The Role of IgA in S. aureus Mediated Inflammation

描述（由申请人提供）：金黄色葡萄球菌感染通常导致血行播散，导致炎症和关节破坏。虽然与这种细菌相关的毒力因子已经被确定，但宿主免疫反应在限制炎症过程中的作用仍然知之甚少。使用具有伊加基因表达靶向破坏的小鼠（伊加-/-小鼠），我们最近显示了伊加的另一种尚未被认识的作用。具体而言，伊加似乎在维持明显的炎性细胞因子和一氧化氮（NO）的产生中起重要作用。我们现在将详细研究伊加在细菌损伤后调节全身炎症反应中的免疫调节作用的基础。利用S.金黄色葡萄球菌，诱导脓毒症和关节破坏，我们将首先检查伊加在限制炎症过程中使用伊加-/-小鼠的确切作用。感染后，将在血液、脾脏和肾脏中评估菌血症。将分别通过ELISA和核糖核酸酶保护分析监测血液和淋巴组织中的炎性细胞因子产生。将通过免疫组织化学评估这些动物关节中的炎症。由于NO的产生在S.金黄色葡萄球菌感染后，我们将通过组织学分析来检查伊加的缺乏是否增强了感染小鼠关节中的NO表达。鉴于NF-kB途径是必不可少的调节iNOS和NO的生产，我们将研究如何伊加的情况下，通过细胞和分子分析影响这一途径的各个组成部分。最后，我们将确定伊加是否调节细菌刺激后巨噬细胞中的抑制性信号通路。总之，这些研究将确定伊加是否通过与先天免疫系统的直接相互作用来调节对全身性细菌感染的炎症反应。这些结果将提供关于血清伊加调节炎症过程如细菌性脓毒症的作用的见解，并可能导致使用伊加作为治疗性抗炎剂。

DESCRIPTION (provided by applicant): Staphylococcus aureus infections often lead to hematogenous spread that result in inflammation and joint destruction. Although the virulence factors associated with this bacteria have been defined, the role of the host immune response in limiting the inflammatory process is still poorly understood. Using mice with a targeted disruption in IgA gene expression (IgA-/- mice), we have recently shown another yet unrecognized role for IgA. Specifically, IgA appears to serve an essential role in maintenance of overt inflammatory cytokine and nitric oxide (NO) production. We will now investigate in detail the basis for the immunoregulatory role of IgA in modulating systemic inflammatory responses upon bacterial insult. Using a strain of S. aureus that induces sepsis and joint destruction, we will initially examine the precise role of IgA in limiting inflammatory processes using IgA-/- mice. Bacteremia will be assessed in the blood, spleen and kidneys after infection. Inflammatory cytokine production will be monitored in the blood and lymphoid tissues by ELISA and ribonuclease protection analysis respectively. Inflammation in the joints of these animals will be assessed by immunohistochemistry. Since NO production may have both detrimental and beneficial effects during S. aureus infection, we will examine if the absence of IgA potentiates NO expression in the joints of infected mice by histological analyses. Given that the NF-kB pathway is essential in the regulation of iNOS and NO production, we will examine how the absence of IgA affects various components of this pathway by cellular and molecular analyses. Finally we will determine if IgA regulates an inhibitory signaling pathway in macrophages upon bacterial stimulation. Together, these studies will determine if IgA modulates inflammatory responses to systemic bacterial infection by direct interaction with the innate immune system. The results will provide insight on the role of serum IgA to regulate inflammatory processes such as bacterial sepsis and may lead to the use of use of IgA as a therapeutic anti-inflammatory agent.