The function of factor X and PAR-2 in the early immune response against Leishmania major

感染敏感和耐药小鼠品系的硕大利什曼原虫是一种自然抗性和Th 2-或Th 1-细胞发育的模型疾病，我们的重点在于感染部位的事件。我们追求的假设，即淋巴结中的Th细胞分化是至关重要的影响，从早期的信号，在受感染的皮肤，严格管制的炎症微环境。所谓的危险信号产生于感染的皮肤，影响抗原呈递细胞的功能之前，他们的迁移到淋巴结和随后的相互作用与T细胞在淋巴结通过第三信号。使用全基因组表征，我们发现了几个局部组织信号，这是早期和敏感和耐药小鼠之间的差异表达。值得注意的是，几种已知的Th 1诱导细胞因子的表达在时间上限于感染的前两天，与确定T细胞应答的时间范围一致。一个重要的来源是角质形成细胞。由于其数量众多，它们能够产生足够量的细胞因子。在易感小鼠中高度表达的少数基因之一是趋化因子CXCL 11。当将其注射到抗性C57 BL/6小鼠中时，其引起Th 2应答和更高的寄生虫滴度，但其局部中和在BALB/c小鼠中不引起Th 1应答。我们以前专注于已经暗示在Th 1分化的基因。我们现在已经扩大了我们的范围，因为我们还发现了在耐药C57 BL/6小鼠的皮肤中凝血因子X（FX）的更高表达。在缺乏已知FX受体（即蛋白酶激活受体2（PAR-2））的抗性背景小鼠中，我们观察到更高的寄生虫滴度和Th 2应答。由于凝血系统和免疫系统相互影响，并且PAR-2和FX可能在其中发挥关键作用，因此我们现在希望进一步研究这些发现，因此，本项目的目标是阐明PAR-2有助于抵抗的机制以及FX和其他PAR-2激动剂在此过程中的相关性。此外，我们希望建立凝血系统的其他因素是否参与Th 1/Th 2免疫应答，以及凝血系统是否是利什曼病和其他infection.We的药理学靶点，我们期望进一步了解利什曼病的病理生理学以及在一般机制的Th细胞分化，所有的背景下，相互依存的凝血系统和炎症。这些结果可能有助于其他Th 1或Th 2依赖性炎症的新治疗方法。

The Infection of susceptible and resistant mice strains with Leishmania major is a model disease for natural resistance and the development of Th2- or Th1-cells.Our focus lies on the events at the site of infection. We pursue the hypothesis that Th-cell differentiation in the lymph node is crucially influenced by signals from the early, tightly regulated inflammatory micromilieu in the infected skin. So called danger signals produced in the infected skin influence the function of antigen presenting cells prior to their migration to the lymph node and the subsequent interaction with T-cells in the lymph node via third signals.Using a genome wide characterization, we found several local tissue signals which are early and differentially expressed between susceptible and resistant mice. Remarkably, the expression of several known Th1-inducing cytokines was temporally restricted to the first two days of infection, coinciding with the time frame during which the T-cell response is determined. One important source are keratinocytes. Due of their high number, they are able to produce sufficient amounts of cytokines. One of the few genes more highly expressed in susceptible mice is the chemokine CXCL11. It causes a Th2 response and higher parasite titers when injected in resistant C57BL/6 mice, but its local neutralization did not cause a Th1 response in BALB/c mice.Therefore we have focused again on potential Th1-inducing signals. We had previously focused on genes already implied in Th1 differentiation. We now have widened our scope as we had also found higher expression of coagulation factor X (FX) in the skin of resistant C57BL/6 mice. In mice of resistant background which are deficient for a known receptor of FX, i.e. protease-activated receptor 2 (PAR-2), we then observed higher parasite titers and a Th2 response. Since the coagulatory and immune systems influence each other and because PAR-2 and FX probably play a key role in this, we now want to further investigate these findings.Thus, the goal of this project is to unravel the mechanisms by which PAR-2 contributes to resistance and the relevance of FX and other PAR-2 agonists in this process. Moreover, we want to establish whether other factors of the coagulation system are involved in the Th1/Th2 immune response and whether the coagulation system is a pharmacological target in leishmaniasis and other infections.We expect further insights in both the pathophysiology of leishmaniasis as well as in general mechanisms of Th-cell differentiation, all in context of the interdependence of the coagulatory system and inflammation. The results may facilitate new therapeutic approaches in other Th1- or Th2-dependent inflammations.