Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia

Wang, Jun; Xu, Yanhui; Chen, Zhanghua; Liang, Jianhua; Lin, Zefeng; Liang, Huiying; Xu, Yuanyuan; Wu, Qi; Guo, Xuanjie; Nie, Junli; Lu, Bingtai; Huang, Bing; Xian, Huifang; Wang, Xiaohui; Wu, Qiang; Zeng, Jixiao; Chai, Chengwei; Zhang, Mei-Xue; Lin, Yunting; Zhang, Li; Zhao, Shiwei; Tong, Yanlu; Zeng, Liang; Gu, Xiaoqiong; Chen, Zhuang‐Gui; Yi, Shuhong; Zhang, Tong; Delfouneso, David; Zhang, Yan; Nutt, Stephen L.; Lew, Andrew M.; Lü, Lei; Bai, Fan; Xia, Huimin; Wang, Zhe; Zhang, Yuxia

doi:10.1016/j.cell.2020.10.048

Cited by 85 publications

(102 citation statements)

References 94 publications

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“…In ammation, as a trigger factor, can cause an autoimmune response against antigens from biliary epithelium [76]. Immune-mediated biliary injury is characterized by an overexpression of histocompatibility antigens on bile ducts and an obvious in ltration of immunologically active T lymphocytes, which is a central feature of adult liver diseases and also related to obstruction of neonatal extrahepatic bile ducts.…”

Section: Discussionmentioning

confidence: 99%

Biomarkers for Diagnosis and Post-Kasai Portoenterostomy Prognosis of Biliary Atresia: Systematic Review and Meta-Analysis

Tam

Lui

et al. 2021

Preprint

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Objectives To evaluate the accuracy of biomarkers for the early diagnosis of biliary atresia (BA) and prognostic stratification after Kasai portoenterostomy (KPE). Methods We conducted a systematic review of PubMed, Web of Science, Embase, Scopus and OVID for English literatures reporting BA biomarkers published before August, 2020. Biomarkers selected for study was based on a good evidence-level (better than Grade B, level 2b). Screening, data extraction, and quality assessment were done in duplicate. Results A total of 51 eligible studies were involved for systematic review, and data from 12 of them (4182 subjects) were extracted for meta-analysis in the following 2 domains: (1) serum matrix metallopeptidase-7 (MMP-7), interleukin33 (IL-33) and γ-glutamyl transferase (GGT) to differentiate BA from non-BA; and (2) aspartate aminotransferase to platelet ratio index (APRi) to predict post-KPE liver fibrosis/cirrhosis. Summary sensitivity, specificity and the area under the curve (AUC) of MMP-7 for diagnosing BA were 96%, 91% and 0.9847, respectively. Summary sensitivity and specificity of IL-33 for diagnosing BA were 77% and 85%, respectively. Summary sensitivity, specificity and AUC of GGT for diagnosing BA were 80%, 79% and 0.9645, respectively. Summary sensitivity and specificity of APRi for predicting post-KPE liver fibrosis were 61% and 80%, respectively. Summary sensitivity, specificity and AUC of APRi for predicting post-KPE cirrhosis were 78%, 83% and 0.8729, respectively. Moreover, good evidence-level was shown in the investigations of serum IL-18 and IL-33 in distinguishing BA from healthy control, serum IL-18 for prognosing post-KPE persistent jaundice, and serum hyaluronic acid and MMP-7 for prognosing post-KPE significant liver fibrosis. Conclusions MMP-7, IL-33 and GGT are useful biomarker to assist the diagnosis of BA. APRi could be used to predict post-KPE significant liver fibrosis and cirrhosis. These non-invasive biomarkers could be integrated into the management protocol of BA.

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Section: Discussionmentioning

confidence: 99%

Biomarkers for Diagnosis and Post-Kasai Portoenterostomy Prognosis of Biliary Atresia: Systematic Review and Meta-Analysis

Tam

Lui

et al. 2021

Preprint

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“…Liver biopsies obtained from patients during laparoscopy or Kasai's operation were processed according to published procedures by Wang. et al [9]. Peripheral blood mononuclear cells or hepatic lymphocytes were incubated for 45 min at 4℃ with saturating concentrations of uorescently labeled antibodies and analyzed on a FACSAria SORP ow cytometer (BD Science).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Lymphocytes isolated from liver biopsies of patients or mice models were cultured on V-bottom 96-well plates in RPMI 1640 (Gibco) medium (R10) containing 10% heat-inactivated FBS (Gibco), 100 U/ml penicillin/streptomycin (Gibco) and 100 μM nonessential amino acids (Gibco) at 37℃ in 5% CO 2 . 100 ng/ml Phorbol 12-myristate 13-acetate (PMA, Sigma-Aldrich, St Louis, MO), 2 μM/ml Ionomycin (Sigma-Aldrich) and 2 μM/ml monensin (Sigma-Aldrich) were used to stimulate the lymphocytes for 4-6 hours [9]. Intracellular staining was performed using eBioscience™ Intracellular Fixation & Permeabilization Buffer Set (Invitrogen) following the manufacturer's protocol.…”

Section: Intracellular Cytokine Stainingmentioning

confidence: 99%

“…Studies using patients biopsies [6] and rotavirus-induced BA mouse models provide strong evidence for virus-induced autoimmune pathways [7,8]. We [9] and others [7,9,10] have shown that IFNg, secreted from CD4 + T helper 1 (Th1) cells, ex-CD4 + T helper 17 (Th17) T cells and CD8 + T cells, are involved in the pathogenesis of BA. IFN-γ + cells are present within the portal tracts in the livers of infant with biliary atresia [11].…”

Section: Introductionmentioning

confidence: 99%

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PD-1 Protects Liver Damage by Suppressing IFN-γ Expression in T Cells in Infants and Neonatal Mice

Guo

Luo

et al. 2021

Preprint

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Background: Biliary atresia (BA) is a severe cholangiopathy resulting from virus-induced and immune-mediated injury of the biliary system. IFN-g, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death 1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Methods: Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. Results: PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver. Blockade of PD-1 increased IFN-g expression in CD4+ T and CD8+ T cells, suppressed bilirubin production and exacerbated liver immunopathology.Conclusions: PD-1 plays a protective role in infants with BA by suppressing IFN-g production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA.

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“…Subsequent studies followed this paradigm and used genetically engineered mice and antibody-mediated cell depletion to show the relevance of regulatory T cells in controlling disease susceptibility during the early postnatal period. These single-cell transcriptomes and performed lymphocyte single-cell V(D)J profiling to assess T cell clonotypes and gene expression levels in six patients with biliary atresia and control children with normal liver function who required surgery for either choledochal cysts or other non-cholestatic diseases 7 . In support of previous studies, the numbers of cytotoxic T H 1 cells and transitional cytotoxic T helper 17 (T H 17) cells were increased in biliary atresia relative to controls.…”

mentioning

confidence: 99%

A single-cell view of biliary atresia

Russi

Bezerra

2021

Nat Rev Gastroenterol Hepatol

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Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia

Cited by 85 publications

References 94 publications

Biomarkers for Diagnosis and Post-Kasai Portoenterostomy Prognosis of Biliary Atresia: Systematic Review and Meta-Analysis

Biomarkers for Diagnosis and Post-Kasai Portoenterostomy Prognosis of Biliary Atresia: Systematic Review and Meta-Analysis

PD-1 Protects Liver Damage by Suppressing IFN-γ Expression in T Cells in Infants and Neonatal Mice

A single-cell view of biliary atresia

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