Huang Li, Ye Bo, Cao Feinan, Ruan Bing, Li Xuefen
Zhejiang Key Laboratory of Clinical In Vitro Diagnostic Techniques, Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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 Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
J Med Virol. 2025 May;97(5):e70360. doi: 10.1002/jmv.70360.
Cellular immune responses are crucial in determining outcomes of the hepatitis B virus (HBV) infection. Ineffective immune responses enable persistent HBV infection and contribute to progressive liver disease. Understanding the mechanisms underlying immunological HBV tolerance and restoring functional adaptive immune responses is essential for successful chronic hepatitis B (CHB) treatment. This study examined the dysregulated immune responses and immunopathological cell states associated with CHB using single-cell RNA sequencing of peripheral blood mononuclear cells to investigate immune cell composition and transcriptional differences between patients with CHB and healthy donors. Phenotypic alterations in the lymphoid and myeloid compartments were observed following HBV infection. T cell immune profiling in patients with CHB showed enrichment of exhausted CD8+ T cells, impaired cytotoxicity of effector CD8+ T cells, and increased regulatory T cell (Treg) suppressive activity. Immature neutrophils and a unique CD14+ monocyte subset (myeloid-derived suppressor cells) exhibited potent immunosuppressive abilities. A novel population of CD14+CD163+VSIG4+ M2-like macrophages with immunosuppressive and anti-inflammatory phenotypes was enriched in a patient with severe CHB and liver failure, indicating a potential contribution to dysfunctional immune responses. Our study demonstrated immune exhaustion and evasion in chronic HBV infection, elucidating its immunopathological features and suggesting new therapeutic strategies for immune-mediated disorders and unresolved chronic HBV infection.
细胞免疫反应在决定乙型肝炎病毒（HBV）感染的结果中起着关键作用。无效的免疫反应会导致HBV持续感染，并促使肝病进展。了解免疫性HBV耐受的潜在机制并恢复功能性适应性免疫反应对于成功治疗慢性乙型肝炎（CHB）至关重要。本研究使用外周血单核细胞的单细胞RNA测序来研究CHB患者与健康供体之间的免疫细胞组成和转录差异，从而检测与CHB相关的失调免疫反应和免疫病理细胞状态。HBV感染后观察到淋巴细胞和髓细胞区室的表型改变。CHB患者的T细胞免疫谱显示耗竭的CD8 + T细胞富集，效应性CD8 + T细胞的细胞毒性受损，以及调节性T细胞（Treg）抑制活性增加。未成熟的中性粒细胞和独特的CD14 +单核细胞亚群（髓系来源的抑制细胞）表现出强大的免疫抑制能力。在一名重症CHB和肝衰竭患者中富集了一群具有免疫抑制和抗炎表型的新型CD14 + CD163 + VSIG4 + M2样巨噬细胞，表明其对功能失调的免疫反应有潜在贡献。我们的研究证明了慢性HBV感染中的免疫耗竭和逃逸，阐明了其免疫病理特征，并为免疫介导的疾病和未解决的慢性HBV感染提出了新的治疗策略。
