Allergic rhinitis (AR, also called allergic coryza) is a common allergic disease of the respiratory tract that is mediated by immunoglobulin E (IgE) and characterised by chronic inflammation of the nasal mucosa. Its typical clinical manifestations include paroxysmal sneezing, watery rhinorrhoea, nasal itching and nasal obstruction after allergen exposure, and it is often accompanied by conjunctival symptoms such as ocular itching or lacrimation.过敏性鼻炎（Allergic Rhinitis, AR，变应性鼻炎）是一种由免疫球蛋白E（IgE）介导的、以鼻黏膜慢性炎症为特征的常见呼吸道过敏性疾病。其典型临床表现包括接触过敏原后阵发性喷嚏、水样鼻涕、鼻痒及鼻塞，并常伴有眼部瘙痒或流泪等结膜炎症状。[1][2]
Worldwide, the epidemiological curve of AR has climbed steeply over the past decades, and the disease burden is especially heavy in highly urbanised and tropical regions. In Singapore, for example, epidemiological data show that about 48.9% of the population reported two or more rhinitis symptoms during the previous 12 months, while among children and adolescents aged 4 to 17 years the prevalence of AR reaches 50%. In these tropical urban settings, where the climate is warm and humid all year round, perennial allergic rhinitis driven mainly by indoor allergens plays an absolutely dominant role. Studies indicate that more than 80% of local AR patients are highly sensitised to house dust mite (HDM), and the principal allergens involved are Dermatophagoides pteronyssinus, Dermatophagoides farinae and Blomia tropicalis.在全球范围内，AR的流行病学曲线在过去数十年间呈现出陡峭的上升趋势。特别是在高度城市化及热带气候地区，AR的疾病负担尤为沉重。以新加坡为例，流行病学数据显示该国约有48.9%的人口在过去12个月内出现过两种或以上的鼻炎症状，而在4至17岁的儿童和青少年群体中，AR的患病率甚至高达50%。在这些热带城市环境中，气候常年温暖潮湿，主要由室内过敏原驱动的常年性过敏性鼻炎占据了绝对主导地位。研究表明，超过80%的当地AR患者对屋尘螨（House Dust Mite, HDM）高度致敏，其中最主要的致敏原包括户尘螨（Dermatophagoides pteronyssinus）、粉尘螨（Dermatophagoides farinae）以及热带无爪螨（Blomia tropicalis）。[1][3][1]
In the traditional model of allergen pathogenesis, AR was described simply as a linear Th2-type hypersensitivity reaction built from allergen stimulation, IgE cross-linking and mast cell or eosinophil degranulation. With the rapid development of molecular immunology, systems biology and multi-omics technologies, however, this classical model can no longer fully explain the clinical heterogeneity of AR, the independence of local immune responses such as local allergic rhinitis, or the decisive role of environmental factors in disease evolution. The current academic consensus holds that the pathogenesis of AR is a highly complex, multi-dimensional network in which the core links cover not only Th2 cell polarisation within adaptive immunity but also, and more deeply, epithelial barrier dysfunction, the early cascade amplification of group 2 innate lymphoid cells (ILC2s), neuroimmune interactions mediated by multiple neuropeptides, epigenetic modifications such as DNA methylation and microRNA regulation, and sinonasal microbiome dysbiosis. This report examines these key dimensions and provides a systematic, detailed analysis of the pathogenesis of AR, with the aim of offering a comprehensive theoretical basis for academic research and for the next generation of targeted therapeutic strategies in this field.在传统的过敏原发病机制模型中，AR被简单地描述为一种由“过敏原刺激-IgE交联-肥大细胞/嗜酸性粒细胞脱颗粒”构成的线性Th2型超敏反应。然而，随着分子免疫学、系统生物学以及多组学技术的飞速发展，这一经典模型已无法全面解释AR在临床表现上的异质性、局部免疫反应的独立性（如局部过敏性鼻炎），以及环境因素在疾病演进中的决定性作用。当下的学术共识认为，AR的发病机制是一个高度复杂的多维网络系统，其核心环节不仅涵盖了适应性免疫中的Th2细胞极化，更深刻依赖于上皮屏障功能障碍（Epithelial Barrier Dysfunction）、第2群固有淋巴细胞（ILC2s）的早期级联放大、由多种神经肽介导的神经-免疫互作（Neuroimmune Interactions）、表观遗传学修饰（如DNA甲基化与微小RNA调控），以及鼻腔微生态失调（Sinonasal Microbiome Dysbiosis）。本报告将围绕上述关键维度，对AR的发病机制进行系统、详尽的深度解析，以期为该领域的学术研究和下一代靶向治疗策略提供全面的理论基础。[4][2][5][6][7][8]
The development and progression of AR result from a long and complex interplay between genetic susceptibility and environmental factors. Family aggregation studies and twin cohort studies provide solid epidemiological evidence for the strong genetic background of AR. In monozygotic twins the concordance rate of AR reaches 45% to 60%, markedly higher than the 25% seen in dizygotic twins, and the heritability of AR calculated from these figures lies between 0.33 and 0.91, which indicates that genetic polymorphism occupies a central position in disease susceptibility.AR的发生和发展是遗传易感性与环境因素长期复杂相互作用的结果。家族聚集性研究和双胞胎队列研究为AR的强遗传背景提供了坚实的流行病学证据。在单卵双生子中，AR的一致性发病率可达45%至60%，显著高于双卵双生子的25%，据此推算的AR遗传度（Heritability）介于0.33至0.91之间，提示基因多态性在疾病易感性中占据了核心地位。[9]
AR and allergic asthma frequently occur in the same patient, either successively or simultaneously, and this clinical observation gave rise to the concept of united airway disease. Among allergic children the phenomenon known as the atopic march is widespread, in which allergic disease usually begins with atopic dermatitis (eczema) and food allergy in infancy and then, with increasing age, evolves into allergic rhinitis and finally into asthma. Clinical statistics show that about 40% of children with AR develop comorbid asthma, while as many as 80% to 90% of children with asthma also suffer from AR.AR与过敏性哮喘常常在同一患者身上先后或同时发生，这种临床现象催生了“同一气道，同一疾病（United Airway Disease）”的概念。在儿童过敏群体中，广泛存在被称为“特应性进程（Atopic March）”的现象，即过敏性疾病通常从婴儿期的特应性皮炎（湿疹）和食物过敏开始，随着年龄增长，逐渐演变为过敏性鼻炎，并最终发展为哮喘。临床统计表明，约40%的AR患儿会并发哮喘，而高达80%至90%的哮喘患儿同时患有AR。[1][10][3]
