老年人重度听力损失相关的周围适应性免疫重塑：一项单中心流式细胞术研究及小鼠耳蜗转录组学背景

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中文摘要

目的： 利用参与者层面的临床免疫表型分析，探讨老年人重度听力损失与全身免疫衰老之间的关联，并利用公开的小鼠耳蜗转录组数据探索潜在的炎症通路和细胞背景。
方法： 我们分析了一个由76名老年人组成的单中心队列，分为听力正常（NH）、轻中度听力损失（MMHL）或重度至极重度听力损失（SPHL）组。使用年龄和性别校正模型评估免疫特征。预设的敏感性和诊断分析评估了年龄规格、重叠权重、有影响的观测值以及倒置模型的稳定性。此外，检查了公开的小鼠耳蜗批量转录组学和单核RNA测序（snRNA-seq）数据，以识别相关的炎症通路和细胞类型特异性免疫应激模块。
结果： SPHL与较高的T细胞/CD8偏斜、增加的CD4分化、升高的EM/naive CD4平衡、较低的CD8活化/检查点评分以及CD4/CD8倒置的几率增加显著相关。这些关联在敏感性分析中保持一致。小鼠批量转录组学突出了炎症反应和IL6/JAK/STAT3信号通路，而snRNA-seq将免疫应激模块主要定位在广泛的巨噬细胞和血管周围巨噬细胞样细胞群。
结论： 老年人重度听力损失与提示全身免疫衰老的独特周围免疫重塑特征相关。这些发现支持一个以关联为重点的框架，将听力损失严重程度与免疫失调联系起来，但需要在更大规模、有临床注释的队列中进行验证。

英文摘要

OBJECTIVE: To investigate the association between severe hearing loss and systemic immune aging in older adults using participant-level clinical immunophenotyping, and to explore potential inflammatory pathways and cellular contexts using public mouse cochlear transcriptomic data.
METHODS: We analyzed a single-center cohort of 76 older adults, classified into normal hearing (NH), mild-to-moderate hearing loss (MMHL), or severe-to-profound hearing loss (SPHL) groups. Age- and sex-adjusted models were used to assess immune profiles. Prespecified sensitivity and diagnostic analyses evaluated age specification, overlap weighting, influential observations, and the stability of the inversion model. Additionally, public mouse cochlear bulk transcriptomics and single-nucleus RNA sequencing (snRNA-seq) data were examined to identify relevant inflammatory pathways and cell-type-specific immune-stress modules.
RESULTS: SPHL was significantly associated with a higher T-cell/CD8 skew, increased CD4 differentiation, an elevated EM/naive CD4 balance, a lower CD8 activation/checkpoint score, and increased odds of CD4/CD8 inversion. These associations remained consistent across sensitivity analyses. Mouse bulk transcriptomics highlighted inflammatory response and IL6/JAK/STAT3 signaling pathways, while snRNA-seq localized immune-stress modules primarily to broad macrophage and perivascular macrophage-like cell populations.
CONCLUSION: Severe hearing loss in older adults is associated with distinct peripheral immune remodeling features indicative of systemic immune aging. These findings support an association-focused framework linking hearing loss severity with immune dysregulation, though validation in larger, clinically annotated cohorts is required.