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，其特征是一种流行病，不成比例地影响代表性不足的少数民族和儿童。哮喘的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Th 2介导的反应。多项独立的哮喘全基因组关联研究（GWAS）已经确定，在不同的种族/人种中，与哮喘相关的基因最一致。然而，IL-33/ST 2在调节哮喘中的天然-适应性免疫相互作用中的生物学作用和机制仍有待确定。最近的证据表明，IL-33激活的树突状细胞（DC）是Th 2介导的过敏性气道炎症的关键。此外，自噬是一个核心的细胞过程，有助于细胞内稳态与新兴的联系，哮喘的发病机制。自噬参与将潜在的细胞质抗原递送至内体以供DC降解、加工、活化和呈递;并且其活性在哮喘气道中增加。我们假设IL-33/ST 2和自噬通路在哮喘和过敏性疾病中起着至关重要的作用，并且IL-33/ST 2通过自噬调节Th 2介导的过敏性气道炎症中的先天适应性免疫相互作用。我们已经完成了ST 2的靶向重测序，以识别罕见的变异以及在非洲血统人群中没有被GWAS平台上的单核苷酸多态性（SNP）很好地“标记”的常见变异。我们确定了一种新的和常见的单倍型，确定血清水平的可溶性ST 2（sST 2），这是由三个启动子的变体，可能会改变转录因子结合。对哮喘GWAS数据库的计算机分析确定了84个选定的关键自噬途径基因中的11个，这些基因的变异与非洲裔美国人的哮喘风险显著相关，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R 01母基金中，我们几乎完成了1,000多例哮喘病例和非哮喘对照的全基因组测序，这些病例和对照组成了“美洲非洲血统人群哮喘联盟”（CAAPA）。由此产生的超过1,000名非洲血统哮喘患者的独特遗传变异目录为识别IL-33/ST 2和自噬途径中的常见和罕见变体提供了独特的机会。本申请的具体目的是：（i）鉴定与哮喘相关的84种自噬途径基因中的罕见和常见变体;和（ii）测试IL-33/ST 2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/ST 2调节哮喘患者和非哮喘对照（每组N=20）中的先天适应性免疫相互作用的机制。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提供新的靶点。

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.