دورية أكاديمية
أعرض في EDS

Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity.

التفاصيل البيبلوغرافية
العنوان: Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity.
المؤلفون: Narmada BC; Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672; Experimental Drug Development Centre, A∗STAR, 10 Biopolis Way, Chromos, Singapore 138670, Singapore., Khakpoor A; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Shirgaonkar N; Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672., Narayanan S; Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore., Aw PPK; Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672., Singh M; Bioinformatics Institute, A∗STAR, 30 Biopolis Street, Matrix, Singapore 138671, Singapore., Ong KH; Bioinformatics Institute, A∗STAR, 30 Biopolis Street, Matrix, Singapore 138671, Singapore., Owino CO; Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Ng JWT; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Yew HC; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Binte Mohamed Nasir NS; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Au VB; Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore., Sng R; Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore., Kaliaperumal N; Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore., Khine HHTW; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., di Tocco FC; Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France., Masayuki O; Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore 169856, Singapore., Naikar S; Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore 169856, Singapore., Ng HX; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Chia SL; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Seah CXY; Department of Medicine, National University Hospital, Singapore., Alnawaz MH; Department of Medicine, National University Hospital, Singapore., Wai CLY; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Tay AYL; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Mangat KS; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Chew V; Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore 169856, Singapore., Yu W; Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore; Bioinformatics Institute, A∗STAR, 30 Biopolis Street, Matrix, Singapore 138671, Singapore., Connolly JE; Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Biomedical Studies, Baylor University, Waco, TX, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Periyasamy G; Experimental Drug Development Centre, A∗STAR, 10 Biopolis Way, Chromos, Singapore 138670, Singapore., Plissonnier ML; Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France., Levrero M; Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France; Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France; University of Lyon Claude Bernard 1 (UCLB1), Lyon, France; Department of Medicine SCIAC and the Italian Institute of Technology (IIT) Center for Life Nanosciences (CLNS), University of Rome La Sapienza, Rome, Italy., Lim SG; Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore; Department of Medicine, National University Hospital, Singapore; Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore. Electronic address: mdclimsg@nus.edu.sg., DasGupta R; Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672. Electronic address: dasguptar@gis.a-star.edu.sg.
المصدر: Journal of hepatology [J Hepatol] 2024 Jul; Vol. 81 (1), pp. 42-61. Date of Electronic Publication: 2024 Feb 28.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2001- : Amsterdam : Elsevier
Original Publication: Copehnagen : Munksgaard International Publishers, [c1984-
مواضيع طبية MeSH: Hepatitis B, Chronic*/immunology , Hepatitis B, Chronic*/virology , Immunity, Innate*/immunology , Adaptive Immunity*/immunology , Single-Cell Analysis*/methods, Humans ; Hepatitis B virus/immunology ; Hepatitis B virus/genetics ; Male ; Female ; T-Lymphocytes, Cytotoxic/immunology ; Adult ; Liver/immunology ; Liver/pathology ; Hepatitis B Surface Antigens/immunology ; Middle Aged ; Killer Cells, Natural/immunology
مستخلص: Background & Aims: Hepatitis B surface antigen (HBsAg) loss or functional cure (FC) is considered the optimal therapeutic outcome for patients with chronic hepatitis B (CHB). However, the immune-pathological biomarkers and underlying mechanisms of FC remain unclear. In this study we comprehensively interrogate disease-associated cell states identified within intrahepatic tissue and matched PBMCs (peripheral blood mononuclear cells) from patients with CHB or after FC, at the resolution of single cells, to provide novel insights into putative mechanisms underlying FC.
Methods: We combined single-cell transcriptomics (single-cell RNA sequencing) with multiparametric flow cytometry-based immune phenotyping, and multiplexed immunofluorescence to elucidate the immunopathological cell states associated with CHB vs. FC.
Results: We found that the intrahepatic environment in CHB and FC displays specific cell identities and molecular signatures that are distinct from those found in matched PBMCs. FC is associated with the emergence of an altered adaptive immune response marked by CD4 cytotoxic T lymphocytes, and an activated innate response represented by liver-resident natural killer cells, specific Kupffer cell subtypes and marginated neutrophils. Surprisingly, we found MHC class II-expressing hepatocytes in patients achieving FC, as well as low but persistent levels of covalently closed circular DNA and pregenomic RNA, which may play an important role in FC.
Conclusions: Our study provides conceptually novel insights into the immuno-pathological control of HBV cure, and opens exciting new avenues for clinical management, biomarker discovery and therapeutic development. We believe that the discoveries from this study, as it relates to the activation of an innate and altered immune response that may facilitate sustained, low-grade inflammation, may have broader implications in the resolution of chronic viral hepatitis.
Impact and Implications: This study dissects the immuno-pathological cell states associated with functionally cured chronic hepatitis B (defined by the loss of HBV surface antigen or HBsAg). We identified the sustained presence of very low viral load, accessory antigen-presenting hepatocytes, adaptive-memory-like natural killer cells, and the emergence of helper CD4 T cells with cytotoxic or effector-like signatures associated with functional cure, suggesting previously unsuspected alterations in the adaptive immune response, as well as a key role for the innate immune response in achieving or maintaining functional cure. Overall, the insights generated from this study may provide new avenues for the development of alternative therapies as well as patient surveillance for better clinical management of chronic hepatitis B.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: CD4-CTL; HBV; HBsAg; accessory APC; immune; liver; neutrophils; single cell RNA-seq; viral hepatitis
المشرفين على المادة: 0 (Hepatitis B Surface Antigens)
تواريخ الأحداث: Date Created: 20240229 Date Completed: 20240621 Latest Revision: 20240710
رمز التحديث: 20240710
DOI: 10.1016/j.jhep.2024.02.017
PMID: 38423478
قاعدة البيانات: MEDLINE
الوصف
تدمد:1600-0641
DOI:10.1016/j.jhep.2024.02.017