Genetic factors that regulate innate immunity

描述（由申请人提供）：所有多细胞生物都具有对入侵微生物产生先天免疫反应的能力，该系统提供了抵抗这些病原体的第一道防线。此外，不同病原体引发的先天反应的差异为生物体提供了有关手头威胁性质的基本早期信息，从而确保适当调整适应性免疫反应以有效消除感染因子。免疫系统细胞检测微生物表达的病原体相关分子模式，或PAMPs，这反过来导致基因表达和细胞功能的巨大变化，这些变化共同起作用，启动对病原体的协调保护反应。巨噬细胞暴露于广谱PAMPs导致细胞因子的产生和释放增加，特别是多效性促炎细胞因子IL-1b的加工和释放。IL-1b的成熟和释放依赖于称为“炎性小体”的细胞质蛋白复合物的组装。炎性小体由NLR蛋白组成，该蛋白在遇到PAMPs或DAMPs（病原体或危险相关分子模式）直接或间接触发细胞变化时寡聚化。寡聚NLR蛋白通过其CARD和PYRIN结构域招募额外的蛋白质到复合物中，包括ASC （PYCARD）和前caspase-1。两个前caspase-1蛋白的募集导致自催化和释放活性酶，然后可用于将前IL-1b切割成其生物活性形式。NLRP蛋白已成为哺乳动物炎性小体活动的关键调节因子，因此也是先天免疫反应的调节因子。其中研究最广泛的是NLRP3。该蛋白在患有家族性感冒自身炎症综合征（FCAS）、Muckle-Wells综合征（MWS）和慢性婴儿神经皮肤关节综合征/新生儿多系统炎症性疾病（CINCA/NOMID）的个体中发生突变。该基因杂合错义突变的个体会出现以血清IL-1b升高为特征的过度炎症。最近，NLRP3基因座的常见变异与越来越多的慢性疾病有关，包括克罗恩病和关节炎。在这个应用中，我们提出了一种新的方法来研究CAPS的分子病理生理学和定义该基因中疾病相关多态性的功能。

DESCRIPTION (provided by applicant): All multicellular organisms have developed the ability to mount an innate immune response to invading microbes, and this system provides the first line of defense against these agents. In addition, differences in the innate response triggered by different pathogens provide essential early information to the organism concerning the nature of the threat at hand, thus ensuring proper tailoring of the adaptive immune response to efficiently eliminate the infectious agent. Cells of the immune system detect pathogen-associated molecular patterns, or PAMPs, expressed by the microbes, and this in turn leads to dramatic changes in gene expression and cell function, changes which together act to initiate a coordinated protective response to the pathogen. Exposure of macrophages to a broad spectrum of PAMPs results in increased production and release of cytokines, notably the processing and release of the pleiotropic, pro-inflammatory cytokine, IL-1b. Maturation and release of IL-1b is dependent on the assembly of cytoplasmic protein complexes referred to as "inflammasomes". The inflammasome is composed of an NLR protein that oligomerizes in response to changes in the cell triggered either directly or indirectly by the encountered PAMPs or DAMPs (pathogen or danger-associated molecular patterns). The oligomerized NLR proteins recruit additional proteins to the complex via their CARD and PYRIN domains, including ASC (PYCARD), and pro-caspase-1. The recruitment of two pro-caspase-1 proteins leads to autocatalysis and release of active enzyme, which is then available for cleavage of pro IL-1b into its biologically active form. The NLRP proteins have emerged as critical regulators of the activity of the inflammasome and thus of the innate immune response in mammals. The most extensively studied of these is NLRP3. This protein is mutated in individuals suffering from familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous articular syndrome/neonatal-onset multisystem inflammatory diseases (CINCA/NOMID). Individuals heterozygous for missense mutations in this gene suffer from excessive inflammation characterized by increased serum IL-1b. More recently, common variants in the NLRP3 locus have been associated with an increasing number of chronic diseases including Crohn's disease and arthritis. In this application we propose a novel approach for study of the molecular pathophysiology of CAPS and for defining the functionality of disease associated polymorphisms in this gene.