A novel pathway for small molecule delivery to Peyer's patch follicles

 描述(由申请人提供)：肠道微环境必须仔细平衡，以维持宿主细胞和共生微生物之间的互惠关系，同时保持对不良病原体的不允许。肠道感染和肠道疾病对应于由于宿主-微生物相互作用的正常途径的破坏而导致的增强的适应性免疫反应。因此，识别和了解宿主免疫细胞访问肠腔中存在的信号和抗原的方式，以及这些方式在疾病状态下是如何改变的，一直是人们感兴趣的问题。我们的初步数据表明，位于小肠Peyer‘s斑块的成纤维细胞基质细胞形成了一个富含胶原的网状管道网络，参与了跨越表面上皮的小分子可溶性分子的选择性运输。目前尚不清楚这种新的分子传输途径是否会使免疫细胞更容易获得可溶信号或抗原。因此，这项拟议研究的第一个目标将解决这样一种可能性，即肠道Peyer‘s Patc的网状管道网络可能作为一种重要的、歧视性的途径，将小分子分子输送到PP毛囊的免疫细胞群。为此，我们将仔细确定管道网络中允许的分子类型，并确定PP中驻留的免疫细胞能够获得流经这些结构的信号或抗原的程度。有趣的是，我们的初步发现还表明，分子通过这些管道网络的运输需要通过上皮细胞的净水吸收提供定向液体流动--这一过程在感染和炎症性疾病的情况下经常被破坏。免疫细胞接触肠腔内容物和感知微生物种群的受控途径可能决定宿主与微生物相互作用的性质。因此，这项研究的第二个目的将从功能上测试在吸收不良和感染性腹泻疾病的条件下，管道介导的运输依赖于定向液体流动可能在功能上限制这一途径的可能性。我们假设，仔细分析Peyer的补片管道用于将管腔内容物在细胞间运输到免疫细胞的程度，以及该系统对改变的液体吸收条件的敏感性，将对微生物感觉和粘膜免疫反应产生重要的见解。

 DESCRIPTION (provided by applicant): The intestinal microenvironment must be carefully balanced to maintain a mutualistic relationship between host cells and commensal microbes while remaining non-permissive to undesirable pathogenic species. Enteric infection and intestinal disorders correspond to enhanced adaptive immune responses resulting from a breakdown in the normal avenues of host-microbe interactions. Identifying and understanding the means by which signals and antigen present in the intestinal lumen are accessed by host immune cells, and how these means are altered in a diseased state, has thus been a longstanding interest. Our preliminary data suggest that fibroblastic stromal cells located in small intestinal Peyer's patches form a network of collagen-rich reticular conduits which participate in the selective transport of small soluble molecules that have crossed the surface epithelium. Whether this novel avenue of molecular transport renders soluble signals or antigen more accessible to immune cells remains unclear. The first aim of this proposed study will therefore address the possibility that the reticular conduit network of the intestinal Peyer's patc functions as an important, discriminatory avenue for delivery of small molecular weight molecules to the immune cell population of the PP follicle. To this end, we will carefully ascertain the types of molecules permitted within the conduit network and determine the extent to which immune cells resident in the PP are capable of acquiring the signals or antigen that flow through these structures. Interestingly, our preliminary findings also suggest that transport of molecules through these conduit networks require directional fluid flow provided by net water absorption across the epithelium - a process that is often disrupted under conditions of infectious and inflammatory disease. The controlled avenues by which immune cells encounter lumenal contents of the intestine and sense microbial populations likely determine the nature of host-microbe interactions. The second aim of this study will therefore functionally test the possibility that the dependence of conduit-mediated transport on directional fluid flow may functionally limit this pathway under conditions of malabsorption and infectious diarrheal disease. We hypothesize that careful analysis of the extent to which peyer's patch conduits are utilized for intercellular transport of lumenal contents to immune cells, and the sensitivity of ths system to conditions of altered fluid absorption, will yield important insights to microbial sensin and mucosal immune responses.