Genome-wide association studies (GWAS) have further verified the genetic basis of this clinical comorbidity at the molecular level, identifying more than 25 independent representative loci associated with both AR and asthma. The C11orf30/LRRC32 locus on chromosome 11 and variants of the nuclear factor I/A (NFIA) gene in the 1p31 region, for instance, are significantly associated with the phenotype of AR combined with asthma. In addition, the 5q31.1 region contains key loci such as IL4-KIF3A and is enriched in genes encoding cytokines including IL3, IL4, IL5, IL13 and GM-CSF, and polymorphisms of these immune-related genes directly determine the intensity of the Th2-type inflammation that a patient mounts against an allergen.全基因组关联分析（GWAS）进一步从分子层面验证了这种临床共病现象的遗传学基础。研究识别出超过25个与AR和哮喘同时相关的独立代表性基因座。例如，位于11号染色体的C11orf30/LRRC32位点，以及1p31染色体区域的核因子I/A（NFIA）基因变异，均与AR合并哮喘的表型显著相关。此外，5q31.1染色体区域包含了IL4-KIF3A等关键位点，该区域富集了大量编码细胞因子的基因（如IL3、IL4、IL5、IL13及GM-CSF），这些免疫相关基因的多态性直接决定了患者面对过敏原时启动Th2型炎症的强度。
Beyond classical immune factors, polymorphisms of enzymes involved in oxidative stress and xenobiotic metabolism also influence the risk of AR. Glutathione S-transferases (GSTs) play a crucial role in detoxification and antioxidant defence. A genetic study of AR patients and healthy controls found that the null genotype of GSTT1 is significantly and negatively associated with the incidence of AR, and individuals carrying the GSTT1 null genotype had a risk of AR reduced by about 70% (OR = 0.30). This apparently paradoxical finding is thought to be related to the fact that the GSTT1-positive genotype, together with the tightly linked LOC391322 gene of the macrophage migration inhibitory factor (MIF) family, provokes stronger release of pro-inflammatory molecules under particular environmental exposures, thereby enhancing the pathogenic pathway of AR.除了经典的免疫因子，参与氧化应激和外源性物质代谢的酶类多态性同样影响AR的发病风险。谷胱甘肽S-转移酶（GSTs）在解毒和抗氧化应激中起着至关重要的作用。一项针对AR患者和健康对照人群的遗传学研究发现，GSTT1基因的缺失（Null genotype）多态性与AR发病率具有显著的负相关性。携带GSTT1缺失基因型的个体患AR的风险降低了约70%（OR = 0.30）。这一看似反常的发现被认为可能与GSTT1阳性基因型（及其紧密连锁的LOC391322基因，属于巨噬细胞迁移抑制因子MIF家族）在特定环境暴露下会引发更强烈的促炎分子释放有关，从而增强了AR的致病途径。
Interleukin-27 (IL-27), a heterodimeric cytokine secreted by macrophages and dendritic cells, also regulates the Th1/Th2 balance. Although some single nucleotide polymorphisms of IL-27p28 such as rs181206 and rs153109 may not directly increase susceptibility to AR, the marked fall in serum IL-27 levels in AR patients has been shown to be closely related to the onset and progression of the disease and to imbalance of the IL-17/IL-23 inflammatory axis.此外，白细胞介素-27（IL-27）作为一种由巨噬细胞和树突状细胞分泌的异二聚体细胞因子，对Th1/Th2平衡具有调节作用。尽管IL-27p28的某些SNP（如rs181206和rs153109）多态性本身可能不直接增加AR的易感性，但AR患者血清中IL-27水平的显著下降被证明与疾病的发生发展以及IL-17/IL-23炎症轴的失衡密切相关。[11]
The traditional view regarded the nasal epithelium simply as a physical barrier. The epithelial barrier hypothesis proposed by Cezmi Akdis and colleagues overturned this conception entirely, placing epithelial cells at the origin of the allergic inflammatory cascade. The hypothesis states that the dramatic change in the exposome brought about by global industrialisation over the past 65 years has caused widespread damage to the epithelial barriers of human skin, airways and intestine, and that this loss of epithelial integrity is the fundamental cause of the surge in allergic diseases, autoimmune diseases and other chronic inflammatory conditions.传统观点将鼻黏膜上皮单纯视为一层物理屏障。然而，Cezmi Akdis 等学者提出的“上皮屏障假说”彻底改变了这一认知，将上皮细胞置于过敏性炎症级联反应的发起者地位。该假说指出，过去65年来全球工业化进程带来的环境暴露组（Exposome）急剧改变，导致了人类皮肤、呼吸道和肠道上皮屏障的广泛破坏，这种上皮完整性的丧失是导致过敏性疾病、自身免疫性疾病等慢性炎症激增的根本原因。[12][13][12][13][14]
In the healthy nasal mucosa, epithelial cells are joined by tight junctions (TJs, composed of occludin, the claudin family and ZO-1/2/3), adherens junctions such as E-cadherin and desmosomes, maintaining a transepithelial electrical resistance (TEER) of 200 to 800 Ω·cm² and effectively blocking the paracellular passage of allergens, pathogens and toxins. Many pollutants in the modern environment, however, can directly cleave these key structural proteins.在健康的鼻黏膜中，上皮细胞之间通过紧密连接（Tight Junctions, TJs，由Occludin、Claudins家族、ZO-1/2/3等构成）、黏附连接（如E-cadherin）和桥粒等结构紧密相连，维持着200-800 Ω·cm²的跨上皮电阻（TEER），有效阻止过敏原、病原体和毒素的旁细胞渗透。然而，现代环境中的多种污染物能够直接裂解这些关键的结构蛋白：[12][15]
Indoor allergens such as those of HDM contain not only sensitising proteins but also abundant active enzymes. The major allergen components of Dermatophagoides farinae and Dermatophagoides pteronyssinus, namely Der p 1, Der p 3 and Der f 3, are serine or cysteine proteases. After contact with the mucosa these allergen enzymes first exert direct physical destructive power, cleaving the extracellular domains of occludin and claudin-1 and promoting redistribution of ZO-1 from tight junction plaques into the cytoplasm, so that epithelial resistance falls markedly within 30 to 60 minutes of exposure.HDM等室内过敏原不仅包含致敏性蛋白，更富含具有活性的酶类。例如，粉尘螨和户尘螨的主要致敏原成分Der p 1、Der p 3和Der f 3均为丝氨酸或半胱氨酸蛋白酶。这些过敏原酶类在接触黏膜后，首先表现出直接的“物理破坏力”，它们能够裂解Occludin和Claudin-1的胞外结构域，并促使ZO-1从紧密连接斑块向细胞质内重新分布，在接触后的30至60分钟内即可导致上皮电阻的显著下降。[15][16][5][15][10]
