本文選題：瘧原蟲　切入點：巨噬細(xì)胞遷移抑制因子　出處：《北京協(xié)和醫(yī)學(xué)院》2010年博士論文

【摘要】：MIF (Macrophage Migration Inhibitory Factor)是一種具有多種生物學(xué)活性的細(xì)胞因子,在細(xì)胞生長、分化、以及天然免疫和獲得免疫中都具有重要的調(diào)節(jié)作用。研究發(fā)現(xiàn),宿主來源的MIF在瘧疾感染病理、特別是瘧疾感染導(dǎo)致的貧血中發(fā)揮了重要作用。近年來,包括本實驗室在內(nèi)的三個研究小組先后報道了三個瘧原蟲來源的MIF分子：Plasmodium falciparum MIF (PfMIF), P.berghei MIF (PbMIF)和P.yoelii MIF (PyMIF)。結(jié)構(gòu)和功能的初步研究結(jié)果顯示,瘧原蟲來源的MIF結(jié)構(gòu)保守,與宿主MIF的活性相似,具有調(diào)節(jié)宿主巨噬細(xì)胞的活性。但是,它如何調(diào)節(jié)宿主免疫系統(tǒng)、以及它在瘧疾感染和病理過程所扮演的角色目前仍然不清楚。 本論文首先通過臨床流行病學(xué)數(shù)據(jù),系統(tǒng)分析了PfMIF和P.vax MIF(PvMIF)水平與瘧疾感染程度和嚴(yán)重性之間的關(guān)系。在兩種瘧原蟲MIF特異性檢測技術(shù)建立的基礎(chǔ)上,定量檢測了瘧疾病人外周血中瘧原蟲MIF的水平,并將其與蟲血率、血紅蛋白、發(fā)熱情況、細(xì)胞因子等相關(guān)因素進(jìn)行統(tǒng)計學(xué)分析。結(jié)果顯示：1)患者外周血瘧原蟲MIF濃度與蟲血率呈正相關(guān)；2)與炎癥因子TNF-α、IL-10、MCP-1相關(guān),但與TGF-β1、IL-12無關(guān)；3) PvMIF水平與人MIF (HuMIF)和發(fā)熱(體溫)相關(guān),而PfMIF水平與二者無關(guān)；4)多元逐步分析結(jié)果顯示蟲血率、IL-10、HuMIF是PfMIF/PvMIF的預(yù)測分子。此外,本研究發(fā)現(xiàn)同時感染HIV、HCV和HBV并不影響患者外周血中瘧原蟲MIF的水平：而遺傳背景(HLA基因)在一定程度上與惡性瘧患者PfMIF是否檢出有關(guān)。患者經(jīng)抗瘧藥物治療過程中,絕大部分瘧疾病人外周血瘧原蟲MIF水平隨著癥狀減退和蟲血率的下降而下降,至治療后三至七天完全消失。以上結(jié)果證實瘧原蟲MIF水平是蟲血率的反映,與瘧疾病情的嚴(yán)重程度相關(guān),與瘧疾病程及轉(zhuǎn)歸相關(guān),因此理論上可以作為臨床診斷瘧疾病情嚴(yán)重程度及轉(zhuǎn)歸的標(biāo)志分子之一。 隨后,本研究嘗試研究P.yoelii MIF(PyMIF)對小鼠骨髓來源的樹突狀細(xì)胞(Bone Marrow Dendritic Cell, BM-DC)的調(diào)節(jié)效應(yīng),以宿主小鼠MIF分子作為對照,分別對BM-DC識別和捕獲抗原、成熟、對T細(xì)胞效應(yīng)等過程進(jìn)行了分析。實驗結(jié)果顯示：1)盡管PyMIF顯著下調(diào)BM-DC表面的TLR4水平,但并不影響B(tài)M-DC的吞噬功能；2)既不能促進(jìn)未成熟BM-DC的成熟,也不能抑制LPS對BM-DC的促成熟作用；3)PyMIF通過BM-DC下調(diào)CD8+T細(xì)胞表面CD69的表達(dá),但不影響CD8+T分泌IL-2,也不影響CD8+T細(xì)胞的細(xì)胞殺傷功能。以上結(jié)果說明盡管PyMIF對BM-DC具有某些微小的調(diào)節(jié)作用,但并不改變BM-DC的功能以及BM-DC誘導(dǎo)的CD8+T細(xì)胞功能。 本論文工作從體內(nèi)流行病學(xué)和體外細(xì)胞生物學(xué)兩方面探討了瘧原蟲MIF與瘧疾感染和機體免疫系統(tǒng)之間的關(guān)系,證實瘧原蟲MIF與瘧疾感染程度相關(guān),并為全面認(rèn)識其與機體免疫系統(tǒng)之間的關(guān)系提供重要數(shù)據(jù)。
[Abstract]:MIF Macrophage Migration Inhibitory Factor is a kind of cytokine with many biological activities, which plays an important role in the regulation of cell growth, differentiation, innate and acquired immunity.The study found that host-derived MIF plays an important role in the pathogenesis of malaria infection, especially anemia caused by malaria infection.In recent years, three research groups, including our laboratory, have reported three plasmodium falciparum MIF MIF molecules: Plasmodium falciparum MIF PfMIF, P.berghei MIF PbMIF) and P.yoelii MIF PyMIF.The preliminary results of structure and function showed that the structure of MIF from Plasmodium was conserved, similar to the activity of host MIF, and had the activity of regulating macrophage.But how it regulates the host immune system and its role in malaria infection and pathology remains unclear.Based on the clinical epidemiological data, the relationship between the levels of PfMIF and P.vax vMIF and the degree and severity of malaria infection was analyzed systematically in