The autophagic pathway and atopic asthma: role of IL-33 and ST2

描述（由申请人提供）：哮喘是一种主要的公共卫生负担，其特点是流行病，不成比例地影响代表性不足的少数民族和儿童。哮喘下气道炎症特征的通常来源是由常见的环境过敏原引发的th2介导的反应。多个独立的哮喘全基因组关联研究（GWAS）已经确定，在不同的民族/种族群体中，与哮喘相关的基因最为一致。然而，IL-33/ST2在哮喘中调节先天适应性免疫相互作用的生物学作用和机制仍有待明确。最近的证据表明，il -33激活的树突状细胞（dc）对Th2介导的过敏性气道炎症至关重要。此外，自噬是促进细胞稳态的核心细胞过程，与哮喘的发病机制有新的联系。自噬参与将潜在的细胞质抗原传递到核内体，由dc降解、加工、激活和递呈；它的活性在哮喘气道中增加。我们假设IL-33/ST2和自噬途径在哮喘和过敏性疾病中都起着至关重要的作用，IL-33/ST2在th2介导的过敏性气道炎症中通过自噬调节先天适应性免疫相互作用。我们已经完成了ST2的靶向重测序，以确定非洲血统人群GWAS平台上的罕见变异以及未被单核苷酸多态性（snp）很好“标记”的常见变异。我们发现了一种新的和常见的单倍型，它决定血清可溶性ST2 （sST2）的水平，它由三个启动子变体组成，可能改变转录因子的结合。对哮喘GWAS数据库的计算机分析发现，84个选定的关键自噬途径基因中的11个变异与非裔美国人哮喘风险显著相关，表明该途径的变异可能普遍导致哮喘风险。在这项新申请的亲本R01拨款中，我们几乎完成了由“美洲非洲裔人群哮喘联盟”（CAAPA）组成的bb1000例哮喘病例和非哮喘对照的全基因组测序。由此产生的独特的遗传变异目录在1000000个非洲血统的哮喘患者中被选中，为鉴定IL-33/ST2和自噬途径中的常见和罕见变异提供了独特的机会。该应用程序的具体目的是：(i)识别与哮喘相关的84种自噬途径基因的罕见和常见变异；（ii）检测IL-33/ST2介导的自噬通量作为树突状细胞稳态的关键决定因素，以及IL-33/ST2调节哮喘患者和非哮喘对照组先天适应性免疫相互作用的机制（每组N=20）。这些研究的结果将为哮喘的发病机制、遗传基础和种族差异以及临床治疗的新靶点提供见解。

DESCRIPTION (provided by applicant): Asthma represents a major public health burden characterized as an epidemic that disproportionately affects underrepresented minorities and children. The usual source of the lower airway inflammation characteristic of asthma is a Th2-mediated reaction initiated by common environmental allergens. Multiple independent genome-wide association studies (GWAS) on asthma have identified, as the most consistently associated genes with asthma among diverse ethnic/racial groups. However, the biological role and mechanism of IL-33/ST2 in modulating the innate-adaptive immunity interaction in asthma remains to be defined. Recent evidence suggests that IL-33-activated dendritic cells (DCs) are critical for Th2- mediated allergic airway inflammation. Moreover, autophagy is a core cellular process that contributes to cellular homeostasis with emerging links to the pathogenesis of asthma. Autophagy is involved in the delivery of potential cytoplasmic antigens to the endosome for degradation, processing, activation and presentation by DCs; and its activity is increased in asthmatic airways. We hypothesize that both the IL-33/ST2 and autophagic pathways play a crucial role in asthma and allergic diseases and IL-33/ST2 modulates the innate-adaptive immunity interaction via autophagy in Th2-mediated allergic airway inflammation. We have completed targeted resequencing of ST2 to identify rare variants as well as common variation that is not well "tagged" by the single nucleotide polymorphisms (SNPs) on the GWAS platforms in populations of African ancestry. We identified a novel and common haplotype that determines serum levels of soluble ST2 (sST2), which is comprised of three promoter variants that potentially alter transcription factor binding. In silico analyses of asthma GWAS databases identify 11 out of 84 selected key autophagic pathway genes for which variants are significantly associated with risk of asthma in African Americans, suggesting variation in this pathway may universally contribute to asthma risk. In the parent R01 grant to this new application, we have nearly completed whole-genome sequencing of >1,000 asthma cases and non-asthmatic controls comprising the 'Consortium on Asthma among African-ancestry Populations in the Americas' (CAAPA). The resulting unique catalog of genetic variation in >1,000 individuals of African ancestry selected for asthma provides a unique opportunity to identify common and rare variants in the IL-33/ST2 and autophagic pathways. Specific aims of this application are: (i) To identify rare and common variants in 84 autophagic pathway genes associated with asthma; and (ii) To test IL-33/ST2-mediated autophagic flux as a critical determinant of dendritic cell homeostasis and the mechanisms by which IL-33/ST2 regulates the innate-adaptive immunity interaction in asthmatic patients and non-asthmatic controls (N=20 each group). Results from these studies will provide insight into the pathogenesis, the genetic underpinnings and ethnic disparities of asthma as well as novel targets for therapy in the clinic.