Investigating the role of follicular dendritic cells in TSE agent neuroinvasion from lymphoid tissues

传染性海绵状脑病是一种致命的神经退行性疾病。例子包括人类的克雅氏病（CJD）、牛海绵状脑病（BSE）、骡子鹿和麋鹿的慢性消耗性疾病（CWD）以及绵羊和山羊的痒病。大多数TSE媒介的自然传播是通过外周暴露发生的，例如：摄入（口服）。接种后，TSE制剂通常在感染中枢神经系统（CNS）之前在淋巴组织的滤泡树突状细胞（FDCs）上积累。fdc对于疾病向中枢神经系统（神经侵袭）的传播至关重要，因为缺少fdc时，淋巴组织中的药物积累和神经侵袭受到损害。TSE病原体的性质尚不清楚，但宿主细胞朊病毒蛋白（PrPc）的异常亚型（PrPSc）与传染性共同纯化。事实上，在接种某些TSE剂后，在fdc上检测到PrPSc。细胞必须表达细胞PrPc才能复制TSE试剂。尽管在未感染小鼠的fdc上检测到PrPc，但尚不清楚fdc是否表达PrPc并复制TSE因子。消耗fdc的治疗可降低对TSE制剂的易感性。因此，在确定风险和设计针对外周获得性TSE的治疗策略时，全面了解fdc在TSE发病机制中的作用是非常重要的。fdc在其表面长时间捕获和保留天然抗原。因此，它们参与TSE的发病机制可能是捕获从感染细胞释放的TSE因子并介导它们向神经元的转移。许多细胞类型分泌富含细胞特异性蛋白的外泌体。fdc可以结合外泌体，并因此在其表面显示不以mRNA水平表达的蛋白质。PrPc和PrPSc可以在外泌体中释放，这为fdc从其他感染细胞获得PrPc和TSE提供了一种机制。实验排除了骨髓来源的细胞作为在fdc上检测到的PrPc和PrPSc的主要提供者。然而，不能排除非造血细胞（如肌肉细胞、内皮细胞、上皮细胞或神经细胞）的参与。我们将使用新的方法提供关于FDC生物学及其参与TSE发病机制的重要信息。O-1: fdc是表达PrPc还是从其他宿主细胞获得？O-2: fdc是否复制TSE因子，还是从其他受感染的宿主细胞获得TSE因子？加深对fdc参与TSE发病机制的了解可能有助于制定治疗策略。

Transmissible spongiform encephalophathies (TSEs) are fatal neurodegenerative diseases. Examples include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) in mule deer and elk, and scrapie in sheep and goats. Most natural transmissions of TSE agents occur by peripheral exposure, eg: ingestion (oral). After inoculation, TSE agents usually accumulate upon follicular dendritic cells (FDCs) in lymphoid tissues before they infect the central nervous system (CNS). FDCs are critical for the spread of disease to the CNS (neuroinvasion) as in their absence agent accumulation in lymphoid tissues and neuroinvasion are impaired. The nature of the TSE agent is not known, but an abnormal isoform (PrPSc) of the host cellular prion protein (PrPc), co-purifies with infectivity. Indeed, PrPSc is detected upon FDCs after inoculation with some TSE agents. Cells must express cellular PrPc to replicate TSE agents. Although PrPc is detected on FDCs in uninfected mice, it is not known if FDCs express PrPc and replicate TSE agents. Treatments that deplete FDCs reduce susceptibility to TSE agents. Thus, a thorough understanding of the involvement of FDCs in TSE pathogenesis is important when determining risk, and designing therapeutic strategies against peripherally-acquired TSEs. FDCs trap and retain native antigens on their surfaces for long durations. Thus their involvement in TSE pathogenesis may be to trap TSE agents released from infected cells and mediate their transfer to neurones. Many cell types secrete exosomes enriched in cell-specific protein. FDCs can bind exosomes, and as a consequence display proteins on their surfaces that they do not express at the mRNA level. PrPc and PrPSc can be released in exosomes, providing a mechanism by which FDCs might acquire PrPc and TSE agents from other infected cells. Experiments have excluded bone marrow-derived cells as major providers of the PrPc and PrPSc detected on FDCs. However, the involvement of non-haematopoietic cells (eg: muscle, endothelial, epithelial or nerve cells) cannot be excluded. We will use novel approaches to provide important information on FDC biology and their involvement in TSE pathogenesis. In particular we will address the following objectives: O-1: Do FDCs express PrPc or acquire it from other host cells? O-2: Do FDCs replicate TSE agents, or acquire them from other infected host cells? Increased understanding of the FDCs involvement in TSE pathogenesis may aid the development of therapeutic strategies.