Pub Date : 2024-10-01Epub Date: 2024-03-27DOI: 10.1097/HEP.0000000000000855
Ka Shing Cheung, Ho Yu Ng, Rex Wan Hin Hui, Lok Ka Lam, Lung Yi Mak, Yuen Chi Ho, Jing Tong Tan, Esther W Chan, Wai Kay Seto, Man Fung Yuen, Wai K Leung
Background and aims: We investigated whether empagliflozin reduces hepatic steatosis in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus.
Approach and results: This was an investigator-initiated, double-blind, randomized, placebo-controlled trial recruiting adult subjects from the community. Eligible subjects without diabetes mellitus (fasting plasma glucose < 7 mmol/L and HbA1c < 6.5%) who had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 5% were randomly allocated to receive empagliflozin 10 mg daily or placebo (1:1 ratio) for 52 weeks (end of treatment, EOT). MRI-PDFF was conducted at baseline and EOT. The primary outcome was the difference in change of MRI-PDFF between the 2 groups at EOT. Secondary outcomes were hepatic steatosis resolution (MRI-PDFF < 5%), alanine aminotransferase drop ≥ 17 U/L, MRI-PDFF decline ≥ 30%, a combination of both, and changes of anthropometric and laboratory parameters at EOT. All outcomes were based on intention-to-treat analysis. Of 98 recruited subjects (median age: 55.7 y [IQR:49.5-63.4]; male:54 [55.1%]), 97 (empagliflozin:49, placebo:48; median MRI-PDFF:9.7% vs 9.0%) had MRI-PDFF repeated at EOT. The Empagliflozin group had a greater reduction in median MRI-PDFF compared to the placebo group (-2.49% vs. -1.43%; p = 0.025), with a nonsignificant trend of resolution of hepatic steatosis (44.9% vs. 28.6%; p = 0.094). There was no significant difference in alanine aminotransferase drop ≥ 17 U/L (16.3% vs. 12.2%; p = 0.564), MRI-PDFF drop ≥ 30% (49.0% vs. 40.8%; p = 0.417), and composite outcome (8.2% vs. 8.2%; p = 1.000). Empagliflozin group had a greater drop in body weight (-2.7 vs. -0.2 kg), waist circumference (-2.0 vs. 0 cm), fasting glucose (-0.3 vs. 0 mmol/L), and ferritin (-126 vs. -22 pmol/L) (all p < 0.05).
Conclusions: Empagliflozin for 52 weeks reduces hepatic fat content in subjects with nondiabetic metabolic dysfunction-associated steatotic liver disease. (ClinicalTrials.gov Identifier: NCT04642261).
{"title":"Effects of empagliflozin on liver fat in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus: A randomized, double-blind, placebo-controlled trial.","authors":"Ka Shing Cheung, Ho Yu Ng, Rex Wan Hin Hui, Lok Ka Lam, Lung Yi Mak, Yuen Chi Ho, Jing Tong Tan, Esther W Chan, Wai Kay Seto, Man Fung Yuen, Wai K Leung","doi":"10.1097/HEP.0000000000000855","DOIUrl":"10.1097/HEP.0000000000000855","url":null,"abstract":"<p><strong>Background and aims: </strong>We investigated whether empagliflozin reduces hepatic steatosis in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus.</p><p><strong>Approach and results: </strong>This was an investigator-initiated, double-blind, randomized, placebo-controlled trial recruiting adult subjects from the community. Eligible subjects without diabetes mellitus (fasting plasma glucose < 7 mmol/L and HbA1c < 6.5%) who had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 5% were randomly allocated to receive empagliflozin 10 mg daily or placebo (1:1 ratio) for 52 weeks (end of treatment, EOT). MRI-PDFF was conducted at baseline and EOT. The primary outcome was the difference in change of MRI-PDFF between the 2 groups at EOT. Secondary outcomes were hepatic steatosis resolution (MRI-PDFF < 5%), alanine aminotransferase drop ≥ 17 U/L, MRI-PDFF decline ≥ 30%, a combination of both, and changes of anthropometric and laboratory parameters at EOT. All outcomes were based on intention-to-treat analysis. Of 98 recruited subjects (median age: 55.7 y [IQR:49.5-63.4]; male:54 [55.1%]), 97 (empagliflozin:49, placebo:48; median MRI-PDFF:9.7% vs 9.0%) had MRI-PDFF repeated at EOT. The Empagliflozin group had a greater reduction in median MRI-PDFF compared to the placebo group (-2.49% vs. -1.43%; p = 0.025), with a nonsignificant trend of resolution of hepatic steatosis (44.9% vs. 28.6%; p = 0.094). There was no significant difference in alanine aminotransferase drop ≥ 17 U/L (16.3% vs. 12.2%; p = 0.564), MRI-PDFF drop ≥ 30% (49.0% vs. 40.8%; p = 0.417), and composite outcome (8.2% vs. 8.2%; p = 1.000). Empagliflozin group had a greater drop in body weight (-2.7 vs. -0.2 kg), waist circumference (-2.0 vs. 0 cm), fasting glucose (-0.3 vs. 0 mmol/L), and ferritin (-126 vs. -22 pmol/L) (all p < 0.05).