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产生IL-15的骨B细胞在自身免疫性肝炎的发展中起病原性作用

Sota Fujimori^1,2, Po-Sung Chu¹, Toshiaki Teratani¹

¹Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

JHEP reports : innovation in hepatology

|June 12, 2023

概括

B细胞枯竭疗法有效治疗自身免疫性肝炎 (AIH). 这项研究表明,产生IL-15的B细胞通过扩大细胞毒性T淋巴细胞 (CTLs) 加剧AIH,提供新的治疗点.

科学领域:

免疫学免疫学免疫学
肝病学肝病学是一种肝病学.
自免疫性疾病自免疫性疾病

背景情况:

使用抗CD20的B细胞枯竭疗法对耐火性自身免疫性肝炎 (AIH) 有效.
B细胞参与AIH病变的确切机制尚不清楚.
了解这些机制对于开发有针对性的疗法至关重要.

研究的目的:

阐明B细胞在自身免疫性肝炎 (AIH) 病原发生中的作用.
确定B细胞在AIH中导致肝损伤的分子机制.
基于B细胞相互作用,探索AIH的潜在治疗点.

主要方法:

使用了腺相关病毒 (AAV) IL-12 的AIH小鼠模型.
分析了被诊断为AIH的患者的临床样本.
采用B细胞枯竭策略 (抗CD20,脊髓切除术) 和采用B细胞转移实验.
进行了RNA测序,细胞因子中和和体外共同培养试验.

主要成果:

B细胞枯竭改善了肝功能,并减少了肝脏内细胞毒性CD8+ T细胞 (CTLs).
从AAVIL-12治疗的小鼠中采用B细胞的转移加剧了AIH和增加了CTLs.
鉴定出IL-15是致病性B细胞的关键媒介,通过CXCL9/CXCR3轴促进CTL扩张和肝脏迁移.
IFNγ和CD40L/CD40信号传递对于B细胞中的IL-15产生至关重要,CD40L+CD8+T细胞促进B细胞中的IL-15表达.
在AIH患者中,血清IL-15和IL-15+B细胞计数增加与肝损伤标志物相关.

结论:

产生IL-15的骨B细胞通过促进CTL扩张在加剧实验AIH方面发挥着关键作用.
CD40L+ CD8+ T细胞和B细胞之间存在相互相互作用,推动IL-15的产生和随后的CTL增殖.
这些发现突显了IL-15/CTL轴在AIH病变发生过程中的重要性,并表明其作为人类AIH治疗点的潜力.

关键词:

自体免疫性肝炎是一种自身免疫性肝炎.B细胞是B细胞的组成部分.在 CD8+ T 细胞中.在IL-15中,IL-15是最常见的.

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