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Taurocholic acid inhibits the response to interferon-αtherapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8^(+)T and NK cell function

查看全文 作　　者：Zhen [1,2,3]Xun;Jinpiao [1,2,3]Lin;Qingqing [3]Yu;Can [1,2,3]Liu;Jinlan [1,2,3]Huang;Hongyan [1,2]Shang;Jianhui [1,2]Guo;Yuchen [3]Ye;Wennan [1,2]Wu;Yongbin [1,2]Zeng;Songhang [1,2]Wu;Siyi [1,2]Xu;Tianbin [1,2,3]Chen;Jing [4]Chen;Qishui [1,2,3]Ou 高影响力作者 机构地区：[1]Department of Laboratory Medicine,Gene Diagnosis Research Center,The First Affiliated Hospital,Fujian Medical University,Fuzhou,China;[2]Fujian Key Laboratory of Laboratory Medicine,The First Affiliated Hospital,Fujian Medical University,Fuzhou,China;[3]First Clinical College,Fujian Medical University,Fuzhou,China;[4]Center of Liver Diseases,The First Affiliated Hospital,Fujian Medical University,Fuzhou,China高影响力机构 出　　处：《Cellular & Molecular Immunology》索引2021年第18卷第2期,共11页高影响力期刊 基　　金：We thank all the staff and patients of our hospital for the provision of the samples used in this study.This work was supported by the National Natural Science Foundation of China(Grant numbers 81971996,82030063,81672101,81702073);the Joint Funds for the Innovation of Science and Technology,Fujian Province(Grant number 2019Y9017). 摘　　要：Pegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3^(+)CD8^(+) T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3^(+)CD8^(+) T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3^(+)CD8^(+) T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment. 关 键 词：Bile acids Pegylated interferon Hepatitis B virus Immune cells Mechanism
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