More importantly, these proteases specifically cleave and activate protease-activated receptors on the epithelial surface, especially PAR-2, and PAR-2 activation triggers a series of intense intracellular signals. Through the Gαq/phospholipase C (PLC)/inositol 1,4,5-trisphosphate/diacylglycerol pathway, PAR-2 first activates protein kinase C (PKC), leading to further phosphorylation and complex disassembly of occludin and ZO-1. At the same time intracellular calcium (Ca2+) is mobilised, and β-arrestin-mediated EGFR transactivation launches the MAPK and NF-κB pathways in a non-G-protein-dependent manner. This signalling cascade transforms epithelial cells from a physical barrier into a factory of inflammatory mediators that releases large amounts of chemokines and alarmins. In vitro experiments and mouse models have confirmed that highly selective PAR-2 inhibitors such as punicalagin effectively suppress HDM-induced intracellular calcium signalling, ERK/NF-κB cascade activation and the subsequent mixed Th1/Th2 inflammatory response, highlighting the considerable potential of PAR-2 as a target in AR therapy.更为关键的是，这些蛋白酶能够特异性地切割并激活上皮细胞表面的蛋白酶激活受体（尤其是PAR-2）。PAR-2的激活引发了一系列强烈的细胞内信号传导。首先，通过Gαq/磷脂酶C（PLC）/肌醇1,4,5-三磷酸/二酰甘油通路，PAR-2激活蛋白激酶C（PKC），导致Occludin和ZO-1的进一步磷酸化和复合物解聚。同时，胞内钙离子（Ca2+）发生动员，并通过β-arrestin介导的EGFR反式激活，非G蛋白依赖性地启动MAPK和NF-κB通路。这一系列信号级联促使上皮细胞从物理屏障转变为炎症介质工厂，释放出大量趋化因子和警报素。体外实验及小鼠模型证实，使用高选择性的PAR-2抑制剂（如石榴皮素，Punicalagin）可以有效抑制HDM诱导的细胞内钙信号、ERK/NF-κB级联活化，并全面抑制随后的Th1/Th2混合炎症反应，突显了PAR-2在AR靶向治疗中的巨大潜力。[10][17][15][15][17][17]
As the epithelial barrier breaks down and the epithelium becomes leaky, environmental allergens can penetrate deep into the subepithelial layer. At the same time, damaged nasal epithelial cells release large amounts of damage-associated molecular patterns (DAMPs such as ATP and HMGB1) together with epithelial cytokines known as alarmins, principally thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25/IL-17E) and interleukin-33 (IL-33).随着上皮屏障的破坏（“渗漏”上皮），环境过敏原得以深入黏膜下层。与此同时，受损的鼻黏膜上皮细胞大量释放损伤相关模式分子（DAMPs，如ATP、HMGB1）和被称为“警报素（Alarmins）”的上皮源性细胞因子，主要包括胸腺基质淋巴细胞生成素（TSLP）、白细胞介素-25（IL-25/IL-17E）和白细胞介素-33（IL-33）。[4][15]
For a long time the initiation of allergic disease was generally thought to depend entirely on the adaptive immunity of T cells and B cells. The discovery of group 2 innate lymphoid cells (ILC2s) completely reshaped this view. ILC2s lack specific antigen recognition receptors such as the TCR or BCR, yet they highly express the receptors for TSLP, IL-33 and IL-25 on their surface, namely the TSLPR/IL-7Rα heterodimer, ST2 and IL-17RB respectively.在过去，学界普遍认为过敏性疾病的启动完全依赖于T细胞和B细胞的适应性免疫。然而，第2群固有淋巴细胞（ILC2s）的发现彻底重塑了这一认知。ILC2s缺乏特异性抗原识别受体（如TCR或BCR），但在其表面高表达TSLP、IL-33和IL-25的受体（分别为TSLPR/IL-7Rα异二聚体、ST2和IL-17RB）。[18][19][20][19][21]
Within a very short time after AR patients encounter allergen stimulation, high concentrations of alarmins such as IL-33 bind rapidly to ST2 receptors on the surface of ILC2s and activate the MyD88/IRAK/TRAF6 signalling pathway, causing vigorous expansion and activation of ILC2s both locally in the mucosa and in peripheral blood. Activated ILC2s secrete large amounts of the classical Th2-type cytokines IL-4, IL-5 and IL-13, and their output per cell is even far higher than that of mature Th2 cells.在AR患者遭遇过敏原刺激后的极短时间内，高浓度的IL-33等警报素迅速结合到ILC2s表面的ST2受体上，激活MyD88/IRAK/TRAF6信号通路，导致ILC2s在黏膜局部及外周血中发生剧烈扩增和活化。活化后的ILC2s能够分泌大量经典的Th2型细胞因子（IL-4、IL-5、IL-13），其分泌量在单位细胞水平上甚至远高于成熟的Th2细胞。[20][21][20][19][22]
Within the AR microenvironment the activity of ILC2s is not unrestricted but is finely tuned by subsets of dendritic cells. Studies show that in the nasal mucosa of AR patients, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) exert diametrically opposite effects on ILC2s.在AR的微环境中，ILC2s的活性并非不受限制，而是受到树突状细胞亚群的精细调控。研究表明，在AR患者的鼻黏膜中，髓系树突状细胞（mDCs）和浆细胞样树突状细胞（pDCs）对ILC2s发挥着截然相反的作用。[21][18]
After encountering allergen, mDCs can synthesise and secrete IL-33 themselves. This mDC-derived IL-33 binds ST2 on ILC2s and potently activates the GATA-3 transcription factor and STAT signalling, promoting ILC2 secretion of Th2 cytokines and forming a pro-inflammatory positive feedback loop. Conversely, when pDCs are activated they secrete interleukin-6 (IL-6), which markedly suppresses the proliferation and function of ILC2s derived from AR patients. This dynamic activation-suppression balance mediated by different DC subsets, namely the mDC-IL-33/ST2 activating axis versus the pDC-IL-6 suppressive axis, illustrates the complexity of innate immune network regulation against allergens and offers new cellular targets for intervention in AR.mDCs在遇到过敏原后，能够自行合成并分泌IL-33。这种mDCs来源的IL-33通过结合ILC2s表面的ST2受体，强效激活GATA-3转录因子及STAT信号通路，促进ILC2s分泌Th2细胞因子，形成促炎的正向反馈环。相反，当pDCs被激活时，它们会通过分泌白细胞介素-6（IL-6），显著抑制AR患者来源的ILC2s的增殖和功能。这种由不同DC亚群介导的“激活-抑制”动态平衡（mDC-IL-33/ST2 激活轴 vs. pDC-IL-6 抑制轴），展示了固有免疫网络在应对过敏原时的复杂调控机制，也为AR的干预提供了新的细胞靶标。[21][21][18]
