Immunoregulation /immune Recognition In Filarial/Nonfilarial Parasitic Infection

在淋巴丝虫病中，寄生虫抗原特异的人类T细胞反应的深刻调节的机制已经通过展示所涉及的多个途径来解决。通过使用活体寄生虫和寄生虫抗原，我们证明了丝虫感染时抗原提呈细胞(APC)功能在转录和蛋白质水平上都发生了深刻的变化。此外，这种APC功能障碍还延伸到TLR-3和-4信号通路。 除了APC功能障碍外，来自专利感染患者的T细胞还诱导了多种途径(SoCs基因、泛素连接酶、调节网络)，共同阻止Th1型T细胞的激活。此外，诱导细胞凋亡似乎是活丝虫影响宿主反应(至少在树突状细胞和NK细胞中)的一种常见机制，并且这种机制依赖于TRAIL和caspase 3。 由于下调机制是在慢性蠕虫感染中诱导的，我们试图研究这种下调机制对非寄生性反应和疾病的溢出效应。为此，我们有正在进行的临床试验和体外模型，这些模型已经证明了先前存在的慢性蠕虫感染对分枝杆菌易感性的影响，对调节对空气过敏原的反应，以及对艾滋病毒的潜在影响。 由于与丝虫感染相关的大部分病理与淋巴功能障碍有关，我们建立了一个人体体外模型来检查寄生虫/淋巴细胞的相互作用。通过从血管内皮细胞(BEC)中纯化淋巴管内皮细胞(LEC)，我们已经能够证明丝虫分子的存在可以诱导淋巴管生成和异常的血管形成。此外，丝虫寄生虫在LEC中诱导的基因表达的全球变化也得到了表征。 丝虫引起的CD4+和CD8+反应已在一般反应较敏感的外籍患者和反应较差的本土(终生暴露)丝虫感染患者中得到充分表征(使用微阵列/定量RT-PCR)。这些数据提供了感染诱导的途径和慢性蠕虫感染中所见的系统性变化的线索。使用非常类似的方法，我们也能够展示感染由系统发育不同的寄生虫(例如Loa Loa和Mansonella perstans)密切相关的患者的表达特征。

The mechanisms underlying the profound modulation of parasite antigen-specific human T cell responses in lymphatic filariasis have been addressed by demonstrating the multiple pathways involved. By using live parasites and parasite antigen, we have demonstrated that antigen presenting cell (APC) function is profoundly altered in filarial infection both at the transcriptional and protein level. Moreover, this APC dysfunction extends to TLR-3 and -4 signaling pathways. Beyond the APC dysfunction, T cells from patients with patent infection have induced pathways (SOCS genes, ubiquin ligases, regulatory networks) that in concert prevent Th1-type T cell activation. Moreover, the induction of apoptosis appears to be a common mechanism by which live filarial parasites influence the host response (in dendritic cells and NK cells at least) and does so in a TRAIL- and caspase 3-dependent fashion. Because downregulatory mechanims are induced in chronic helminth infection, we have attempted to study the spillover effect of the this downregulation on responses and diseases that are non-parasitic. To this end, we have both clinical trials underway and in vitro models that have demonstrated the influence of pre-existing chronic helminth infection on susceptibility to mycobacteria, on modulating the response to aeroallergens, and potentially to HIV. Because much of the pathology associated with filarial infections is related to lymphatic dysfunction, we have established a human in vitro model to examine parasite/lymphatic cell interaction. By purifying lymphatic endothelial cells (LEC) from blood vascular endothelial cells (BEC), we have been able to demonstrate the presence of filarial parasite molecules that induce lymphangiogenesis and abnormal vasculuar tube formation. In addition, the global changes in gene expression induced by filarial parasites in LEC have been characterized. Filarial-induced CD4+ and CD8+ responses have been characterized fully (using microarray/quantitative RT-PCR) in both the generally more-responsive expatriate patients and the less responsive indigenous (with lifelong exposure) filarial-infected patients. These data provide clues to the pathways induced by infection and those systemic alterations seen in chronic helminth infection. Using a very similar approach, we have also been able to demonstrate expression signatures among patients infected with closely-related by phylogenetically distinct parasites (e.g., Loa loa and Mansonella perstans).