受體(pattern recognition receptors, PRRs)識別病原體相關的分子模式(pathogen-associated molecular pattern,.PAMP),啟動信號轉導和基因表達,分泌各種細胞因子對免疫應答起重要的調節(jié)作用。本研究基于APCs在啟動和調節(jié)免疫應答中的關鍵作用,著眼于血吸蟲抗原對MHCⅡ表達的調節(jié),著重觀察了血吸蟲感染早期和晚期階段涉及的兩種重要抗原,即NCA、ACA和SEA對小鼠巨噬細胞模型細胞系RAW264.7的免疫調節(jié)。 本研究結果證實,日本血吸蟲SEA可以顯著抑制IFN-γ誘導的巨噬細胞MHCⅡ的表達;IFN-γ可以促進SEA誘導巨噬細胞分泌IL-10和IL-6;IL-10對介導SEA誘導的MHCⅡ下調起重要作用,SEA也通過誘導IL-6抑制MHCⅡ表達;在IFN-γ存在條件下,SEA誘導巨噬細胞分泌TGF-β的過程受到抑制并且未顯示TGF-β對MHCⅡ的抑制作用; SEA通過TLR4識別下調巨噬細胞MHCⅡ表達。 本研究結果顯示,NCA與ACA不同地調節(jié)巨噬細胞MHCⅡ分子表達,NCA可以顯著下調IFN-γ誘導巨噬細胞表達MHCⅡ,而ACA對IFN-γ誘導巨噬細胞表達MHCⅡ不具有明顯影響;NCA在IFN-γ存在條件下誘導巨噬細胞產(chǎn)生的IL-10、IL-6和PGE2均顯著高于ACA刺激組。這些結果提示正常尾蚴可能通過誘導APCs分泌抑制性因子下調MHCⅡ表達實現(xiàn)免疫逃避,而輻照則可能由于導致尾蚴成分變化而廢除或者抑制了其中抑制MHCⅡ表達的因素,從而有效地致敏和活化了T細胞。 總之,本研究從日本血吸蟲尾蚴和蟲卵抗原對MHCⅡ表達的調節(jié)的角度,為血吸蟲感染后期免疫應答的下調和抑制以及正常尾蚴感染與輻照尾蚴免疫誘導的免疫應答活化和效應的差異提供了合理的解釋,其中的相關分子機制值得進一步探討。
[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，

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