If epithelial cells and ILC2s constitute the early vanguard response of AR, then the polarisation of T and B lymphocytes mediated by antigen-presenting cells constitutes the core of long-term immune memory and specific sensitisation.如果说上皮细胞和ILC2s构成了AR的早期先锋反应，那么由抗原递呈细胞介导的T、B淋巴细胞极化，则构成了长期免疫记忆和特异性致敏的核心。
Once antigens such as HDM that have crossed the damaged barrier are taken up and processed by antigen-presenting cells, particularly mDCs, these DCs migrate to the draining lymph nodes and present antigen peptide-MHC class II complexes to naive CD4+ T cells. In a microenvironment with a high local concentration of IL-4, activation of the STAT6 signalling pathway and marked up-regulation of the master transcription factor GATA-3, together with suppression of the Th1-related transcription factor T-bet, drive naive T cells to differentiate into specific Th2 cells.当穿过受损屏障的HDM等抗原被抗原递呈细胞（特别是mDCs）摄取并加工后，这些DCs会向引流淋巴结迁移，将抗原肽-MHC II复合物递呈给初始T细胞（Naïve CD4+ T cells）。在局部高浓度IL-4的微环境下，通过激活STAT6信号通路并显著上调主效转录因子GATA-3（同时抑制Th1相关的T-bet转录因子），初始T细胞分化为特异性的Th2细胞。
Recent work has shown that, in addition to classical Th2 cells, type 2 follicular helper T cells (Tfh2) play a more direct and dominant role in inducing B cells to produce IgE. In the germinal centres of AR patients, Tfh2 cells not only secrete high concentrations of IL-4 but also more effectively induce expression of CD23 on the surface of memory B cells, CD23 being a key low-affinity IgE receptor and co-stimulatory molecule. This direct cell-cell contact together with paracrine IL-4 forces B cells to undergo gene rearrangement, namely immunoglobulin class switch recombination (CSR), and to start synthesising and secreting large amounts of allergen-specific IgE (sIgE). These sIgE molecules then enter the blood and tissue fluid and bind firmly to high-affinity IgE receptors (FcεRI) on the surface of mast cells and basophils in the nasal mucosa and in the periphery. When the same allergen re-enters the nasal cavity and cross-links adjacent IgE molecules, explosive mast cell degranulation is triggered and histamine, leukotrienes (LTC4 and LTD4) and prostaglandins such as PGD2 are released within minutes, producing vasodilatation and increased permeability together with the sneezing, rhinorrhoea and nasal itching of the immediate-phase reaction.近年来的研究发现，除了经典Th2细胞，第2型滤泡辅助性T细胞（Tfh2）在诱导B细胞产生IgE的过程中发挥了更为直接和主导的作用。在AR患者的生发中心，Tfh2细胞不仅分泌高浓度的IL-4，还能更有效地诱导记忆B细胞表面表达CD23（一种关键的低亲和力IgE受体及共刺激分子）。这种细胞间的直接接触及IL-4的旁分泌，迫使B细胞发生基因重排，即免疫球蛋白同型转换（Class Switch Recombination, CSR），开始大量合成并分泌过敏原特异性IgE（sIgE）。这些sIgE随后进入血液和组织液，牢固地结合在鼻黏膜局部及外周肥大细胞和嗜碱性粒细胞表面的高亲和力IgE受体（FcεRI）上。当同种过敏原再次进入鼻腔并交联相邻的IgE分子时，将触发肥大细胞的暴发性脱颗粒，在数分钟内释放组胺、白三烯（LTC4, LTD4）、前列腺素（如PGD2），导致血管扩张、通透性增加，产生打喷嚏、流涕和鼻痒等速发相反应。[23][4][24]
Healthy individuals maintain immune tolerance to harmless environmental antigens such as pollen and house dust mites, a process dominated by regulatory T cells (Tregs). According to their origin, Tregs are divided into thymus-derived natural Tregs (tTregs) and allergen-induced peripheral Tregs (pTregs). Through stable expression of the transcription factor FOXP3 and secretion of inhibitory factors such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), they potently suppress the excessive responses of Th2 cells and ILC2s.健康个体能够对环境中的无害抗原（如花粉、尘螨）保持免疫耐受，这一过程主要由调节性T细胞（Regulatory T cells, Tregs）主导。Tregs根据起源可分为胸腺衍生的天然Tregs（tTregs）和在外周微环境中由过敏原诱导产生的pTregs。它们通过稳定表达转录因子FOXP3，并分泌白细胞介素-10（IL-10）和转化生长因子-β（TGF-β）等抑制性因子，强效压制Th2细胞和ILC2s的过度反应。[10][8][25]
In AR patients, Tregs are not only absolutely reduced in number but also severely defective in suppressive function and may even undergo pathogenic conversion. Studies show that under prolonged exposure to chronic allergic inflammation, some Tregs lose FOXP3 expression and become ex-Tregs. These cells abandon their original suppressive function and instead express a Th2-like phenotype, expressing GATA-3 and CCR4 and secreting IL-4 and IL-13, thereby aggravating rather than inhibiting allergic inflammation. In addition, the lack of IL-10 production is the key reason why AR fails to induce spontaneous tolerance. It has been clinically confirmed that in successful allergen immunotherapy (AIT), induction of IL-10+ FOXP3+ Tregs and even of a special population of IL-10+ FOXP3- CD8+ Treg-like cells is the most central mechanism for halting disease progression and establishing lasting desensitisation.在AR患者中，Tregs不仅数量绝对减少，其抑制功能也出现了严重缺陷，甚至表现出“致病性转化”。研究表明，在长期慢性过敏性炎症暴露下，部分Tregs会丧失FOXP3的表达，转变为“ex-Tregs”。这些细胞不仅放弃了原本的抑制功能，反而开始表达类似于Th2细胞的表型（如表达GATA-3和CCR4，分泌IL-4、IL-13），从而加剧而非抑制过敏性炎症。此外，缺乏IL-10的产生是AR无法诱导自发耐受的关键。临床证实，在成功的过敏原特异性免疫治疗（AIT）中，诱导产生IL-10+ FOXP3+ Tregs，甚至诱导一种特殊的IL-10+ FOXP3- CD8+ Treg样细胞，是阻断AR疾病进程并建立长期脱敏状态的最核心机制。[26][27][8][25][28]