this paper.Based on the establishment of two MIF specific detection techniques, the level of Plasmodium MIF in the peripheral blood of malaria patients was quantitatively detected, and the relative factors such as blood rate, hemoglobin, fever and cytokines were analyzed statistically.The results showed that the concentration of MIF in peripheral blood of the patients was positively correlated with the blood rate of the parasite. (2) it was correlated with the inflammatory factor TNF- 偽, IL-10, MCP-1, but not with the level of TGF- 尾 1, IL-12). The level of PvMIF was correlated with MIF HuMIF) and fever (body temperature).The results of multivariate stepwise analysis showed that IL-10 HuMIF was the predictor of PfMIF/PvMIF.In addition, it was found that co-infection of HBV and HIV did not affect the level of MIF of Plasmodium falciparum in peripheral blood of patients. The genetic background of MIF gene was related to the detection of PfMIF in falciparum malaria patients to some extent.In the course of antimalarial drug treatment, the MIF level of the peripheral blood of most malaria patients decreased with the decrease of symptoms and blood rate, and disappeared completely 3 to 7 days after treatment.The above results confirm that the MIF level of Plasmodium is a reflection of the blood rate of the parasite, which is related to the severity of malaria, the course and outcome of malaria. Therefore, it can be used as a marker for clinical diagnosis of the severity and outcome of malaria.Subsequently, this study attempted to study the regulatory effects of P.yoelii MIF PyMIF on bone Marrow Dendritic cell (BM-DC) of murine bone marrow derived dendritic cells. The host mouse MIF molecule was used as a control group to recognize and capture antigens for BM-DC.The process of T cell effect was analyzed.The results showed that although PyMIF significantly down-regulated the TLR4 level on the surface of BM-DC, it did not affect the phagocytic function of BM-DC.It could not inhibit the effect of LPS on BM-DC maturation. PYMIF could down-regulate the expression of CD69 on the surface of CD8 T cells through BM-DC, but it did not affect the secretion of IL-2 by CD8 T, nor did it affect the cytotoxicity of CD8 T cells.These results suggest that although PyMIF has some minor regulatory effects on BM-DC, it does not alter the function of BM-DC and CD8 T cells induced by BM-DC.In this paper, the relationship between MIF and malaria infection and immune system in vivo and in vitro was studied. The results showed that MIF was related to the degree of malaria infection.It also provides important data for comprehensive understanding of the relationship between the immune system and the body.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2010
【分類號】：R392

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相關(guān)期刊論文 前1條

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本文編號：1698997