</p><p><strong>Conclusions: </strong>Empagliflozin for 52 weeks reduces hepatic fat content in subjects with nondiabetic metabolic dysfunction-associated steatotic liver disease. (ClinicalTrials.gov Identifier: NCT04642261).</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-04-29DOI: 10.1097/HEP.0000000000000909
Carlo La Vecchia, Claudia Santucci
{"title":"Liver cancer in young adults: Validity of global data sets.","authors":"Carlo La Vecchia, Claudia Santucci","doi":"10.1097/HEP.0000000000000909","DOIUrl":"10.1097/HEP.0000000000000909","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140849023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-04-30DOI: 10.1097/HEP.0000000000000916
Manoj Kumar, Shantan Venishetty
{"title":"Reply: Tranexamic acid in upper gastrointestinal bleed in patients with cirrhosis - A randomized controlled trial.","authors":"Manoj Kumar, Shantan Venishetty","doi":"10.1097/HEP.0000000000000916","DOIUrl":"10.1097/HEP.0000000000000916","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140846804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background and aims: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC.
Approach and results: Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758.
Conclusions: PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.
{"title":"A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.","authors":"Yuki Hitomi, Kazuko Ueno, Yoshihiro Aiba, Nao Nishida, Michihiro Kono, Mitsuki Sugihara, Yosuke Kawai, Minae Kawashima, Seik-Soon Khor, Kazuhiro Sugi, Hirotaka Kouno, Hiroshi Kohno, Atsushi Naganuma, Satoru Iwamoto, Shinji Katsushima, Kiyoshi Furuta, Toshiki Nikami, Tomohiko Mannami, Tsutomu Yamashita, Keisuke Ario, Tatsuji Komatsu, Fujio Makita, Masaaki Shimada, Noboru Hirashima, Shiro Yokohama, Hideo Nishimura, Rie Sugimoto, Takuya Komura, Hajime Ota, Motoyuki Kojima, Makoto Nakamuta, Naoyuki Fujimori, Kaname Yoshizawa, Yutaka Mano, Hironao Takahashi, Kana Hirooka, Satoru Tsuruta, Takeaki Sato, Kazumi Yamasaki, Yuki Kugiyama, Yasuhide Motoyoshi, Tomoyuki Suehiro, Akira Saeki, Kosuke Matsumoto, Shinya Nagaoka, Seigo Abiru, Hiroshi Yatsuhashi, Masahiro Ito, Kazuhito Kawata, Akinobu Takaki, Kuniaki Arai, Teruko Arinaga-Hino, Masanori Abe, Masaru Harada, Makiko Taniai, Mikio Zeniya, Hiromasa Ohira, Shinji Shimoda, Atsumasa Komori, Atsushi Tanaka, Kazuyoshi Ishigaki, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura","doi":"10.1097/HEP.0000000000000894","DOIUrl":"10.1097/HEP.0000000000000894","url":null,"abstract":"<p><strong>Background and aims: </strong>Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC.</p><p><strong>Approach and results: </strong>Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758.</p><p><strong>Conclusions: </strong>PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-05-14DOI: 10.1097/HEP.0000000000000928
Cong Luo
{"title":"Letter to the Editor: Chronic hepatitis B baseline viral load and on-treatment liver cancer risk: A multinational cohort study of HBeAg-positive patients.","authors":"Cong Luo","doi":"10.1097/HEP.0000000000000928","DOIUrl":"10.1097/HEP.0000000000000928","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-03-05DOI: 10.1097/HEP.0000000000000830
Mareike Kellerer, Sana Javed, Christian Casar, Nico Will, Laura K Berkhout, Dorothee Schwinge, Christian F Krebs, Christoph Schramm, Katrin Neumann, Gisa Tiegs
Background and aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis. We showed an elevated interferon γ response in patients with primary sclerosing cholangitis and in multidrug resistance protein 2-deficient ( Mdr2-/- ) mice developing sclerosing cholangitis. Interferon γ induced expression of the cytotoxic molecules granzyme B (GzmB) and TRAIL in hepatic lymphocytes and mediated liver fibrosis in sclerosing cholangitis.