AR is not merely a disorder of the immune system, because the nasal cavity is one of the most densely innervated peripheral regions of the human body. As many as 60% to 70% of AR patients are sensitive not only to allergens but also to non-specific stimuli such as hot or cold air, bright light, odours and even changes in osmotic pressure, a phenomenon known as nasal hyperreactivity (NHR). The essence of this hyperreactivity lies in the sensitisation of sensory nerve endings and their bidirectional communication with immune cells, that is, the neuroimmune network.AR不仅是免疫系统的异常，鼻腔还是人体外周神经支配最密集的区域之一。多达60%至70%的AR患者不仅对过敏原敏感，还对冷热空气、强光、异味甚至渗透压变化等非特异性刺激表现出强烈的临床症状，这一现象被称为鼻腔高反应性（Nasal Hyperreactivity, NHR）。这种高反应性的本质在于感觉神经末梢的敏化及其与免疫细胞之间的双向通讯，即神经-免疫网络互作。[7][7][29]
The nociceptors in the human nasal mucosa are mainly the terminals of unmyelinated C fibres and thin myelinated Aδ fibres derived from the trigeminal ganglion. The surface of these nerve endings is rich in receptors and ion channels, particularly channels of the transient receptor potential (TRP) family, including TRPV1, which is sensitive to capsaicin, heat and acid, and TRPA1 and TRPM8, which are sensitive to cold stimuli and certain chemicals.人类鼻黏膜中的痛觉受体（Nociceptors）主要是三叉神经节衍生的无髓鞘C纤维及薄髓鞘Aδ纤维的末梢。这些神经末梢表面富含多种受体和离子通道，特别是瞬时受体电位（TRP）家族通道，包括对辣椒素、热和酸敏感的TRPV1，以及对冷刺激和某些化学物质敏感的TRPA1与TRPM8。[7][29]
In the chronic inflammatory microenvironment of AR, mediators secreted by mast cells and eosinophils, such as histamine, nerve growth factor (NGF) and leukotrienes, markedly up-regulate the expression density of TRPV1 and TRPA1 on sensory nerve endings and lower their activation thresholds. Once activated by a weak environmental stimulus, these afferent nerves not only transmit itch signals to the central nervous system and elicit a strong sneezing reflex (central sensitisation) but also, through local axon reflexes, cause the sensory nerve endings to release large amounts of neuropeptides retrogradely.在AR的慢性炎症微环境中，肥大细胞和嗜酸性粒细胞分泌的组胺、神经生长因子（NGF）和白三烯等介质，会显著上调感觉神经末梢上TRPV1和TRPA1的表达密度，并降低其激活阈值。一旦被微弱的环境刺激激活，这些传入神经（Afferent nerves）不仅向中枢神经系统传递瘙痒信号并诱发强烈的喷嚏反射（中枢敏化，Central Sensitization），还会通过局部的“轴突反射（Axon reflexes）”，导致感觉神经末梢逆向释放大量的神经肽（Neuropeptides）。[7][29][29]
These neurogenic mediators act directly on neighbouring mast cells, eosinophils, T cells and ILC2s, forming an extremely efficient positive feedback loop of signals. The following structured table summarises the functions and receptor mechanisms of the core neuropeptides in AR.这些神经源性介质直接作用于邻近的肥大细胞、嗜酸性粒细胞、T细胞及ILC2s，形成极其高效的信号正反馈环。以下结构化表格总结了AR中核心神经肽的功能与受体机制：
| Neuropeptide神经肽种类 | Main source and localisation主要来源与定位 | Target-cell-specific receptor靶细胞特异性受体 | Neuroimmune regulatory function in the pathogenesis of allergic rhinitis在过敏性鼻炎发病机制中的神经-免疫调节功能 | References参考文献 |
|---|---|---|---|---|
| Substance P (SP)P物质 (Substance P, SP) | Trigeminal ganglion sensory neurons, C-fibre terminals三叉神经节感觉神经元、C纤维末梢 | NK1R (neurokinin 1 receptor)NK1R (Neurokinin 1 Receptor) | Promotes neurogenic inflammation, up-regulates IL-6 and TNF-α and down-regulates IL-10 through the NF-κB and MyD88 pathways, and raises intracellular calcium in mast cells to trigger potent degranulation.促进神经源性炎症；通过NF-κB和MyD88通路，上调IL-6、TNF-α的表达并下调IL-10。增加肥大细胞内钙离子浓度触发强效脱颗粒。 | [7][29] |
| Calcitonin gene-related peptide (CGRP)降钙素基因相关肽 (CGRP) | Secreted in large amounts by trigeminal ganglion neurons (TGNs)三叉神经节神经元 (TGNs) 大量分泌 | CALCRL / RAMP1 complexCALCRL / RAMP1 复合物 | Directly triggers mast cell degranulation and strongly stimulates ILC2 proliferation and subsequent polarisation, inducing large amounts of the eosinophil-recruiting factor IL-5.直接引发肥大细胞脱颗粒；强烈刺激ILC2s的增殖及随后的极化反应，诱导产生大量的促嗜酸性细胞聚集因子IL-5。 | [22][29] |
| Neuromedin U (NMU)神经介素U (Neuromedin U, NMU) | Sensory nerves, epithelial cells and some immune cells感觉神经、上皮细胞及部分免疫细胞 | NMUR1NMUR1 | ILC2s stimulated by IL-25 preferentially up-regulate NMUR1, and binding of NMU induces calcium influx and ERK1/2 activation that, synergising with IL-33 or even acting independently of it, greatly amplifies IL-5 and IL-13 secretion, making NMU one of the strongest activators of ILC2s.ILC2s在IL-25刺激下会优先上调表达NMUR1。NMU与其结合后可引发钙离子内流及ERK1/2活化，不仅能与IL-33协同，甚至能独立于IL-33极大地放大IL-5和IL-13的分泌，是ILC2s最强的激活剂之一。 | [29][30][31] |
| Vasoactive intestinal peptide (VIP)血管活性肠肽 (VIP) | Pterygopalatine ganglion parasympathetic nerves, Th2 cells and others蝶腭神经节副交感神经、Th2细胞等 | VPAC1 / VPAC2VPAC1 / VPAC2 | Exerts bidirectional immunomodulation, activating ILC2s to release type 2 cytokines on the one hand while, under certain conditions, promoting Treg secretion of IL-10 and TGF-β1 and regulating the Th1/Th2 balance on the other.具有双向免疫调节作用。一方面可激活ILC2s释放第2型细胞因子；另一方面在特定条件下也能促进Treg分泌IL-10和TGF-β1，调节Th1/Th2平衡。 | [22][29] |
Particularly striking in this network is the discovery of the NMU-NMUR1-ILC2 signalling axis. During AR, NMU released by neurons binds rapidly to NMUR1 on the surface of ILC2s, and the response speed of this neurogenic activation route far exceeds that of conventional antigen presentation and epithelial cytokine-mediated cascades, which explains why some patients develop severe nasal symptoms the instant they encounter an allergen or cold air. Interventions directed at these receptors, such as knockout of TRPV1 or blockade of the relevant neuropeptides in mouse models, have all been shown to markedly reduce the number of eosinophils infiltrating the nasal mucosa and the level of serum specific IgE, and even to improve the clinical phenotypes of scratching and sneezing.这一网络中尤为令人瞩目的是NMU-NMUR1-ILC2信号轴的发现。在AR发生时，神经元释放的NMU能够迅速与ILC2s表面的NMUR1结合，这种神经源性激活途径的响应速度远超传统的抗原递呈及上皮细胞因子介导的级联，解释了为何某些患者在接触过敏原或冷空气的瞬间，即会爆发严重的鼻部症状。针对这些受体的干预（如在小鼠模型中敲除TRPV1或阻断相关神经肽），均显示出能显著下调鼻黏膜中浸润的嗜酸性粒细胞数量及血清特异性IgE水平，甚至改善抓挠和打喷嚏的临床表型。[29]
