变应性鼻炎的免疫遗传学景观：从细胞效应到基因调控和靶向治疗

摘要(中文译文)

变应性鼻炎（AR）是一种由复杂的免疫遗传背景驱动的高度流行的2型炎症性疾病。本综述旨在系统地描述AR的免疫遗传学景观，阐明从宏观细胞相互作用和微观分子调控到精确靶向治疗的完整知识链。本文首先剖析了驱动AR病理过程的两个核心免疫轴：一个是经典的适应性免疫途径，以Th2细胞为中心，通过分泌IL-4、IL-5和IL-13等细胞因子介导IgE产生、嗜酸性粒细胞浸润和粘液高分泌；另一种是先天免疫启动途径，在该途径中，鼻上皮细胞通过释放TSLP和IL-33等“警告蛋白”充当“哨兵”，导致2型先天淋巴细胞（ILC2s）的快速激活。然后，该综述深入研究了调节这些免疫反应的复杂信号网络，特别关注经典的IL-4/STAT6/GATA3信号轴及其负调控机制。在此基础上，本文进一步阐述了AR的遗传易感性结构，重点介绍了全基因组关联研究（GWAS）确定的关键风险位点，如抗原呈递基因（HLA）、上皮屏障基因（FLG）和与细胞因子信号通路相关的基因的变异。为了将遗传学与环境联系起来，本综述系统地总结了表观遗传调控机制，包括DNA甲基化、组蛋白修饰和microRNAs（miRNAs），并讨论了鼻和肠道微生物群失调通过“肠道-鼻轴”对AR的长期免疫调节作用。最后，从转化医学的角度来看，这篇文章展示了对这些病理生理机制的深刻理解如何成功地促进了高效靶向生物制剂的开发，如奥马珠单抗（靶向IgE）、杜普单抗（靶对IL-4Rα受体，从而阻断IL-4/IL-13信号传导）和特泽普单抗（针对TSLP）。本综述整合了AR免疫学、遗传学、表观遗传学和微生物组研究的最新多维研究进展，为理解其复杂的发病机制和制定未来的个性化治疗策略提供了全面的理论框架。

Abstract

Allergic Rhinitis (AR) is a highly prevalent type 2 inflammatory disease driven by a complex immunogenetic background. This review aims to systematically delineate the immunogenetic landscape of AR, elucidating the complete knowledge chain from macroscopic cellular interactions and microscopic molecular regulation to precision targeted therapies. The article first dissects the two core immune axes driving the pathological process of AR: one is the classic adaptive immune pathway, centered on Th2 cells, which mediates IgE production, eosinophil infiltration, and mucus hypersecretion through the secretion of cytokines such as IL-4, IL-5, and IL-13; the other is the innate immune initiation pathway, in which nasal epithelial cells act as "sentinels" by releasing "alarmins" like TSLP and IL-33, leading to the rapid activation of type 2 innate lymphoid cells (ILC2s). The review then delves into the sophisticated signaling networks that regulate these immune responses, with a particular focus on the classic IL-4/STAT6/GATA3 signaling axis and its negative regulatory mechanisms. Building on this, the article further elaborates on the genetic susceptibility architecture of AR, highlighting key risk loci identified by genome-wide association studies (GWAS), such as variants in antigen presentation genes (HLA), epithelial barrier genes (FLG), and genes related to cytokine signaling pathways. To connect genetics with the environment, this review systematically summarizes epigenetic regulatory mechanisms, including DNA methylation, histone modifications, and microRNAs (miRNAs), and discusses the long-range immunomodulatory effects of nasal and gut microbiota dysbiosis on AR via the "gut-nasal axis". Finally, from a translational medicine perspective, the article demonstrates how a profound understanding of these pathophysiological mechanisms has successfully spurred the development of highly effective targeted biologics, such as omalizumab (targeting IgE), dupilumab (targeting the IL-4Rα receptor, thus blocking IL-4/IL-13 signaling), and tezepelumab (targeting TSLP). This review integrates the latest multidimensional research advances in immunology, genetics, epigenetics, and microbiome studies of AR, providing a comprehensive theoretical framework for understanding its complex pathogenesis and for the development of future personalized treatment strategies.

如何引用

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