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液传播，导致炎症和关节破坏。虽然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。利用靶向破坏IgA基因表达的小鼠（IgA-/-小鼠），我们最近发现了IgA的另一个尚未被认识的作用。具体来说，IgA似乎在维持显性炎症细胞因子和一氧化氮（NO）的产生中起着重要作用。我们现在将详细研究IgA在细菌侵袭时调节全身炎症反应的免疫调节作用的基础。使用一种诱导脓毒症和关节破坏的金黄色葡萄球菌菌株，我们将使用IgA-/-小鼠初步研究IgA在限制炎症过程中的确切作用。感染后将在血液、脾脏和肾脏中评估菌血症。通过ELISA和核糖核酸酶保护分析分别监测血液和淋巴组织中炎症细胞因子的产生。这些动物的关节炎症将通过免疫组织化学来评估。由于NO的产生在金黄色葡萄球菌感染期间可能既有有害的影响，也有有益的影响，我们将通过组织学分析来检查IgA的缺失是否会增强感染小鼠关节中NO的表达。鉴于NF-kB通路在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的缺失如何影响该通路的各种成分。最后，我们将确定IgA是否在细菌刺激下调节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。该结果将提供关于血清IgA在调节炎症过程（如细菌性败血症）中的作用的见解，并可能导致使用IgA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.