Why do only some of the people living in the same polluted or highly allergenic environment develop AR? Besides variation in the DNA sequence itself, the key to this puzzle lies in epigenetic modifications, which leave the DNA sequence unchanged but convert environmental signals into a lasting memory of gene expression.为什么处于同样污染或高致敏环境中的人群，只有部分人会发展为AR？除了DNA序列变异，不改变DNA序列但能将环境信号转化为长期基因表达记忆的表观遗传学（Epigenetics）修饰，是解开这一谜题的关键。
DNA methylation usually occurs in CpG island-rich regions and silences downstream gene transcription. In immune tolerance, the second conserved non-coding sequence (CNS2) of the FOXP3 gene, the master transcription factor of Tregs, contains a Treg-specific demethylated region (TSDR). In Tregs with healthy immunosuppressive function the TSDR is completely demethylated, which keeps chromatin in an open conformation and allows transcription factors such as Ets-1 and Creb to bind, thereby maintaining stable and sustained expression of FOXP3.DNA甲基化通常发生在CpG岛富集区，导致下游基因转录沉默。在免疫耐受中，Treg的主效转录因子FOXP3基因的第2个保守非编码序列（CNS2）上存在一个“Treg特异性去甲基化区（Treg-Specific Demethylated Region, TSDR）”。在具有健康免疫抑制功能的Tregs中，TSDR处于完全去甲基化状态，这使得染色质保持开放构象，允许如Ets-1和Creb等转录因子结合，从而维持FOXP3的稳定、持续表达。[8][32][8][32]
In patients with allergic diseases such as AR, however, the FOXP3 TSDR of Treg cells in peripheral blood or tissue is often found to be markedly hypermethylated. Mechanistic studies indicate that down-regulation of ten-eleven translocation protein 2 (Tet2), the key enzyme mediating active DNA demethylation, is responsible for the hypermethylation of the FOXP3 TSDR. This epigenetic silencing directly causes a precipitous fall in FOXP3 mRNA and protein expression, so that Tregs lose their immunosuppressive capacity and disease ensues. Environmental factors can markedly influence the methylation profile, and exposure to second-hand smoke or a poor maternal diet during pregnancy, for example, affects the methylation status of IL-4, IL-5 and IFN-γ in infancy. Clinically, treatment with an extensively hydrolysed casein formula combined with Lactobacillus rhamnosus GG (EHCF+LGG), as well as sublingual immunotherapy (SLIT), has been shown to re-induce demethylation of the FOXP3 TSDR and restore long-term clinical tolerance, confirming the value of DNA methylation as a biomarker and therapeutic target in AR.然而，在AR等过敏性疾病患者中，常发现外周血或组织中Treg细胞的FOXP3 TSDR发生了显著的异常高甲基化（Hypermethylation）。机制研究指出，介导DNA主动去甲基化的关键酶——十-十一易位蛋白2（Tet2）的表达下调，是导致FOXP3 TSDR高甲基化的元凶。这种表观遗传沉默直接导致FOXP3 mRNA和蛋白表达量断崖式下降，Tregs失去免疫抑制能力，促成疾病发生。环境因素能显著影响甲基化谱，例如，接触二手烟或不良孕期饮食会影响婴儿期IL-4、IL-5和IFN-γ的甲基化状态。临床上，通过深度水解酪蛋白配方奶粉联合鼠李糖乳杆菌（EHCF+LGG）治疗，或采用舌下免疫治疗（SLIT），均被证实能促使FOXP3 TSDR重新发生去甲基化，恢复患者的长期临床耐受，证实了DNA甲基化作为AR生物标志物和治疗靶点的重要价值。[8][8][33][32][34]
miRNAs are a class of non-coding single-stranded RNAs about 22 nt long that bind the 3'UTR of target mRNAs and cause degradation of the target mRNA or inhibition of translation at the post-transcriptional level. The nasal mucosa, peripheral blood and even extracellular vesicles (exosomes) of AR patients show characteristic abnormalities of miRNA expression, which profoundly interfere with the Th1/Th2 balance and the function of ILC2s.miRNAs是一类长约22nt的非编码单链RNA，通过靶向结合mRNA的3'UTR区，在转录后水平导致目标mRNA降解或翻译抑制。AR患者的鼻黏膜、外周血甚至胞外囊泡（Exosomes）中存在特征性的miRNA表达谱异常，它们深刻地干预了Th1/Th2平衡及ILC2s的功能：
| microRNA微小RNA | Expression status in the AR/allergic environment在AR/过敏环境中的表达状态 | Core targets and regulation of pathogenic mechanisms核心靶标与致病机制调节 | References参考文献 |
|---|---|---|---|
| miR-155miR-155 | Markedly up-regulated显著上调 | Highly expressed in peripheral blood and nasal mucosa, and essential for IL-33-mediated ILC2 activation and GATA-3 expression. By targeting negative regulators such as SHIP1 and CTLA-4 on T cells it lifts the self-limitation of the immune system and greatly promotes Th2 polarisation and eosinophilic inflammation.在外周血及鼻黏膜中高表达。对IL-33介导的ILC2s活化及GATA-3表达至关重要。通过靶向负调控因子（如SHIP1和T细胞表面的CTLA-4），解除免疫系统的自我限制，极大地促进Th2型极化和嗜酸性粒细胞炎症。 | [35][36][37] |
| miR-146amiR-146a | Abnormally regulated or compensatorily up-regulated异常调节/代偿性上调 | Normally an anti-inflammatory mediator that negatively regulates IL-33 receptor signalling by inhibiting IRAK1 and TRAF6. In AR models its expression is frequently dysregulated or it is transported by extracellular vesicles, thereby affecting the dialogue between ILC2s and epithelial cells.原本作为抗炎介质，通过抑制IRAK1和TRAF6来负向调节IL-33受体信号传导。在AR模型中其表达常发生失常，或被细胞外的囊泡转运，从而影响ILC2s与上皮细胞间的对话。 | [22][36] |
| miR-375miR-375 | Markedly up-regulated显著上调 | Abnormally elevated in AR patients. This miRNA can act through regulation of epithelial TSLP secretion to indirectly mediate the proliferation and activation of ILC2s.在AR患者中表达量异常升高。该miRNA可通过调节上皮来源的TSLP分泌，进一步间接介导ILC2s的增殖和活化。 | [22] |
