Characterization of intrahepatic B cells in acute-on-chronic liver failure.
Characterization of intrahepatic B cells in acute-on-chronic liver failure.
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急性慢性肝衰竭中肝内 B 细胞的特征
DOI：
10.3389/fimmu.2022.1041176
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
慢加急性肝功能衰竭（ACLF）是一种以免疫失调为特征的慢性肝病。先天性免疫反应和适应性T细胞反应均异常，但B细胞在ACLF发病机制中的作用尚不清楚。以前的报告仅基于外周血样本的免疫表型。在这里，我们的目的是解剖肝浸润B细胞亚群在ACLF。在肝移植过程中，从健康的活体供体和受体新鲜收集成对的肝灌注液和外周血。肝组织取自ACLF患者、肝硬化患者和健康对照。流式细胞术用于描述ACLF、肝硬化和健康对照组肝内和循环B细胞群的表型和功能改变。免疫组化法检测肝组织CD 19+、CD 138+的表达。本研究首先对ACLF患者肝内B细胞亚群进行了研究。我们发现，与肝硬化和健康对照组相比，ACLF肝脏中幼稚B细胞的比例降低，CD 27 + CD 21 −激活的记忆B细胞（AM）、CD 27 − CD 21 −非典型记忆B细胞（atMBC）、CD 27 +IgD−IgM+（IgM+记忆B细胞）和CD 27 + CD 38 ++浆细胞的百分比升高。此外，这些B亚群表现出增强的激活和改变的效应子功能。具体而言，ACLF肝脏富含表达较高的CD 11 c和较低的CD 80分子的atMBC，这与丙氨酸氨基转移酶和天冬氨酸氨基转移酶显著相关。此外，我们还发现肝内CD 27 + CD 38 ++浆细胞在ACLF中优先聚集，其表达更多的CD 273（PD-L2），并分泌更高的颗粒酶B和IL-10。最后，富集的肝血浆B细胞与包括碱性磷酸酶和γ-谷氨酰转移酶在内的疾病严重程度指数呈正相关。在这项初步研究中，我们显示了由ACLF肝脏环境形成的肝内B细胞景观，这与成对的循环B细胞亚群不同。atMBC和浆细胞中的表型和功能扰动突出了ACLF进展期间浸润B细胞的独特性质，从而表明B细胞干预在ACLF治疗中的潜力。
Acute on chronic liver failure (ACLF) is characterized by the immunologic dissonance during the prolonged pathogenic development. Both abnormal innate immune response and adaptive T-cell response have been reported in patients with ACLF; however, less is known regarding B cells in ACLF pathogenesis. Previous reports were only based on immunophenotyping of peripheral blood samples. Here, we aim to dissect liver-infiltrating B-cell subpopulation in ACLF. Paired liver perfusate and peripheral blood were freshly collected from healthy living donors and recipients during liver transplantation. Liver tissues were obtained from patients with ACLF, cirrhosis, and healthy controls. Flow cytometry was used to characterize the phenotypic and functional alterations in intrahepatic and circulating B-cell populations from ACLF, cirrhosis, and healthy controls. The expression of CD19+ and CD138+ on liver tissues was examined by immunohistochemistry staining. In this study, we first deciphered the intrahepatic B cells subsets of patients with ACLF. We found that the ACLF liver harbored reduced fraction of naïve B cells and elevated percentage of CD27+CD21− activated memory B cells (AM), CD27−CD21− atypical memory B cells (atMBC), CD27+IgD−IgM+(IgM+ memory B cells), and CD27+CD38++ plasma cells than cirrhosis and healthy controls. Moreover, these B subpopulations demonstrated enhanced activation and altered effector functions. Specifically, the ACLF liver was abundant in atMBC expressing higher CD11c and lower CD80 molecule, which was significantly correlated to alanine aminotransferase and aspartate aminotransferase. In addition, we found that intrahepatic CD27+CD38++plasma cells were preferentially accumulated in ACLF, which expressed more CD273 (PD-L2) and secreted higher granzyme B and IL-10. Finally, the enriched hepatic plasma B cells were in positive association with disease severity indices including alkaline phosphatase and gamma-glutamyl transferase. In this pilot study, we showed an intrahepatic B-cell landscape shaped by the ACLF liver environment, which was distinct from paired circulating B-cell subsets. The phenotypic and functional perturbation in atMBC and plasma cells highlighted the unique properties of infiltrating B cells during ACLF progression, thereby denoting the potential of B-cell intervention in ACLF therapy.