恩替卡韦诱导的干扰素-λ1抑制乙型肝炎病毒相关性肝硬化患

StephenW

Entecavir-induced Interferon-λ1 suppresses type 2 innate lymphoid Cells in Patients with Hepatitis B virus-related liver cirrhosis
Si-Qi Wang  1   2 , Yue Shen  1   2 , Jing Li  3 , Yun Liu  4 , Li-Sha Cheng  1   2 , Sheng-di Wu  1   2 , Wei-Min She  1   2 , Wei Jiang  1   2   5
Affiliations
Affiliations

    1
    Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
    2
    Shanghai Institute of Liver disease, Shanghai, P.R. China.
    3
    Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai, P.R. China.
    4
    Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
    5
    Department of Gastroenterology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen Fujian, P.R. China.

    PMID: 33482039 DOI: 10.1111/jvh.13476

Abstract

The immunomodulatory effects of entecavir (ETV) in anti-hepatitis B virus (HBV) therapy have long been recognized. This study aimed to determine the effects of ETV on non-natural killer innate lymphoid cells (non-NK ILCs) in HBV-related liver disease progression. We enrolled treatment-naïve chronic hepatitis B (CHB) and HBV-related liver cirrhosis (LC) patients treated with ETV for 24 months. Before and after therapy, the frequency and cytokine profiles of ILC2s and non-NK ILCs subset homeostasis and their clinical significance were determined, and serial serum interferon (IFN)-λ levels were analyzed. Peripheral blood mononuclear cells (PBMCs) of untreated LC patients were cultured with serum from untreated and ETV-treated LC patients in addition to being subject to IFN-λ1 neutralization and stimulation, and the frequency and cytokine production of ILC2s as well as non-NK ILCs subset ratios were calculated. Furthermore, IFN-λ receptor expression on non-NK ILCs and dendritic cells (DCs) was measured. After 24 months of ETV treatment, the frequency and cytokine production of ILC2s (IL-4, IL-13, IFN-γ, TNF-α) decreased with increased ILC1/ILC2 and decreased ILC2/ILC3 ratios, revealing a close association with disease status in LC patients. Long-term ETV administration induced serum IFN-λ1 levels were negatively correlated with ILC2s. ETV-treated LC serum culture and IFN-λ1 stimulation yielded similar effects on suppression of ILC2s, and IFN-λ1 neutralization in serum culture partly inhibited this effect. The IFN-λ receptor was detected on DCs but not on non-NK ILCs. In conclusion, ETV suppresses the frequency and cytokine profiles of ILC2s by increasing IFN-λ1 in LC patients.

Keywords: Entecavir; chronic hepatitis B; interferon-λ1; liver cirrhosis; type 2 innate lymphoid cells.

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StephenW

恩替卡韦诱导的干扰素-λ1抑制乙型肝炎病毒相关性肝硬化患者的2型先天淋巴样细胞
王思奇1 2，岳神1 2，景丽3，刘柳4，程丽莎1 2，吴生di 1 2，魏敏敏1 2，魏江1 2 5
隶属关系
隶属关系

    1个
    复旦大学附属中山医院消化内科，上海市
    2
    中国上海市上海市肝病研究所
    3
    同济大学附属同济医院消化内科，上海
    4
    复旦大学附属中山医院风湿科，上海
    5
    复旦大学中山医院厦门分院消化内科，福建厦门

    PMID：33482039 DOI：10.1111 / jvh.13476

抽象

长期以来，人们已经认识到恩替卡韦（ETV）在抗乙型肝炎病毒（HBV）治疗中的免疫调节作用。这项研究旨在确定ETV对HBV相关肝病进展中非自然杀伤性先天淋巴样细胞（非NK ILC）的影响。我们纳入了未经治疗的慢性乙型肝炎（CHB）和HBV相关肝硬化（LC）患者，接受ETV治疗24个月。治疗前后，确定ILC2和非NK ILC亚稳态的频率和细胞因子谱及其临床意义，并分析血清血清干扰素（IFN）-λ水平。除了接受IFN-λ1中和和刺激作用，ILC2s以及非NK的频率和细胞因子的产生外，未经治疗的LC患者的外周血单个核细胞（PBMC）还应与未经治疗和ETV治疗的LC患者的血清一起培养。计算了ILC的子集比率。此外，测量了非NK ILC和树突状细胞（DC）上的IFN-λ受体表达。经过ETV治疗24个月后，ILC1 / ILC2升高和ILC2 / ILC3比例降低，ILC2s（IL-4，IL-13，IFN-γ，TNF-α）的发生频率和细胞因子降低，表明与疾病密切相关LC患者的健康状况。长期接受ETV诱导的血清IFN-λ1水平与ILC2s呈负相关。 ETV处理的LC血清培养物和IFN-λ1刺激对ILC2s的抑制作用相似，而血清培养物中IFN-λ1的中和作用部分抑制了这一作用。在DC上检测到IFN-λ受体，但在非NK ILC上未检测到。总之，ETV通过增加LC患者的IFN-λ1抑制ILC2的频率和细胞因子谱。

关键字：恩替卡韦；慢性乙型肝炎干扰素-λ1;肝硬化2型先天淋巴样细胞。

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