Approach and results: In patient samples and Mdr2-/- mice, we identified lymphocyte clusters with a cytotoxic gene expression profile using single-cell RNA-seq and cellular indexing of transcriptomes and epitopes by sequencing analyses combined with multi-parameter flow cytometry. CD8 + T cells and NK cells showed increased expression of GzmB and TRAIL in sclerosing cholangitis. Depletion of CD8 + T cells ameliorated disease severity in Mdr2-/- mice. By using Mdr2-/- × Gzmb-/- and Mdr2-/- × Tnfsf10-/- mice, we investigated the significance of GzmB and TRAIL for disease progression in sclerosing cholangitis. Interestingly, the lack of GzmB resulted in reduced cholangiocyte apoptosis, liver injury, and fibrosis. In contrast, sclerosing cholangitis was aggravated in the absence of TRAIL. This correlated with elevated GzmB and interferon γ expression by CD8 + T cells and NK cells enhanced T-cell survival, and increased apoptosis and expansion of cholangiocytes.
Conclusions: GzmB induces apoptosis and fibrosis in sclerosing cholangitis, whereas TRAIL regulates inflammatory and cytotoxic immune responses, subsequently leading to reduced liver injury and fibrosis.
背景目的:原发性硬化性胆管炎(PSC)是一种以胆道炎症和纤维化为特征的慢性胆汁淤积性肝病。我们在 PSC 患者和发生硬化性胆管炎的多药耐药蛋白 2 缺失(Mdr2-/-)小鼠中发现干扰素(IFN)γ 反应升高。干扰素(IFN)γ诱导肝淋巴细胞中细胞毒性分子颗粒酶B(GzmB)和TNF相关凋亡诱导配体(TRAIL)的表达,并介导硬化性胆管炎的肝纤维化:在患者样本和Mdr2-/-小鼠中,我们利用单细胞RNA-seq和CITE-seq分析,结合多参数流式细胞术,确定了具有细胞毒性基因表达谱的淋巴细胞集群。在硬化性胆管炎中,CD8+ T细胞和NK细胞的GzmB和TRAIL表达增加。CD8+T细胞的消耗减轻了Mdr2-/-小鼠的疾病严重程度。通过使用Mdr2-/-xGzmb-/-和Mdr2-/-xTnfsf10-/-小鼠,我们研究了GzmB和TRAIL对硬化性胆管炎疾病进展的意义。有趣的是,缺乏 GzmB 会减少胆管细胞凋亡、肝损伤和纤维化。相反,如果缺乏 TRAIL,硬化性胆管炎则会加重。这与 CD8+ T 细胞和 NK 细胞的 GzmB 和 IFNγ 表达升高、T 细胞存活率提高、胆管细胞凋亡和扩张增加有关:结论:GzmB可诱导硬化性胆管炎患者的细胞凋亡和纤维化,而TRAIL可调节炎症和细胞毒性免疫反应,从而减轻肝损伤和纤维化。
{"title":"Antagonistic effects of the cytotoxic molecules granzyme B and TRAIL in the immunopathogenesis of sclerosing cholangitis.","authors":"Mareike Kellerer, Sana Javed, Christian Casar, Nico Will, Laura K Berkhout, Dorothee Schwinge, Christian F Krebs, Christoph Schramm, Katrin Neumann, Gisa Tiegs","doi":"10.1097/HEP.0000000000000830","DOIUrl":"10.1097/HEP.0000000000000830","url":null,"abstract":"<p><strong>Background and aims: </strong>Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis. We showed an elevated interferon γ response in patients with primary sclerosing cholangitis and in multidrug resistance protein 2-deficient ( Mdr2-/- ) mice developing sclerosing cholangitis. Interferon γ induced expression of the cytotoxic molecules granzyme B (GzmB) and TRAIL in hepatic lymphocytes and mediated liver fibrosis in sclerosing cholangitis.</p><p><strong>Approach and results: </strong>In patient samples and Mdr2-/- mice, we identified lymphocyte clusters with a cytotoxic gene expression profile using single-cell RNA-seq and cellular indexing of transcriptomes and epitopes by sequencing analyses combined with multi-parameter flow cytometry. CD8 + T cells and NK cells showed increased expression of GzmB and TRAIL in sclerosing cholangitis. Depletion of CD8 + T cells ameliorated disease severity in Mdr2-/- mice. By using Mdr2-/- × Gzmb-/- and Mdr2-/- × Tnfsf10-/- mice, we investigated the significance of GzmB and TRAIL for disease progression in sclerosing cholangitis. Interestingly, the lack of GzmB resulted in reduced cholangiocyte apoptosis, liver injury, and fibrosis. In contrast, sclerosing cholangitis was aggravated in the absence of TRAIL. This correlated with elevated GzmB and interferon γ expression by CD8 + T cells and NK cells enhanced T-cell survival, and increased apoptosis and expansion of cholangiocytes.