Immunoregulation /Immune Recognition In Filarial/Nonfilarial Parasitic Infection

淋巴丝虫病中寄生虫抗原特异性人类T细胞应答的深刻调节的机制已经通过证明涉及的多个途径来解决。 通过使用活的寄生虫和寄生虫抗原，我们已经证明，抗原呈递细胞（APC）的功能是深刻的改变，丝虫感染，最近显示，在人类的循环mDCs有显着的改变，在淋巴丝虫病患者的表面表型。 此外，淋巴丝虫病已被证明诱导循环单核细胞的表型（如在小鼠系统中看到的），提示替代激活。 除了APC功能障碍之外，来自专利感染患者的T细胞诱导了共同阻止Th1型T细胞活化的途径。 我们最近已经表明，丝虫感染在稳态与IL-10产生适应性T细胞因子以及nT细胞因子的扩增相关，并且这些与寄生虫抗原诱导的促炎性Th1细胞的抑制相关。 由于下调机制诱导慢性蠕虫感染，我们试图研究的溢出效应的下调反应和疾病是非寄生虫。为此，我们正在进行临床试验和体外模型，证明了预先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HIV和疟疾的潜在影响。具体来说，我们最近已经证明，并发丝虫感染深刻地改变了促炎和Th1/Th17对疟疾抗原（在丝虫/疟疾合并感染）和分枝杆菌抗原（在丝虫/潜伏性结核合并感染）的反应。 由于许多与丝虫感染相关的病理学与淋巴功能障碍有关，我们建立了一个人体体外模型来研究寄生虫/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），我们已经能够证明存在诱导淋巴管生成和异常脉管形成的丝虫寄生虫分子。此外，在LEC丝虫寄生虫诱导的基因表达的全球变化的特点。 丝虫诱导的CD4+和CD8+反应已被充分表征（使用微阵列/定量RT-PCR），在一般更敏感的外籍患者和反应较低的土著（终身暴露）丝虫感染患者。 这些数据为感染诱导的途径和慢性蠕虫感染中观察到的系统性改变提供了线索。 使用非常类似的方法，我们也能够证明感染了与遗传学上不同的寄生虫密切相关的患者中的表达特征（例如，Loa loa和Mansonella perstans）。

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 and most recently showing that circulating mDCs in humans have significant alterations in surface phenotype in patients with lymphatic filariasis. Moreover, lymphatic filariasis has been shown to induce circulating monocytes with a phenotype (like that seen in murine systems) suggestive of alternative activation. Beyond the APC dysfunction, T cells from patients with patent infection have induced pathways that in concert prevent Th1-type T cell activation. We have recently shown that the filarial infection at homeostasis is associated with an expansion of IL-10 producing adaptive Tregs as well as nTregs and that these are associated with the suppression of parasite-antigen induced pro-inflammatory Th1 cells. Because downregulatory mechanims are induced in chronic helminth infection, we have attempted to study the spillover effect of the 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 and malaria. Specifically, we have recently demonstrated that coincident filarial infections profoundly alter the pro-inflammatory and Th1/Th17 responses to malarial antigens (in filarial/malarial coinfections) and to mycobacterial antigens (in filarial/latent tuberculosis coinfections). 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).