慢性鼻窦炎伴鼻息肉中的三级淋巴结构：空间组织、病理功能及其对手术策略和生物治疗的意义

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中文摘要

慢性鼻窦炎伴鼻息肉（CRSwNP）存在三个持续存在的临床谜题，传统免疫学框架未能解决。这些谜题包括：局部特异性IgE升高而全身无致敏的悖论；在技术上完全的功能性内镜鼻窦手术（FESS）后息肉复发率超过60%；以及大多数患者在停用度普利尤单抗后6至12个月内出现疾病反弹。越来越多的证据表明，三级淋巴结构（TLS）——能够维持自主适应性免疫应答的有组织异位淋巴聚集体——可能代表一个统一的结构框架，可能参与所有这三种现象。在CRSwNP组织中，成熟TLS被认为含有功能性生发中心，驱动局部IgE类别转换重组，独立于全身致敏。这些结构也可能作为组织驻留记忆T（TRM）细胞的保护性龛，这些细胞对全身生物制剂阻断具有抵抗性，并且它们可能维持自我维持的免疫回路，在手术切除大体息肉组织后持续存在。本综述综合了目前关于TLS形成生物学的知识，提出了三功能TLS模型作为概念框架。它进一步整合了近期大型队列的空间转录组数据，以假设TLS解剖深度可能决定功能表型和治疗脆弱性。我们进一步提出TLS分级框架作为研究工具，以构建未来的验证研究，并概述了针对手术范围、生物靶向策略和未来研究方向的假设驱动、可测试的意义。如果得到验证，将CRSwNP重新定义为TLS驱动的、结构上半自主的炎症性疾病，可能将治疗范式从症状抑制转向免疫重建。

英文摘要

Chronic rhinosinusitis with nasal polyps (CRSwNP) presents three persistent clinical enigmas that conventional immunological frameworks have failed to resolve. These include the paradox of locally elevated specific IgE in the absence of systemic sensitization, a high polyp recurrence rate exceeding 60% following technically complete functional endoscopic sinus surgery (FESS), and disease rebound observed in the majority of patients within 6 to 12 months after discontinuation of dupilumab. Converging lines of evidence suggest that tertiary lymphoid structures (TLS), organized ectopic lymphoid aggregates capable of sustaining autonomous adaptive immune responses, may represent a unifying structural framework that could contribute to all three phenomena. Within CRSwNP tissue, mature TLS are proposed to harbor functional germinal centers that drive local IgE class-switch recombination independent of systemic sensitization. These structures may also serve as protected niches for tissue-resident memory T (TRM) cells refractory to systemic biologic blockade, and they may maintain self-sustaining immune circuits that persist after surgical removal of gross polyp tissue. This review synthesizes current knowledge of TLS formation biology, proposes a Trifunctional TLS Model as a conceptual framework. It further integrates recent spatial transcriptomic data from large cohorts to hypothesize that TLS anatomical depth may determine functional phenotype and therapeutic vulnerability. We further propose a TLS grading framework as a research instrument to structure future validation studies, and outline hypothesis-driven, testable implications for surgical extent, biologic targeting strategies, and future research directions. If validated, reframing CRSwNP as a TLS-driven, structurally semi-autonomous inflammatory disease could shift the therapeutic paradigm from symptom suppression toward immunological restructuring.