Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom.
Hepatology. 2012 Oct;56(4):1521-31. doi: 10.1002/hep.25790.
B cells are present within chronically inflamed liver tissue and recent evidence implicates them in the progression of liver disease. In addition, a large proportion of hepatic lymphomas are of B-cell origin. The molecular signals that regulate normal and malignant B-cell recruitment into peripheral tissue from blood are poorly understood, leading us to study human B-cell migration through hepatic sinusoidal endothelial cells in flow-based adhesion assays. In such assays, human blood-derived B cells were captured from shear flow without a previous rolling phase and underwent firm adhesion mediated by vascular cell adhesion molecule-1 (VCAM-1). Unlike T cells, which displayed vigorous crawling behavior on the endothelium, B cells remained static before a proportion underwent transendothelial migration mediated by a combination of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion protein-1, common lymphatic endothelial and vascular endothelial receptor-1/stabilin-1, and the chemokine receptors, CXCR3 and CXCR4. B-cell lymphoma cell lines and primary malignant B cells from patients with chronic lymphocytic leukemia and marginal zone B cell lymphoma also underwent integrin-mediated firm adhesion involving ICAM-1 and/or VCAM-1 and demonstrated ICAM-1-dependent shape-change and crawling behavior. Unlike primary lymphocytes, the malignant cells did not undergo transendothelial migration, which could explain why lymphomas are frequently characterized by the intravascular accumulation of malignant cells in the hepatic sinusoids.
Our findings demonstrate that distinct combinations of signals promote B-cell recruitment to the liver, suggesting the possibility of novel targets to modulate liver inflammation in disease. Certain features of lymphocyte homing are maintained in lymphoma recruitment to the liver, suggesting that therapeutic targets for lymphocyte recruitment may also prevent hepatic lymphoma dissemination.
B 细胞存在于慢性炎症的肝组织中，最近的证据表明它们参与了肝病的进展。此外，很大一部分肝淋巴瘤是 B 细胞起源的。调节正常和恶性 B 细胞从血液中募集到外周组织的分子信号知之甚少，这导致我们通过基于流动的粘附测定法研究人类 B 细胞穿过肝窦内皮细胞的迁移。在这种测定法中，人血源性 B 细胞从剪切流中捕获，而没有先前的滚动阶段，并通过血管细胞粘附分子-1（VCAM-1）介导的牢固粘附。与 T 细胞不同，T 细胞在内皮上表现出强烈的爬行行为，B 细胞在一部分通过细胞间粘附分子-1（ICAM-1）、血管粘附蛋白-1、普通淋巴内皮和血管内皮受体-1/稳定素-1以及趋化因子受体 CXCR3 和 CXCR4 介导的跨内皮迁移之前保持静止。B 细胞淋巴瘤细胞系和来自慢性淋巴细胞白血病和边缘区 B 细胞淋巴瘤患者的原发性恶性 B 细胞也经历了涉及 ICAM-1 和/或 VCAM-1 的整合素介导的牢固粘附，并表现出 ICAM-1 依赖性形状变化和爬行行为。与原发性淋巴细胞不同，恶性细胞不会发生跨内皮迁移，这可以解释为什么淋巴瘤通常以肝窦内恶性细胞的血管内积聚为特征。
我们的发现表明，不同的信号组合促进 B 细胞向肝脏募集，这表明有可能调节疾病中的肝脏炎症的新靶点。在淋巴瘤向肝脏募集中保持了淋巴细胞归巢的某些特征，这表明用于淋巴细胞募集的治疗靶点也可能阻止肝淋巴瘤的扩散。
