Heparan Sulfate-TLR in Health, Injury and Immunity

描述（由申请人提供）：对多细胞生物体健康的许多感染性和有害性挑战由保护性免疫反应控制。保护性免疫的一些方面是组成性的，而一些方面是当外来生物或其产物与免疫和炎症细胞上的专门受体（称为toll样受体）相互作用时诱导的。这一概念可以完全解释对产生刺激分子（如脂多糖）的细菌生物体的免疫唤醒，但不能解释对不能产生外源性激动剂的病毒、某些毒素、肿瘤或移植物的免疫是如何提高的。当其他人和我们最近证明某些内源性β受体可以通过toll样受体刺激细胞时，这种限制被克服了。在炎症和组织损伤的过程中产生硫酸乙酰肝素蛋白聚糖和透明质酸的这些片段，从而在对生物体健康的威胁与先天性和适应性免疫应答的激发之间提供关键联系。因为toll样受体的一些内源性激活剂是组织组分的裂解产物，所以推测toll样受体可以在感知健康状况和潜在伤害状况两者中更广泛地起作用。本申请中提出的研究将确定硫酸乙酰肝素与类阿片受体相互作用的方式。这项工作将确定硫酸乙酰肝素如何与受体结合，产生信号并引起生物反应。将使用表达正常或突变的toll样受体的鼠细胞和其中受体表达被诱导的细胞来解决该目的。该研究还将阐明Toll样受体如何在正常的静息条件下与硫酸乙酰肝素蛋白聚糖相互作用，并在受体受到刺激的条件下结束。该研究将确定Toll样受体如何在T细胞非依赖性和T细胞依赖性B细胞反应的产生中起作用。

DESCRIPTION (provided by applicant): Many infectious and noxious challenges to the well being of multi-cellular organisms are controlled by protective immune responses. Some facets of protective immunity are constitutive while some are induced when foreign organisms or their products interact with specialized receptors, called toll-like receptors, on immune and inflammatory cells. This concept may account completely for the arousal of immunity to bacterial organisms that produce stimulatory molecules such lipopolysaccharide but fails to account for how immunity is raised against viruses, certain toxins, tumors or transplants that fail to produce extrinsic agonists. This limitation was overcome when others and we recently demonstrated that certain endogenous saccharides could stimulate cells via toll-like receptors. These saccharides, fragments of heparan sulfate proteoglycans and hyaluronic acid, are generated in course of inflammation and tissue injury and thus provide a critical link between threats to the well being of the organism and arousal of innate and adaptive immune responses. Because some endogenous activators of toll-like receptors are the cleavage products of components of tissues, it is postulated that the toll like receptors may function more broadly in sensing both conditions of well being and conditions of potential harm. The research proposed in this application will determine the means by which heparan sulfate interacts with toil-like receptors. The work will determine how heparan sulfate associates with the receptors, generates a signal and gives rise to a biological response. This objective will be addressed using murine cells, which express normal or mutant toll-like receptors and cells in which receptor expression is induced. The research will also elucidate how toll-like receptors interact with heparan sulfate proteoglycans in the normal, resting conditions and end in conditions in which the receptors become stimulated. The research will determine how toll-like receptors function in the generation of T cell independent and T cell dependent B cell responses.