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

被引：12

作者：

Narmada, Balakrishnan Chakrapani ^{[1
,2
]}

Khakpoor, Atefeh ^{[3
]}

Shirgaonkar, Niranjan ^{[1
]}

Narayanan, Sriram ^{[4
]}

Aw, Pauline Poh Kim ^{[1
]}

Singh, Malay ^{[5
]}

Ong, Kok Haur ^{[5
]}

Owino, Collins Oduor ^{[1
,6
]}

Ng, Jane Wei Ting ^{[3
]}

Yew, Hui Chuing ^{[3
]}

Nasir, Nu Soibah Binte Mohamed ^{[3
]}

Au, Veonice Bijin ^{[4
]}

Sng, Reina ^{[4
]}

Kaliaperumal, Nivashini ^{[4
]}

Khine, Htet Htet Toe Wai ^{[3
]}

di Tocco, Francesca Casuscelli ^{[7
]}

Masayuki, Otsuka ^{[8
]}

Naikar, Shamita ^{[8
]}

Ng, Hui Xin ^{[3
]}

Chia, Su Li ^{[3
]}

Seah, Cindy Xin Yi ^{[9
]}

Alnawaz, Myra H. J. ^{[9
]}

Wai, Chris Lee Yoon ^{[3
]}

Tay, Amy Yuh Ling ^{[3
]}

Mangat, Kamarjit Singh ^{[3
]}

Chew, Valerie ^{[8
]}

Yu, Weimiao ^{[4
,5
]}

Connolly, John Edward ^{[4
,6
,10
,11
]}

Periyasamy, Giridharan

Plissonnier, Marie-Laure

Levrero, Massimo ^{[7
,12
,13
,14
,15
]}

Lim, Seng Gee ^{[4
,9
,16
]}

DasGupta, Ramanuj ^{[1
]}

机构：

[1] ASTAR, Genome Inst Singapore, Lab Precis Med & Canc Evolut, 60 Biopolis St,0201 Genome, Singapore 138672, Singapore

[2] ASTAR, Expt Drug Dev Ctr, 10 Biopolis Way,Chromos, Singapore 138670, Singapore

[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore

[4] ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr,Proteos, Singapore 138673, Singapore

[5] ASTAR, Bioinformat Inst, 30 Biopolis St,Matrix, Singapore 138671, Singapore

[6] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Microbiol & Immunol, Singapore, Singapore

[7] CNRS, Canc Res Ctr Lyon CRCL, INSERM U1052, UMR5286, Lyon, France

[8] SingHlth DukeNUS Acad Med Ctr, Translat Immunol Inst TII, Singapore 169856, Singapore

[9] Natl Univ Singapore Hosp, Dept Med, Singapore, Singapore

[10] Baylor Univ, Inst Biomed Studies, Waco, TX USA

[11] Parker Inst Canc Immunotherapy, San Francisco, CA USA

[12] Hosp Civils Lyon, Hop Croix Rousse, Dept Hepatol, Lyon, France

[13] Univ Lyon Claude Bernard 1 UCLB1, Lyon, France

[14] Univ Roma La Sapienza, Dept Med SCIAC, Rome, Italy

[15] Univ Roma La Sapienza, Italian Inst Technol, IIT Ctr Life Nanosci CLNS, Rome, Italy

[16] Natl Univ Singapore Hosp, Natl Univ Hlth Syst, Div Gastroenterol & Hepatol, Singapore, Singapore

来源：

JOURNAL OF HEPATOLOGY | 2024年 / 81卷 / 01期

基金：

英国医学研究理事会;

关键词：

NATURAL-KILLER-CELLS; T-CELLS; CLASS-I; VIRAL-ANTIGEN; LIVER-DAMAGE; NK CELLS; HEPATOCYTES; HBV; EXPRESSION; MEMORY;

D O I：

10.1016/j.jhep.2024.02.017

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

引用

页码：42 / 61

页数：21