Eosinophil extracellular traps drive T follicular helper cell differentiation via VIRMA-dependent MAF stabilization in bullous pemphigoid.

IF 11.4 1区医学 Q1 ALLERGY Journal of Allergy and Clinical Immunology Pub Date : 2024-10-28 DOI:10.1016/j.jaci.2024.09.030

Shengxian Shen, Hui Fang, Xia Li, Yifan Zhou, Xin Tang, Haijun Miao, Liang Li, Jiaoling Chen, Ke Xue, Chen Zhang, Mengyang Chu, Bingyu Pang, Yaxing Bai, Hongjiang Qiao, Erle Dang, Shuai Shao, Gang Wang

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Abstract

Background: Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by the presence of pathogenic autoantibodies and a substantial influx of immune cells into skin lesions. However, the role of eosinophils in BP remains inadequately elucidated.

Objective: We sought to determine the pathologic involvement of eosinophils and eosinophil extracellular traps (EETs) in BP.

Methods: Human samples collected from BP patients and healthy controls were utilized to explore the potential role of eosinophils and their EETs in BP patients through serologic detection, flow cytometry, and immunofluorescence. Naive CD4⁺ T cells isolated from healthy donors were stimulated and subjected to further analysis via RNA sequencing. We additionally evaluated the potential of targeting EETs in BP180-immunized BP-like mice and in in vitro settings.

Results: We found that elevated levels of eosinophils and EETs in BP patients correlated with disease severity. The DNA components within EETs played a crucial role in driving the differentiation of naive CD4⁺ T cells into follicular helper T (Tfh) cells by activating coil domains containing 25 (CCDC25). Treatment with DNase I, which disrupts the structural integrity of EETs, or neutralizing antibody against CCDC25 reduced the expansion of Tfh cells and suppressed the production of autoantibodies in BP180-immunized BP-like mouse models. Additionally, we discovered that EETs induced the N⁶-methyladenosine methylation of the transcription factor musculoaponeurotic fibrosarcoma (MAF) via the DNA-CCDC25-VIRMA pathway, thereby enhancing its mRNA stability and promoting Tfh cell differentiation.

Conclusion: Our study revealed a previously unrecognized mechanism by which EETs trigger abnormal Tfh cell differentiation through CCDC25, followed by Vir-like m⁶A methyltransferase-associated protein (VIRMA)-mediated N⁶-methyladenosine modification of MAF. These insights provide promising avenues for the development of targeted therapeutic interventions in the field of BP and potentially other autoimmune diseases.

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在大疱性类天疱疮中，嗜酸性粒细胞胞外捕获器通过 VIRMA 依赖性 MAF 稳定作用驱动 T 滤泡辅助细胞分化。

背景：大疱性类天疱疮（BP）是一种自身免疫性水疱病，其特点是存在致病性自身抗体和大量免疫细胞涌入皮损。然而，嗜酸性粒细胞在 BP 中的作用仍未得到充分阐明：我们试图确定嗜酸性粒细胞和嗜酸性粒细胞胞外捕获器（EETs）在良性前列腺增生症中的病理参与作用。方法：我们利用从良性前列腺增生症患者和健康对照组采集的人体样本，通过血清学检测、流式细胞术和免疫荧光法探讨嗜酸性粒细胞及其 EETs 在良性前列腺增生症患者中的潜在作用。从健康供体中分离出的新生 CD4+ T 细胞受到了刺激，并通过 RNA 测序进行了进一步分析。此外，我们还评估了在 BP180 免疫的类 BP 小鼠和体外环境中靶向 EETs 的潜力：结果：我们发现，BP 患者体内嗜酸性粒细胞和 EETs 水平的升高与疾病的严重程度相关。EETs中的DNA成分通过激活含线圈结构域25（CCDC25），在驱动幼稚CD4+ T细胞分化为滤泡辅助T细胞（Tfh）的过程中发挥了关键作用。DNase I 会破坏 EETs 的结构完整性，用 DNase I 或 CCDC25 的中和抗体处理 BP180 免疫 BP 类小鼠模型可减少 Tfh 细胞的扩增并抑制自身抗体的产生。此外，我们还发现，EETs可通过DNA-CCDC25-VIRMA途径诱导转录因子MAF的N6-甲基腺苷（m6A）甲基化，从而增强其mRNA的稳定性并促进Tfh细胞的分化：我们的研究揭示了一种以前从未认识到的机制，即 EETs 通过 CCDC25 触发 Tfh 细胞异常分化，然后 VIRMA 介导 MAF 的 m6A 修饰。这些见解为开发针对 BP 及其他潜在自身免疫性疾病的靶向治疗干预措施提供了前景广阔的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Allergy and Clinical Immunology 医学-过敏

CiteScore

25.90

自引率

7.70%

发文量

1302

审稿时长

38 days

期刊介绍： The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.