| let-7 familylet-7 家族 | Markedly down-regulated显著下调 | Abundant in healthy individuals, where it targets and suppresses excessive expression of cytokines such as IL-13. It falls markedly in AR patients, releasing the brake on IL-13 and aggravating mucus hypersecretion and epithelial tight junction damage.在健康人群中含量丰富，靶向抑制IL-13等细胞因子的过度表达。在AR患者中显著下降，从而释放了对IL-13的控制，加剧了黏液高分泌和上皮紧密连接损伤。 | [35] |
On the basis of these mechanisms, delivery of specific miRNA inhibitors such as anti-miR-155 or of miRNA mimics by lentivirus or liposome to reshape the post-transcriptional regulatory network has already shown favourable effects in animal models, alleviating sneezing, lowering serum IgE and reducing ILC2 infiltration.基于这些机制，通过慢病毒或脂质体递送特定的miRNA抑制剂（如anti-miR-155）或类似物（miRNA mimics）以重塑转录后调控网络，已在动物模型中展现出缓解打喷嚏、降低血清IgE和减少ILC2s浸润的良好效果。[22][36][38]
In the healthy state the nasal cavity and paranasal sinuses harbour a rich commensal flora that trains the mucosal immune system by competing for ecological niches and releasing metabolites, thereby maintaining the barrier function of the epithelium. Metagenomic and 16S rRNA sequencing data show, however, that the microbial diversity of nasal mucus and mucosa in AR patients is greatly reduced and that the community structure has changed fundamentally, a state known as dysbiosis.健康状态下的鼻腔及鼻窦孕育着丰富的共生菌群，它们通过竞争生态位和释放代谢产物来训练黏膜免疫系统，维持上皮的屏障功能。然而，宏基因组和16S rRNA测序数据表明，AR患者鼻腔黏液及黏膜中的微生物组多样性大幅降低，群落结构发生了根本性的改变，即微生态失调（Dysbiosis）。[39]
The most characteristic change in the dysbiosis of AR is a marked increase in the abundance of Staphylococcus aureus. The colonisation rate of Staphylococcus aureus in the nasal mucosa of AR patients is higher than in healthy people, and its abundance is closely related to the clinical severity of the disease and to allergic airway inflammation.在AR的生态失调中，最标志性的改变是金黄色葡萄球菌（Staphylococcus aureus）丰度的显著增加。金黄色葡萄球菌在AR患者鼻黏膜中的定植率不仅高于健康人群，且其丰度与疾病的临床严重程度及过敏性气道炎症密切相关。[39][40]
This pathogen is by no means merely a bystander of environmental change, but participates deeply in the deterioration of AR pathogenesis.这种致病菌绝不仅仅是环境变迁的“旁观者”，而是深度参与了AR发病机制的恶化过程：
Direct degradation of the barrier: abnormally proliferating Staphylococcus aureus secretes large amounts of virulence factors such as α-haemolysin. This toxin interacts with ADAM10 metalloprotease on the surface of host cells and specifically degrades the adherens junction protein E-cadherin and the tight junction protein ZO-1, greatly increasing mucosal permeability and allowing pollen and HDM from the external environment to enter the subepithelial layer unhindered.屏障直接降解：异常增殖的金葡菌会分泌大量的毒力因子，如α-溶血素。该毒素能与宿主细胞表面的ADAM10金属蛋白酶相互作用，特异性降解黏附连接蛋白E-cadherin及紧密连接蛋白ZO-1，从而极大地增加了黏膜的通透性，方便外部环境中的花粉和HDM肆无忌惮地进入黏膜下层。[5][41]
Reshaping of alarmin release and the direction of type 2 inflammation: Staphylococcus aureus isolated from the nasal cavity of AR patients (AR-SA) can invade epithelial cells and has been shown in vitro to suppress normal immune tolerance signals and to reverse the pattern of expression of epithelial factors such as IL-33. Staphylococcal enterotoxins, which can act as superantigens, bypass conventional MHC-restricted antigen presentation to activate large numbers of T cells and mast cells directly, aggravating local Th2 polarisation and tissue damage. This host-microbial commensalism makes microbiome reconstruction a promising complementary approach for the future treatment of AR.重塑警报素的释放与第2型炎症方向：AR患者鼻腔分离出的金黄色葡萄球菌（AR-SA）可侵袭上皮细胞，并在体外模型中被证明能抑制正常的免疫耐受信号，反向调节IL-33等上皮源性因子的表达模式。同时，葡萄球菌肠毒素（可作为超级抗原）能够绕过常规的MHC限制性抗原递呈，直接激活大量的T细胞和肥大细胞，加剧局部的Th2极化和组织损伤。这种细菌-宿主的病理共生关系（Host-microbial commensalism）使得微生态重建有望成为未来治疗AR的重要补充手段。[41]
For a long time, patients with typical seasonal or perennial rhinitis symptoms such as sneezing, clear rhinorrhoea and nasal obstruction but with negative skin prick tests (SPT) and negative serum specific IgE (sIgE) were usually diagnosed with non-allergic rhinitis (NAR) or idiopathic rhinitis. In recent years, however, the establishment of the concept of local allergic rhinitis (LAR), also termed entopy, has overturned this classification and revealed a mechanism in which allergic inflammation is highly localised.长久以来，临床上面对有典型季节性或常年性鼻炎症状（喷嚏、清涕、鼻塞），但皮肤点刺试验（SPT）和血清特异性IgE（sIgE）检测均呈阴性的患者，通常将其诊断为非过敏性鼻炎（NAR）或特发性鼻炎。然而，近年来“局部过敏性鼻炎（Local Allergic Rhinitis, LAR）”或称为“特应性（Entopy）”概念的确立，彻底颠覆了这一分类，揭示了过敏性炎症高度局部化的发病机制。[24][42]
Epidemiological surveys show that about 20% to 25% of adults and children previously diagnosed with NAR actually have LAR. The gold standard for the diagnosis of LAR is a positive nasal allergen provocation test (NAPT). In the nasal lavage fluid of such patients, specific IgE against a particular allergen, most often Dermatophagoides pteronyssinus, can be detected, and after antigen challenge there is an acute rise in local inflammatory mediators such as tryptase and eosinophil cationic protein (ECP).流行病学调查显示，约20%至25%既往被诊断为NAR的成年和儿童患者，实际上患有LAR。LAR的诊断金标准是鼻腔过敏原激发试验（Nasal Allergen Provocation Test, NAPT）阳性。在此类患者的鼻腔灌洗液中，可检测到针对特定过敏原（最常见为户尘螨 D. pteronyssinus）的特异性IgE，且在抗原激发后表现出局部的类胰蛋白酶（Tryptase）和嗜酸性粒细胞阳离子蛋白（ECP）等炎症介质急剧升高。[42][43][44][43][44]
