State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Infectious Diseases, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China.
Front Immunol. 2021 Jun 23;12:660312. doi: 10.3389/fimmu.2021.660312. eCollection 2021.
Patients with decompensated HBV-related liver cirrhosis (HBV D-LC) showed compromised immune responses, which manifested as a proneness to develop infections and hyporesponsiveness to vaccines, resulting in accelerated disease progression. The alterations in T cell-dependent B cell responses in this pathophysiological process were not well understood. This study aimed to investigate T cell-dependent B cell responses in this process and discuss the mechanism from the perspective of metabolism.
Changes in phenotypes and subsets of peripheral B cells between HBV D-LC patients and healthy controls (HCs) were compared by flow cytometry. Isolated B cells were activated by coculture with circulating T follicular (cTfh) cells. After coculture, the frequencies of plasmablasts and plasma cells and immunoglobin levels were analyzed. Oxidative phosphorylation (OXPHOS) and glycolysis were analyzed by a Seahorse analyzer. Mitochondrial function and the AKT/mTOR pathway were analyzed by flow cytometry.
The proliferation and differentiation capacities of B cells after T cell stimulation were impaired in D-LC. Furthermore, we found that B cells from D-LC patients showed reductions in OXPHOS and glycolysis after activation, which may result from reduced glucose uptake, mitochondrial dysfunction and attenuated activation of the AKT/mTOR pathway.
B cells from HBV D-LC patients showed dysfunctional energy metabolism after T cell-dependent activation. Understanding the regulations of B cell metabolic pathway and their changes may provide a new direction to rescue B cell hyporesponsiveness in patients with HBV D-LC, preventing these patients be infected and improving sensitivity to vaccines.
失代偿期乙型肝炎病毒相关肝硬化（HBV D-LC）患者的免疫应答受损，表现为易发生感染和对疫苗反应低下，导致疾病加速进展。在这一病理生理过程中，T 细胞依赖性 B 细胞反应的改变尚不清楚。本研究旨在探讨该过程中 T 细胞依赖性 B 细胞反应，并从代谢角度探讨其机制。
采用流式细胞术比较 HBV D-LC 患者和健康对照（HCs）外周血 B 细胞的表型和亚群变化。将分离的 B 细胞与循环滤泡辅助 T 细胞（cTfh）共培养激活。共培养后，分析浆母细胞和浆细胞的频率和免疫球蛋白水平。采用 Seahorse 分析仪分析氧化磷酸化（OXPHOS）和糖酵解。采用流式细胞术分析线粒体功能和 AKT/mTOR 通路。
D-LC 患者 T 细胞刺激后 B 细胞的增殖和分化能力受损。此外，我们发现 D-LC 患者的 B 细胞在激活后 OXPHOS 和糖酵解减少，这可能是由于葡萄糖摄取减少、线粒体功能障碍和 AKT/mTOR 通路激活减弱所致。
HBV D-LC 患者的 B 细胞在 T 细胞依赖性激活后表现出功能失调的能量代谢。了解 B 细胞代谢途径的调节及其变化可能为挽救 HBV D-LC 患者 B 细胞反应低下、预防感染和提高疫苗敏感性提供新方向。
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