CC10调控ILC2在变应性鼻炎发病机制中的作用研究

Immune response imbalance plays an important role in the pathogenesis of allergic rhinitis (AR). Recently, it is discovered that type 2 innate lymphoid cells (ILC2) can modulate immune response polarization in the early phase of allergic disease, but the regulation of ILC2 in tissue microenvironment and particular disease environment is unknown. Our previous study demonstrated that Clara cell 10-kDa protein (CC10) is able to inhibit Th2 and Th17 immune response and can suppress the expression of cytokines which promote ILC2 proliferation and activation in AR mice model. On this basis, we speculate that CC10 can regulate the function of ILC2 and may play an important role in AR. To illuminate the specific mechanism of CC10 regulated ILC2 in AR, we intent to establish wild type, CC10 knockout mice and CC10 protein treatment AR mice model, compare the number and function of ILC2 in nasal mucosa; screen difference in gene expression of ILC2 between groups by gene array technology; then blocking abnormal expression of genes selectively; clarify the precise molecular mechanisms of ILC2 regulation by CC10 in mice; next isolate ILC2 from the AR patients nasal mucosa and cultured in vitro, observe the molecular mechanism and illuminate the signal pathway underlying the regulation of CC10 on ILC2 in vitro. This project seeks to clarify the precise role of CC10 regulated ILC2 in the early phase of AR mucosal inflammation and may offer a novel target in the management for AR.

免疫反应失衡在变应性鼻炎（AR）发病过程中起重要的作用，最近发现的2型固有淋巴细胞（ILC2）可在变应性疾病早期调节免疫反应分化，但ILC2在组织微环境及特定疾病环境中的调控不明，我们前期研究发现clara细胞10-kDa蛋白（CC10）可抑制Th2及Th17免疫反应，并能在AR小鼠模型中抑制促ILC2增殖活化的细胞因子表达。由此推测CC10能具有调控ILC2的功能，为明确CC10调控的ILC2在AR发病的机制，我们拟建立野生型、CC10基因敲除及重组CC10蛋白处理的小鼠AR模型，比较各组鼻黏膜ILC2的数量和功能及基因表达差异，进而选择性阻断异常表达的基因，阐明小鼠体内CC10调控ILC2的分子机制；然后分离培养AR患者鼻黏膜ILC2，在体外环境研究CC10调控ILC2的精确分子机制及信号通路。本课题力图揭示CC10调控的ILC2在AR黏膜炎症早期的作用机制，为AR临床研究提供依据。

免疫反应失衡在变应性鼻炎（AR）发病过程中起重要的作用，AR主要表现为TH2免疫反应增强，最近发现的固有淋巴细胞（ILCs）可在变应性疾病早期调节免疫反应分化，ILC2在炎症反应早期可分泌TH2细胞因子，促使免疫反应向TH2方向分化，我们前期研究发现CC10可抑制Th2及Th17免疫反应，在呼吸道上皮细胞中发挥抗炎和免疫调节的作用，因此我们推测CC10能具有调控ILC2的功能，在AR发病早期起抑制作用。本研究建立了野生型和CC10过表达AR小鼠模型，研究发现在小鼠AR鼻黏膜上皮组织中，促ILC2增殖分化的细胞因子IL-25和IL-33的表达明显增高，ILC2表面标志c-kit、CD127和IL-17RB也有明显上调，说明ILC2参与AR发病过程，而在CC10过表达AR模型中，上述上调反应均受到明显抑制，CC10可通过抑制ILC2来抑制变应性鼻炎的发病，可在AR发病早期发挥抑制作用。在体外培养的鼻黏膜上皮细胞试验中，变应原尘螨刺激的鼻黏膜上皮细胞促ILC2增殖分化的细胞因子IL-25和IL-33的表达也有明显增高，CC10质粒转染处理可抑制尘螨刺激的鼻黏膜上皮细胞IL-25和IL-33的上调表达，说明ILC2的激活也参与了人变应性鼻炎的发病，CC10亦可通过抑制ILC2的活化来抑制人变应性鼻炎的发病。最后，为了解CC10调控 ILC2 可能作用的靶点，我们用小鼠AR对照组和CC10过表达AR模型做了基因芯片分析，下一步工作需筛选出表达差异较大的基因，并进行验证，为AR基础和临床研究提供依据。

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