TLR2-FcεRI crosstalk调节IDEC功能在ASIT治疗特应性皮炎的作用及其机制研究

The inflammatory dendritic epidermal cells (IDEC) bearing the high-affinity receptor for immunoglobulin E (FcεRI) and Toll-like receptor 2 on their cell surface, plays important roles in the development and maintenance of skin inflammation of atopic dermatitis. In previous study suported by national natural science fund, we have found that, activation of TLR2 could up-regulate the expression of FcεRI on monocytes and IDEC from patients with atopic dermatitis through p38 MAPK, and allergen specific immunotherapy (ASIT) could decrease the severity of clinical symtoms, and change related important immunological parameter, and down-regulate the expression of FcεRI and TLR2 and decrease the cytokine secretion from IDEC. However, the underlying mechanism on the effect of ASIT in AD patients has not been completely clarified. It is is presumed that such regulation is closely to function of IDEC mediated by FcεRI and TLR2. In present study, we will focus on the function changes of IDEC and their relationships with the crosstalk between TLR2 and FcεRI. The aim of present study is to clarify the underlying mechanisms that ASIT lessen the allergic reaction through FcεRI and TLR2 in patients with AD, by comparing the differecnes in function of IDEC, expression of FcεRI and TLR2 and the level of proinflammatory cytokines, T cell response and signal transduction pathway, before and after ASIT. Result of this continual study will provide experimental foundation to understand the mechanism of ASIT for AD patients and develop new immunological treament for AD patients.

高表达IgE高亲和力受体(FcεRI)和Toll样受体2(TLR2)的炎症性树突状表皮细胞（IDEC）在特应性皮炎(AD)的持续和加重中起重要作用。我们在上一个国家自然科学基金课题研究中发现，中重度AD患者单核细胞-IDEC上TLR2活化可通过p38 MAPK上调FcεRI表达，而变应原免疫治疗(ASIT)可显著减轻AD临床症状、改变重要免疫学参数和下调IDEC上FcεRI表达及其介导的促炎症因子分泌。ASIT治疗AD的机制尚不清楚，推测可能与FcεRI和TLR2表达、crosstalk及其介导的IDEC功能改变密切相关。本研究将围绕ASIT治疗前后IDEC的功能变化及其与TLR2-FcεRI表达和crosstalk的联系，从细胞功能、受体表达和信号通路等方面入手，阐明ASIT调控IDEC功能并影响随后T细胞反应的分子机制，为理解ASIT治疗AD的机制和发展新的治疗理念提供理论和实验基础。

特应性皮炎（Atopic Dermatitis，AD）是一种慢性、复发性、炎症性皮肤病，难以治愈，严重影响患者生活质量。变应原免疫治疗(allergen specific immunotherapy，ASIT)可显著减轻AD临床症状、改变重要免疫学参数。ASIT治疗虽然是唯一可以治愈或减缓特应性疾病的方法，但其治疗AD的机制尚不十分清楚，在治疗AD的临床应用中受到限制且存在一定争议。高表达IgE高亲和力受体(FcεRI)和Toll样受体2(TLR2)的炎症性树突状表皮细胞（IDEC）在特应性皮炎(AD)的持续和加重中起重要作用。推测ASIT作用机制可能与FcεRI和TLR2表达、crosstalk及其介导的IDEC功能改变密切相关。一方面，本研究分析了ASIT临床治疗特应性皮炎的长期疗效，证实ASIT可显著降低AD患者的疾病严重程度和瘙痒症状，患者可以达到长期效果。另一方面，在收集ASIT治疗前后的AD患者外周血进行相关指标评估的同时，课题组在小鼠中验证了ASIT的朗格汉斯细胞和炎症性树突状细胞的功能和作用。结果表明，ASIT可以显著改善AD小鼠的Th2反应，并能一定程度上减少朗格汉斯细胞的数量和活性，而对TLR2在朗格汉斯细胞和炎症性树突状细胞的表达影响不显著。同时，体外实验表明，配体激活TLR2后，AD患者外周血来源的炎症性树突状表皮细胞IDEC，对FcεRI产生负调控作用。FcεRI的表达显著降低，IDEC细胞趋化作用增强、吞噬能力降低、凋亡率增加。激活FcεRI后，流式TLR2的平均荧光强度有所上调，提示FcεRI激活可能对TLR2信号通路有一定正向调节作用，FcεRI-TLR2 crosstalk影响单核-树突状细胞功能。总而言之，ASIT能够改变AD皮损树突状细胞的功能，是一种十分有效的AD治疗手段。本研究为ASIT治疗方案的改善和以树突状细胞为脱敏治疗靶点的新方法的研究提供了理论和实验基础。