</p><p><strong>Conclusions: </strong>GzmB induces apoptosis and fibrosis in sclerosing cholangitis, whereas TRAIL regulates inflammatory and cytotoxic immune responses, subsequently leading to reduced liver injury and fibrosis.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11407778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-07-17DOI: 10.1097/HEP.0000000000001014
Neelam Giri, Marena R Niewisch, Philip S Rosenberg, Anusha Vittal, Sharon A Savage, Theo Heller
{"title":"Reply: Accurate predictor for liver disease progression in patients with DC/TBD.","authors":"Neelam Giri, Marena R Niewisch, Philip S Rosenberg, Anusha Vittal, Sharon A Savage, Theo Heller","doi":"10.1097/HEP.0000000000001014","DOIUrl":"10.1097/HEP.0000000000001014","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-02-09DOI: 10.1097/HEP.0000000000000769
Hosun Yu, Eui-Cheol Shin
{"title":"Duet of humoral and cellular immunity for conquering HCV.","authors":"Hosun Yu, Eui-Cheol Shin","doi":"10.1097/HEP.0000000000000769","DOIUrl":"10.1097/HEP.0000000000000769","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-01-12DOI: 10.1097/HEP.0000000000000753
John Gridley, Brantley Holland, Eduardo Salinas, Sheetal Trivedi, Piyush Dravid, Elizabeth Elrod, Fengzhi Jin, Anuradha Kumari, Mariana N Batista, Manoj Thapa, Charles M Rice, Joseph Marcotrigiano, Amit Kapoor, Arash Grakoui
Background and aims: Evidence assessing the role of B cells and their antibodies, or lack thereof, in the spontaneous resolution of acute HCV infection is conflicting. Utilization of a strictly hepatotropic, HCV-related rodent hepacivirus (RHV) model circumvents many of the challenges facing the field in characterizing the immunological correlates of dichotomous infection outcomes. This study seeks to elucidate the importance of B cells in the clearance of acute RHV infection.
Approach and results: µMT mice were infected i.v. with RHV and found to develop chronic infection for over a year. Wild-type (WT) mice depleted of B cells also exhibited persistent viremia that resolved only upon B cell resurgence. The persistent infection developed by B1-8i and AID cre/cre mice revealed that antigen-specific, class-switched B cells or their antibodies were crucial for viral resolution. Virus-specific CD8 + and CD4 + T cells were characterized in these mice using newly developed major histocompatibility complex class I and II tetramers and ex vivo peptide stimulation. Immunoglobulin G (IgG) was purified from the serum of RHV- or lymphocytic choriomeningitis virus Armstrong-infected mice after viral clearance and passively transferred to AID cre/cre recipients, revealing viral clearance only in αRHV IgG recipients. Further, the transfer of αRHV IgG into B cell-depleted recipients also induced viral resolution. This ability of RHV-specific IgG to induce viral clearance was found to require the concomitant presence of CD8 + T cells.
