Feedback regulation of innate immune signaling at mucosal surfaces

描述（由申请人提供）：作为人类，我们持续暴露于病原体。我们的先天免疫系统必须能够区分致病性和非致病性生物体，并且必须能够调整免疫反应以应对致病性生物体。这个问题在粘膜表面特别严重，粘膜表面是身体的一个区域，其中表面细胞与细菌、真菌和病毒直接接触。当病原体被根除后初始先天免疫应答未充分下调时，在这些粘膜表面引发许多炎性病症，包括克罗恩病。在本研究中，我们研究了在粘膜表面控制这种下调的机制。我们已经发现，一个关键的抗炎蛋白，A20，是磷酸化和激活的中央激酶在NF-？B信号通路（IKK 2）。我们绘制了磷酸化位点，并表明它是完全A20抑制活性所必需的。我们产生了一个磷酸化特异性抗体对这个网站，我们已经表明，这种磷酸化发生在体内响应一些炎症刺激。我们的中心假设是IKK依赖的A20磷酸化导致一种新的反馈机制，以抑制NF-？B反应，使得在粘膜表面不发生太多炎症。IKK不能磷酸化A20可能导致炎症病理学，如克罗恩病中所见。这项补助金旨在验证这一假设。粘液免疫调节对多种病毒、细菌和真菌病原体的初始免疫应答。粘膜免疫失调是多种炎性疾病的起始事件，包括炎性肠病、哮喘、肾盂肾炎和许多原发性免疫缺陷。了解这种失调是如何发生的，对于了解慢性炎症性疾病的病理生理学和预防暴露于病原体后发生这种失调都具有相关性。 粘液免疫调节对多种病毒、细菌和真菌病原体的初始免疫应答。粘膜免疫失调是免疫系统疾病的起始事件， 多种炎性疾病，包括炎性肠病、哮喘、肾盂肾炎和许多原发性免疫缺陷。了解这种失调是如何发生的，对于了解慢性炎症性疾病的病理生理学和预防暴露于病原体后发生这种失调都具有相关性。

DESCRIPTION (provided by applicant): As humans, we are continuously exposed to pathogens. Our innate immune system must be able to differentiate pathogenic from nonpathogenic organisms, and it must be able to tailor an immune response to respond to that pathogenic organism. This problem is particularly acute at mucosal surfaces, an area of the body in which the surface cells are in direct contact with bacteria, fungi and viruses. A number of inflammatory disorders, including Crohn's Disease, are initiated at these mucosal surfaces when the initial innate immune response is not adequately down-regulated after the pathogen is eradicated. In this grant, we study the mechanisms that control this down-regulation at mucosal surfaces. We have found that a key anti-inflammatory protein, A20, is phosphorylated and activated by the central kinase in the NF-?B signaling pathway (IKK2). We mapped the site of phosphorylation and have shown that it is required for full A20 inhibitory activity. We generated a phospho-specific antibody against this site, and we have shown that this phosphorylation occurs in vivo in response to a number of inflammatory stimuli. Our central hypothesis is that the IKK-dependent phosphorylation of A20 leads to a novel feedback mechanism to inhibit the NF-?B response such that too much inflammation does not occur at mucosal surfaces. Failure of IKK to phosphorylate A20 may lead to inflammatory pathology such as that seen in Crohn's Disease. This grant is designed to test this hypothesis. Mucosal immunity regulates the initial immune response to a variety of viral, bacterial and fungal pathogens. Dysregulation of mucosal immunity is an initiating event in a variety of inflammatory disorders including Inflammatory Bowel Disease, Asthma, Pyelonephritis and a number of primary immunodeficiencies. Understanding how this dysregulation occurs will have relevance both for understanding the pathophysiology of chronic inflammatory diseases and for preventing this dysregulation from occurring after exposure to pathogens. PUBLIC HEALTH RELEVANCE Mucosal immunity regulates the initial immune response to a variety of viral, bacterial and fungal pathogens. Dysregulation of mucosal immunity is an initiating event in a variety of inflammatory disorders including Inflammatory Bowel Disease, Asthma, Pyelonephritis, and a number of primary immunodeficiencies. Understanding how this dysregulation occurs will have relevance both for understanding the pathophysiology of chronic inflammatory diseases and for preventing this dysregulation from occurring after exposure to pathogens.