白介素2介导的嗜碱性粒细胞活化在特应性皮炎中作用研究

Atopic dermatitis (AD) is a chronic inflammatory disease that greatly affects the health and quality of life of patients with AD. As one of the key effector cells, increased basophils in AD are associated with accumulated eosinophils and type 2 innate lymphoid cells (ILC2). However, the association of basophils with the severity of atopic dermatitis as well as the functions of basophils in regulating the biology of eosinophils and ILC2 in humans is not known yet. Our pilot studies by gene expression microarray analysis, for the first time, identified that human basophils highly expressed novel cytokines IL-1α/β, IL-5 and GM-CSF in response to IL-2 stimulation. We hypothesize that novel cytokines IL-1α/β, IL-5 and GM-CSF derived from IL-2-activated basophils regulate the activations of basophils, eosinophils and ILC2, thereby contributing to the pathogenesis of atopic dermatitis. In the proposed study, we therefore aim to I) determine the function and molecular mechanism of IL-2 in regulating the activation of human basophils; II) characterize the functions of IL-1α/β, IL-5 and GM-CSF derived from IL-2-stimulated basophils in regulating the functions of basophils, eosinophils and ILC2; III) elucidate the expression of basophils and their cytokines IL-1α/β, IL-5 and GM-CSF in mild-to-moderate and moderate-to-severe atopic dermatitis and their correlation with the disease severity. The proposed study, if successfully accomplished, will further unravel the role of basophils in regulating atopic dermatitis and provide evidence for developing effective strategies for treating atopic dermatitis.

特应性皮炎(AD)是慢性的炎症性皮肤疾病，严重影响患者的健康和生活质量，嗜碱性粒细胞（Ba）在AD中显著上升，且与嗜酸性粒细胞(Eo)和II型天然淋巴细胞（ILC2）正相关。然而Ba与AD的严重程度相关性未知，且人的Ba对Eo和ILC2的调控作用不明。我们通过基因芯片分析首次发现，IL-2介导Ba高度表达新的细胞因子IL-1α/β、IL-5和GM-CSF。我们假设IL-2介导活化的Ba通过新的细胞因子调控自身、Eo和ILC2活化参与调控AD。因此，我们拟I)探究IL-2对Ba活化的调控作用和分子机制；II）探讨IL-2介导Ba活化后的IL-1α/β、IL-5和GM-CSF对Ba、Eo和ILC2的功能调控；以及III) 揭示嗜碱性粒细胞及其新的细胞因子在轻中度和中重度特应性皮炎中的表达及其与疾病严重程度的相关性。我们的研究将进一步阐述Ba在AD中的免疫调控机制，为免疫治疗手段开发奠定基础。

特应性皮炎是由Th2细胞、嗜酸性粒细胞、II型天然淋巴细胞（ILC2）等多种过敏性效应细胞活化介导的慢性的炎症性皮肤疾病，严重影响患者的健康和生活质量。过敏性效应细胞嗜碱性粒细胞在特应性皮炎中显著上升，且与嗜酸性粒细胞和ILC2正相关。然而嗜碱性粒细胞与特应性皮炎的严重程度相关性未知，且人的嗜碱性粒细胞对其他过敏性效应细胞的调控作用不明。..在本研究中，我们通过基因芯片、QPCR及ELISA等多种手段分析首次发现，白介素2（IL-2）可体外活化外周血来源的嗜碱性粒细胞，并诱导其释放细胞因子IL-5、IL-13、GM-CSF和CCL17等。IL-2介导的嗜碱性粒细胞活化不依赖于经典的嗜碱性粒细胞活化通路IL-3和IgE/FcεRI通路的激活。此外，IL-3和IgE/FcεRI通路激活不能诱导嗜碱性粒细胞表达IL-5和GM-CSF。进一步体外实验分析表明，嗜碱性粒细胞来源的IL-5和GM-CSF促进嗜酸性粒细胞的存活、活化及相关效应分子的表达。我们通过临床样本免疫荧光分析证实，特应性皮炎患者的皮肤组织中嗜碱性粒细胞显著表达IL-5和GM-CSF，且与嗜酸性粒细胞分布正相关。..我们的研究首次揭示①IL-2是嗜碱性粒细胞新的活化调控因子；②IL-2激活的嗜碱性粒细胞可通过释放IL-5和GM-CSF调控嗜酸性粒细胞的功能；③嗜碱性粒细胞可能通过分泌IL-5和GM-CSF调控嗜酸性粒细胞浸润及特应性皮炎炎症反应。我们的研究进一步阐明了嗜碱性粒细胞在特应性皮炎中的免疫调控机制，为免疫治疗手段开发奠定基础。