HBcAg-induced upregulated 4-1BB ligand on B cells contributes to B-cell hyperactivation during chronic hepatitis B infection
HBcAg-induced upregulated 4-1BB ligand on B cells contributes to B-cell hyperactivation during chronic hepatitis B infection
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HBcAg 诱导的 B 细胞上 4-1BB 配体上调导致慢性乙型肝炎感染期间 B 细胞过度激活
DOI：
10.1002/jmv.25377
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通讯作者：
Chao Wu
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作者：
Yong Liu;Guiyang Wang;Yuxin Chen;Rui Huang;Chen Tian;Yang Li;Xiang‐An Zhao;Chao Wu
在慢性乙型病毒性肝炎(CHB)的自然病程中，B细胞的功能仍不清楚。一些有限的研究表明，B细胞在慢性乙肝患者中高度活跃。在本工作中，我们报道了CHB患者B细胞表面4-1BB配体(4-1BBL)的表达明显高于正常人，同时CHB患者的血清免疫球蛋白水平也高于正常人。此外，经sCD40L或HBcAg刺激后，B细胞有较高水平的4-1BBL。与4-1BBL+B细胞共培养后，CD69和4-1BB在CD4+T细胞上的表达明显高于与4-1BBL-B细胞共培养后的表达。4-1BBL+B细胞共培养组培养上清液中IL-2、IL-4、IL-6水平明显高于4-1BBL-B细胞共培养组，而4-1BBL+B细胞共培养组上清液中干扰素-γ、肿瘤坏死因子-α水平显著低于4-1BBL+B细胞组。4-1BBL+B细胞组培养上清液中总免疫球蛋白水平显著高于对照组。因此，慢性乙型病毒性肝炎患者B细胞的高活性状态可能部分源于HBcAg诱导B细胞表面4-1BBL的高表达。4-1BBL信号通路参与了B细胞的活化，并通过调节细胞因子的分泌进一步调节B细胞与T细胞的相互作用，这可能是CHB感染时B细胞功能障碍的重要原因。
During the natural history of chronic hepatitis B infection (CHB)，the function of B cells is still obscure. Several limited studies have suggested that B cells are highly active in CHB patients. In present work, we reported that the 4-1BB ligand (4-1BBL) expression on B cells was significantly higher in CHB patients than that in healthy subjects, meanwhile the CHB patients had higher serological IgG levels. Further, after stimulated with sCD40L or HBcAg, B cells had higher levels of 4-1BBL. After co-cultured with 4-1BBL+ B cells, the expressions of CD69 and 4-1BB on CD4+ T cells were significantly higher than that co-cultured with 4-1BBL- B cells. Cytokines including IL-2, IL-4 and IL-6 were significantly higher in the supernatant from 4-1BBL+ B cells co-culture group than those from co-culture group of 4-1BBL- B cells group, respectively; while IFN-γ and TNF-α in co-cultured supernatant of 4-1BBL+ B cells group were significantly lower. Consistently, the total IgG levels in culture supernatant were significantly higher in 4-1BBL+ B cells group. Thus, hyperactive status of B cells in CHB patients could be partially derived from higher 4-1BBL expression on B cells triggered by HBcAg. 4-1BBL signaling pathway is involved in B cells activation, and further regulates B cell-T cells interaction by modulating the cytokines secretion, which might be critical in B cells dysfunction during CHB infection.