Genetic factors that regulate innate immunity

描述(申请人提供)：所有多细胞生物体都已发展出对入侵微生物产生先天免疫反应的能力，该系统提供了抵御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有机体提供了关于手头威胁性质的重要早期信息，从而确保适当调整适应性免疫反应，以有效地消除感染源。免疫系统的细胞检测微生物表达的病原体相关分子模式，即PAMP，这反过来会导致基因表达和细胞功能的急剧变化，这些变化共同作用，启动对病原体的协调保护反应。巨噬细胞暴露于广谱的PAMPs会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被称为“炎性小体”的细胞质蛋白复合体的组装。炎症体由一种NLR蛋白组成，它根据遇到的PAMP或DAMP(病原体或危险相关的分子模式)直接或间接触发的细胞变化而寡聚。寡聚化的NLR蛋白通过其CARD和PYRIN结构域向复合体招募额外的蛋白质，包括ASC(PYCARD)和原caspase-1。两个前caspase-1蛋白的募集导致自身催化和活性酶的释放，然后可以将前IL-1b裂解成具有生物活性的形式。NLRP蛋白已成为哺乳动物体内炎性小体活性的关键调节因子，并因此成为先天免疫反应的重要调节因子。其中研究最广泛的是NLRP3。该蛋白在家族性感冒自体炎症综合征(FCAS)、Muckle-Wells综合征(MWS)和慢性婴儿神经皮肤关节综合征/新生儿起病多系统炎症性疾病(CINCA/NOMID)患者中发生突变。该基因错义突变杂合子的个体患有以血清IL-1b升高为特征的过度炎症。最近，NLRP3基因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。在这一应用中，我们提出了一种新的方法来研究CAPS的分子病理生理学，并定义该基因中与疾病相关的多态的功能。

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.