Mechanistic studies have demonstrated that LAR does not lack IgE. Rather, B cells in the local germinal centres of the nasal mucosa undergo restricted class switching, and sIgE is synthesised only locally in the target organ, the nasal mucosa, without being released into the peripheral blood, so that routine systemic tests cannot detect it. Moreover, LAR is not a stable and benign quiescent state. Long-term follow-up over 5 to 10 years shows that LAR has an obvious tendency to worsen, and some patients eventually develop systemic sensitisation with serum sIgE becoming positive, converting to classical AR and developing comorbid asthma or allergic conjunctivitis. Even more interestingly, some classical AR patients who are sensitised in serum only to seasonal pollen have a positive NAPT to perennial house dust mite, a phenomenon called dual allergic rhinitis (DAR) that further illustrates the dissociation and complex interweaving between the local mucosal immune microenvironment and systemic immunity. Local nasal steroid treatment or specific immunotherapy directed at the positive allergen has been shown to relieve symptoms markedly in LAR patients, underlining the practical value of these mechanistic findings.机制研究证明，LAR并非没有IgE，而是由于B细胞在鼻黏膜局部的生发中心发生了局限性的同型转换，sIgE仅在靶器官（鼻黏膜）局部合成，未释放进入外周血，因此常规系统性检查无法检出。此外，LAR并非一种稳定的、良性的静止状态。长期随访（如5至10年）发现，LAR表现出明显的恶化趋势，部分患者最终会发生系统性致敏（血清sIgE转阳），转变为经典的AR，并合并哮喘或过敏性结膜炎。更有趣的是，部分在血清中仅对季节性花粉致敏的经典AR患者，其NAPT却对常年性尘螨呈现阳性，这种被称为“双重过敏性鼻炎（Dual Allergic Rhinitis, DAR）”的现象，进一步说明了局部黏膜免疫微环境与全身系统性免疫之间的脱节与复杂交织。针对LAR患者实施局部的鼻腔类固醇治疗，或针对阳性过敏原进行特异性免疫治疗，已证实可显著缓解症状，突显了机制发现对临床实践的指导意义。[43][24][43][44][42]
In summary, the pathogenesis of allergic rhinitis is not a single Th2-mediated linear allergic reaction but a highly complex three-dimensional network built on a foundation of genetic susceptibility, triggered by the modern exposome and interwoven at the cellular and molecular levels.综上所述，过敏性鼻炎的发病机制并非单一的Th2介导的线性变态反应，而是一个由遗传易感性铺垫、受现代环境暴露组触发、并交织着多细胞及多分子层面的高度复杂的立体网状模型。
Physical destruction of the epithelial barrier and activation of protease-activated receptors (PAR-2) by allergen enzymes constitute the trigger that sets the disease in motion. Alarmins released by the damaged epithelium, namely IL-33, TSLP and IL-25, then activate the group 2 innate lymphoid cells (ILC2s) beneath the mucosa at unprecedented speed. Under the fine control of dendritic cells (mDCs and pDCs), ILC2s interweave with the adaptive immune system, comprising Th2 and Tfh2 polarisation and defective Treg function, to produce large amounts of IgE and eosinophil infiltration. On this basis, the neuroimmune axis built from sensitised sensory nerve endings and the release of neuropeptides such as NMU and CGRP greatly amplifies mucosal hyperresponsiveness. All of this abnormal intercellular communication is anchored at the deepest level in the epigenetic and post-transcriptional remodelling of FOXP3 TSDR DNA methylation and of miRNAs such as miR-155 and miR-146a, and finally the dysbiosis of the local nasal microbiome with Staphylococcus aureus adds further momentum and removes any possibility of self-repair. The discovery of local allergic rhinitis (LAR) is a further reminder that clinicians should attend to the capacity of the target organ itself to remodel its immune microenvironment independently.上皮屏障（Epithelial Barrier）的物理破坏以及过敏原酶类对蛋白酶激活受体（PAR-2）的激活，构成了启动疾病的扳机；随后，由受损上皮释放的警报素（IL-33、TSLP、IL-25）以前所未有的速度激活了黏膜下方的第2群固有淋巴细胞（ILC2s）；而在树突状细胞（mDCs/pDCs）的精细调控下，ILC2s与适应性免疫系统（Th2、Tfh2极化及Treg功能缺陷）相互交织，导致了大量IgE的产生与嗜酸性粒细胞浸润；在此基础上，由于感觉神经末梢敏化及神经肽（如NMU、CGRP）释放构建的神经-免疫轴，极大地放大了黏膜的高反应性；这所有异常的细胞间通讯，底层都被固化在FOXP3 TSDR的DNA甲基化和miRNAs（如miR-155、miR-146a）的表观遗传学转录后重塑中，最后，局部鼻腔微生态（金黄色葡萄球菌）的失调进一步推波助澜，打破了机体自我修复的可能。局部过敏性鼻炎（LAR）的发现，则再次提醒临床应关注靶器官自身独立重塑免疫微环境的能力。
This paradigm shift from a purely molecular-cellular view to a barrier-neuro-microbiome-epigenetic one points to entirely new directions for precision medicine in allergic rhinitis. Clinical strategy is moving from symptom control that relies solely on antihistamines or glucocorticoids towards a new era of blocking the core cascade nodes. Biologics targeting epithelial alarmins such as the anti-TSLP antibody tezepelumab and the anti-IL-4Rα antibody dupilumab, highly selective PAR-2 antagonists such as punicalagin, next-generation immunotherapeutic targets based on restoring the FOXP3 methylation landscape, and even experimental treatments that reshape the nasal microbiome or deliver miRNAs all show far-reaching potential in preclinical and clinical studies. Deeper dissection of this multi-dimensional pathogenic network will provide the most essential theoretical support for the cure and prevention of allergic airway disease.这种从单纯“分子-细胞”向“屏障-神经-微生态-表观遗传”的范式转变，为未来过敏性鼻炎的精准医学干预指明了全新的方向。临床策略正从单一依赖抗组胺药或糖皮质激素的症状控制，逐步迈向阻断核心级联节点的新时代。例如，靶向上皮警报素的生物制剂（如抗TSLP单抗Tezepelumab、抗IL-4Rα单抗Dupilumab）、高选择性PAR-2拮抗剂（如石榴皮素）、基于恢复FOXP3甲基化图谱的下一代免疫治疗靶点，乃至重塑鼻腔微生态及靶向miRNA递送的实验性治疗，均在临床前及临床试验中展现出深远的潜力。深入解析这一多维发病网络，将为彻底治愈和预防过敏性呼吸道疾病提供最核心的理论支持。
References