Sensitization to Cockroach Allergen: Immune Regulation and Genetic Determinants

描述（由申请人提供）：哮喘是一种严重的慢性疾病，影响世界各地的许多儿童。生命早期接触蟑螂过敏原可导致过敏性致敏 并增加患哮喘的风险。然而，潜在的免疫机制和遗传病因学仍不清楚。最近的研究表明，C型凝集素受体（C-type lectin receptor，C-Lectin receptor，C-Lectin receptor）家族成员与过敏原相互作用，在免疫应答中起着关键作用。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新的途径。在这方面，编码甘露糖受体的CD 206（MRC 1），甘露糖受体家族的主要成员，已显示介导Bla g2（蟑螂变应原）摄取。具体而言，我们正在进行的研究已经导致了一个新的观察结果，即CD 206在人单核细胞来源的纤维细胞中高度表达，这种独特的细胞表达造血细胞（CD 34，CD 45，MHC II类）和基质细胞（胶原蛋白I和III），并在功能上与Bla g2相互作用。我们的初步研究也提供了初步证据，支持CD 206在哮喘小鼠模型中介导蟑螂过敏原诱导的过敏反应中的作用。此外，我们的遗传分析表明，在两个独立的人群中，CD 206序列变异与哮喘有显著的相关性。因此，该阶段被设置为批判性地评估蟑螂过敏原-CD 206轴在过敏反应中的功能意义。假设：CLRs，特别是由纤维细胞表达的CD 206，可能在对蟑螂过敏原的过敏反应中起关键作用。目的1研究蟑螂变应原与CD 206在纤维细胞中的相互作用。我们将使用一个完善的离体模型，研究CD 206介导的蟑螂过敏原诱导的纤维细胞成熟，激活和抗原呈递细胞（APC）的功能，T细胞增殖和极化（Th 1/Th 2/Th 17），通过使用基因沉默和受体阻断方法。目的2提出实验以确定CD 206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。我们将使用蟑螂过敏性哮喘的小鼠模型来测试CD 206缺陷小鼠是否免受蟑螂变应原诱导的气道炎症的影响，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CD 206对纤维细胞功能的调节作用。最后，目标3提出了研究，以评估CD 206序列变异和蟑螂致敏之间的关联，并确定其在基因表达和功能中的作用。我们将使用靶向深度测序来识别CD 206的遗传变异，并测试它们与非裔美国人中蟑螂致敏的关联。然后，我们将测试基因与环境的相互作用，以确定接触蟑螂对蟑螂致敏性的影响。我们将最终确定CD 206遗传变异在基因功能调节中的作用。这将为蟑螂变应原-CD 206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.