Conclusions: Our findings demonstrate a cooperative interdependence between immunoglobulins and the T cell compartment that is required for RHV resolution. Thus, HCV vaccine regimens should aim to simultaneously elicit robust HCV-specific antibody and T cell responses for optimal protective efficacy.
评估 B 细胞及其抗体在丙型肝炎病毒(HCV)感染自发缓解中的作用或缺乏 B 细胞及其抗体的证据相互矛盾。利用严格意义上的趋肝性、与 HCV 相关的啮齿类动物肝病毒 (RHV) 可以规避该领域在描述二分法感染结果的免疫学相关性时所面临的许多挑战。虽然 WT 小鼠能在约 4 周内清除这种感染,但选择性免疫扰乱能诱导小鼠终生持续感染,就像人类的慢性 HCV 感染一样。因此,人们发现先天性缺乏成熟 B 细胞的 µMT 小鼠会出现慢性 RHV 感染。在确定小鼠存在抗病毒 Th1 反应缺陷后,我们又发现,尽管 WT 小鼠的 T 细胞反应功能完全正常,但它们仍会持续感染,这证实了 RHV 清除直接依赖 B 细胞的特性。B1-8i和AIDcre/cre小鼠的持续感染揭示了抗原特异性、类别转换B细胞或其抗体对病毒清除的关键作用。将从RHV或LCMV清除供体中纯化的IgG被动转移到AIDcre/cre受体中,只有αRHV IgG受体才能清除病毒。此外,将 αRHV IgG 转移到 B 细胞耗竭的受体中也能诱导病毒清除。研究发现,RHV 特异性 IgG 诱导病毒清除的能力需要 CD8+ T 细胞的同时存在。由于这些免疫球蛋白和 T 细胞在推动 RHV 清除过程中的协同作用,HCV 疫苗方案应旨在同时引起强有力的 HCV 特异性抗体和 T 细胞反应,以达到最佳保护效果。
{"title":"Concerted synergy between viral-specific IgG and CD8 + T cells is critical for clearance of an HCV-related rodent hepacivirus.","authors":"John Gridley, Brantley Holland, Eduardo Salinas, Sheetal Trivedi, Piyush Dravid, Elizabeth Elrod, Fengzhi Jin, Anuradha Kumari, Mariana N Batista, Manoj Thapa, Charles M Rice, Joseph Marcotrigiano, Amit Kapoor, Arash Grakoui","doi":"10.1097/HEP.0000000000000753","DOIUrl":"10.1097/HEP.0000000000000753","url":null,"abstract":"<p><strong>Background and aims: </strong>Evidence assessing the role of B cells and their antibodies, or lack thereof, in the spontaneous resolution of acute HCV infection is conflicting. Utilization of a strictly hepatotropic, HCV-related rodent hepacivirus (RHV) model circumvents many of the challenges facing the field in characterizing the immunological correlates of dichotomous infection outcomes. This study seeks to elucidate the importance of B cells in the clearance of acute RHV infection.</p><p><strong>Approach and results: </strong>µMT mice were infected i.v. with RHV and found to develop chronic infection for over a year. Wild-type (WT) mice depleted of B cells also exhibited persistent viremia that resolved only upon B cell resurgence. The persistent infection developed by B1-8i and AID cre/cre mice revealed that antigen-specific, class-switched B cells or their antibodies were crucial for viral resolution. Virus-specific CD8 + and CD4 + T cells were characterized in these mice using newly developed major histocompatibility complex class I and II tetramers and ex vivo peptide stimulation. Immunoglobulin G (IgG) was purified from the serum of RHV- or lymphocytic choriomeningitis virus Armstrong-infected mice after viral clearance and passively transferred to AID cre/cre recipients, revealing viral clearance only in αRHV IgG recipients. Further, the transfer of αRHV IgG into B cell-depleted recipients also induced viral resolution. This ability of RHV-specific IgG to induce viral clearance was found to require the concomitant presence of CD8 + T cells.</p><p><strong>Conclusions: </strong>Our findings demonstrate a cooperative interdependence between immunoglobulins and the T cell compartment that is required for RHV resolution. Thus, HCV vaccine regimens should aim to simultaneously elicit robust HCV-specific antibody and T cell responses for optimal protective efficacy.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11239798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}