The Role of IgA in S. aureus Mediated Inflammation

描述(申请人提供)：金黄色葡萄球菌感染通常导致血液传播，导致炎症和关节破坏。尽管与这种细菌相关的毒力因素已经确定，但宿主免疫反应在限制炎症过程中的作用仍然知之甚少。利用有针对性地干扰IgA基因表达的小鼠(IgA-/-小鼠)，我们最近展示了IgA的另一个尚未被认识的角色。具体地说，IgA似乎在维持明显的炎性细胞因子和一氧化氮(NO)的产生方面起着至关重要的作用。我们现在将详细研究免疫球蛋白A在调节细菌伤害时全身炎症反应中的免疫调节作用的基础。利用一株能引起脓毒症和关节破坏的金黄色葡萄球菌，我们将首先利用IgA-/-小鼠研究IgA在限制炎症过程中的确切作用。感染后将对血液、脾和肾脏进行菌血症评估。血液和淋巴组织中炎性细胞因子的产生将分别通过酶联免疫吸附试验和核糖核酸酶保护分析进行监测。这些动物关节的炎症将通过免疫组织化学进行评估。由于一氧化氮的产生在金黄色葡萄球菌感染过程中可能既有害又有益，我们将通过组织学分析来检查缺乏IgA是否会增强感染小鼠关节中的一氧化氮表达。鉴于核因子-kB途径在iNOS和NO产生的调控中是必不可少的，我们将通过细胞和分子分析来研究IgA的缺失如何影响这一途径的各个组成部分。最后，我们将确定IgA是否调节细菌刺激下巨噬细胞的抑制信号通路。总之，这些研究将确定IgA是否通过直接与先天性免疫系统相互作用来调节对系统性细菌感染的炎症反应。这一结果将有助于深入了解血清IgA在调节细菌败血症等炎症过程中的作用，并可能导致将IgA用作治疗性抗炎剂。

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.