Sensitization to Cockroach Allergen: Immune Regulation and Genetic Determinants

描述(申请人提供)：哮喘是一种严重的慢性疾病，影响着世界各地的许多儿童。在生命早期接触蟑螂变应原可导致过敏反应 并增加患哮喘的风险。然而，其潜在的免疫机制和遗传病因仍不清楚。最近的研究表明，C型凝集素受体(CLR)家族的成员在功能上与变应原相互作用，在控制免疫反应中起着关键作用。这为研究它们在过敏反应中的生物学作用及其遗传效应提供了一种新的途径。在这方面，编码甘露糖受体的CD206(MRC1)是CLR家族的主要成员，已被证明介导Bla G2(蟑螂变应原)的摄取。具体地说，我们正在进行的研究导致了一个新的观察结果，即CD206在人类单核细胞来源的纤维细胞中高表达，这种独特的细胞既表达造血细胞(CD34，CD45，MHC II类)又表达基质细胞(I型和III型胶原)，并在功能上与Bla G2相互作用。我们的初步研究还提供了初步证据，支持CD206在介导蟑螂变应原诱导的哮喘小鼠模型中的过敏反应中的作用。此外，我们的遗传分析表明，CD206的序列变异与两个独立人群中的哮喘存在显著关联。因此，该阶段将对蟑螂变应原-CD206轴在过敏反应中的功能意义进行批判性评估。假设：CLRs，特别是纤维细胞表达的CD206，可能在蟑螂变应原过敏反应中发挥关键作用。目的1研究蟑螂变应原与CD206在纤维细胞中的功能相互作用。我们将使用成熟的体外模型，通过基因沉默和受体阻断的方法，研究CD206介导的蟑螂变应原诱导的纤维细胞成熟、激活和抗原提呈细胞(APC)在T细胞增殖和极化(Th1/Th2/Th17)中的功能。目的研究CD206和纤维细胞在蟑螂变应原诱导的炎症和气道重塑中的作用。我们将利用蟑螂过敏性哮喘的小鼠模型来测试CD206基因缺陷小鼠是否对蟑螂变应原诱导的呼吸道炎症有保护作用，并研究纤维细胞在调节气道免疫和纤维化反应中的作用以及CD206对纤维细胞功能的调节作用。最后，目标3建议进行研究，以评估CD206序列变异与蟑螂致敏之间的关联，并确定它们在基因表达和功能中的作用。我们将使用有针对性的深度测序来识别CD206的遗传变异，并测试它们与非裔美国人蟑螂敏感化的关系。然后，我们将测试基因与环境的交互作用，以确定蟑螂暴露对蟑螂敏化的影响。我们将最终确定CD206基因变异在基因功能调节中的作用。这将为了解蟑螂变应原CD206轴在变态反应性疾病发病机制中的作用提供新的见解，并为新的治疗方法提供机会。

DESCRIPTION (provided by applicant): Asthma is a serious chronic illness that affects many children worldwide. Exposure to cockroach allergen in early life can lead to allergic sensitization and increase the risk of developing asthma. However, the underlying immune mechanisms and genetic etiology remain unclear. Recent advances have demonstrated that members of the C-type lectin receptor (CLR) family functionally interact with allergens and are critical in controllng immune response. This offers a novel avenue to investigate their biological role in allergic responses and their genetic effects. In this regard, CD206 (MRC1), encoding mannose receptor, a major member of the CLR family, has been shown to mediate Bla g2 (cockroach allergen) uptake. Specifically, our ongoing study has led to a novel observation that CD206 is highly expressed in human monocyte-derived fibrocytes, unique cells expressing both hematopoietic cells (CD34, CD45, MHC class II) and stromal cells (collagen I and III), and functionally interacts with Bla g2. Our preliminary studies have also provided initial evidence supporting a role of CD206 in mediating cockroach allergen -induced allergic responses in a mouse model of asthma. Furthermore, our genetic analysis has demonstrated a significant association for sequence variants in CD206 and asthma in two independent populations. The stage is thus set to critically evaluate the functional significance of the cockroach allergen-CD206 axis in allergic responses. HYPOTHESIS: CLRs, particularly CD206 expressed by fibrocytes, may play a pivotal role in allergic responses to cockroach allergen. Aim 1 proposes experiments to investigate the functional interaction of cockroach allergen and CD206 in fibrocytes. We will use a well-established ex vivo model to investigate the CD206-mediated cockroach allergen induced fibrocyte maturation, activation, and antigen presenting cell (APC) function in T cell proliferation and polarization (Th1/Th2/Th17) by using gene silencing and receptor blocking approaches. Aim 2 proposes experiments to determine the role of CD206 and fibrocytes in cockroach allergen-induced inflammation and airway remodeling. We will use mouse models of cockroach allergic asthma to test whether CD206 deficient mice are protected from cockroach allergen-induced airway inflammation, and to study the role of fibrocytes in regulating both airway immunological and fibrotic responses and the modulatory effects of CD206 on fibrocyte function. Finally, Aim 3 proposes studies to assess association between sequence variants in CD206 and cockroach sensitization and to determine their role in gene expression and function. We will identify genetic variants in CD206 using targeted deep-sequencing and test their associations with cockroach sensitization among African Americans. We will then test for gene-environment interactions to determine the effect of cockroach exposure on the association with cockroach sensitization. We will finally determine the role of CD206 genetic variants in regulation of gene function. This will provide novel insights into the role of cockroach allergen-CD206 axis in the pathogenesis of allergic diseases and offer an opportunity for novel therapies.