Argonaute-2 Autoantibodies: a Promising Biomarker for Predicting Mortality in HBV-related Acute-on-chronic Liver Failure Patients with Cirrhosis

Overview

Journal Front Cell Infect Microbiol

Specialties Cell Biology
Infectious Diseases
Microbiology

Date 2024 Aug 9

PMID 39119295

Authors

Yixuan Wang

Yue Hu

Jiaqi Li

Huailu Ma

Zongqi Shi

Chaojing Wen

Yu Long

Ziwei Li

Hang Sun

Yixuan Yang

Xiaofeng Shi

Affiliations

Soon will be listed here.

Abstract

Background & Aims: HBV infection initiates autoimmune responses, leading to autoantibody generation. This research explores the role of autoantibodies in HBV-related Acute-on-Chronic Liver Failure (ACLF), offering novel perspectives for clinical management.

Method: We applied immunoprecipitation and iTRAQ techniques to screen for autoantibodies in serum from HBV-related cirrhosis patients and conducted detection with conformation- stabilizing ELISA in a cohort of 238 HBV-infected individuals and 49 health controls. Our results were validated in a retrospective cohort comprising 106 ACLF patients and further assessed through immunohistochemical analysis in liver tissues from an additional 10 ACLF cases.

Results: Utilizing iTRAQ, we identified Argonaute1-3 autoantibodies (AGO-Abs) in this research. AGO2-Abs notably increased in cirrhosis, decompensation, and further in ACLF, unlike AGO1-Abs and AGO3-Abs. This reflects disease severity correlation. Logistic regression and COX models confirmed AGO2-Abs as independent prognostic indicators for decompensated liver cirrhosis (DLC) and ACLF. In the ROC analysis, AGO2-Abs showed significant diagnostic value for predicting 28- and 90-day mortality (AUROC = 0.853 and 0.854, respectively). Furthermore, combining AGO2-Abs with the Child-Pugh, MELD, and AARC scores significantly improved their predictive accuracy (P < 0.05). Kaplan-Meier analysis showed poorer survival for AGO2-Abs levels above 99.14μg/ml. These findings were supported by a retrospective validation cohort. Additionally, immunohistochemistry revealed band-like AGO2 expression in periportal liver areas, with AGO2-Abs levels correlating with total bilirubin, indicating a potential role in exacerbating liver damage through periportal functions.

Conclusions: AGO2-Abs is a robust biomarker for predicting the mortality of patients with HBV-related ACLF.

References

Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T . Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell. 2004; 15(2):185-97. DOI: 10.1016/j.molcel.2004.07.007. View

Zhang S, Liu Y, Chen J, Shu H, Shen S, Li Y . Autoantibody signature in hepatocellular carcinoma using seromics. J Hematol Oncol. 2020; 13(1):85. PMC: 7330948. DOI: 10.1186/s13045-020-00918-x. View

Shimakami T, Yamane D, Jangra R, Kempf B, Spaniel C, Barton D . Stabilization of hepatitis C virus RNA by an Ago2-miR-122 complex. Proc Natl Acad Sci U S A. 2012; 109(3):941-6. PMC: 3271899. DOI: 10.1073/pnas.1112263109. View

Geekiyanage H, Rayatpisheh S, Wohlschlegel J, Brown Jr R, Ambros V . Extracellular microRNAs in human circulation are associated with miRISC complexes that are accessible to anti-AGO2 antibody and can bind target mimic oligonucleotides. Proc Natl Acad Sci U S A. 2020; 117(39):24213-24223. PMC: 7533700. DOI: 10.1073/pnas.2008323117. View

Hsu Y, Huang D, Nguyen M . Global burden of hepatitis B virus: current status, missed opportunities and a call for action. Nat Rev Gastroenterol Hepatol. 2023; 20(8):524-537. DOI: 10.1038/s41575-023-00760-9. View

Asrani S, Larson J, Yawn B, Therneau T, Kim W . Underestimation of liver-related mortality in the United States. Gastroenterology. 2013; 145(2):375-82.e1-2. PMC: 3890240. DOI: 10.1053/j.gastro.2013.04.005. View

Maya R, Gershwin M, Shoenfeld Y . Hepatitis B virus (HBV) and autoimmune disease. Clin Rev Allergy Immunol. 2008; 34(1):85-102. DOI: 10.1007/s12016-007-8013-6. View

Sarin S, Choudhury A . Acute-on-chronic liver failure: terminology, mechanisms and management. Nat Rev Gastroenterol Hepatol. 2016; 13(3):131-49. DOI: 10.1038/nrgastro.2015.219. View

Bernal W, Ma Y, Smith H, Portmann B, Wendon J, Vergani D . The significance of autoantibodies and immunoglobulins in acute liver failure: a cohort study. J Hepatol. 2007; 47(5):664-70. DOI: 10.1016/j.jhep.2007.05.011. View

10.

Loureiro D, Tout I, Narguet S, Bed C, Roinard M, Sleiman A . Mitochondrial stress in advanced fibrosis and cirrhosis associated with chronic hepatitis B, chronic hepatitis C, or nonalcoholic steatohepatitis. Hepatology. 2022; 77(4):1348-1365. PMC: 10026976. DOI: 10.1002/hep.32731. View

11.

Jakymiw A, Ikeda K, Fritzler M, Reeves W, Satoh M, Chan E . Autoimmune targeting of key components of RNA interference. Arthritis Res Ther. 2006; 8(4):R87. PMC: 1779426. DOI: 10.1186/ar1959. View

12.

Mookerjee R, Lackner C, Stauber R, Stadlbauer V, Deheragoda M, Aigelsreiter A . The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol. 2011; 55(5):1103-11. DOI: 10.1016/j.jhep.2011.02.021. View

13.

Vazquez-Del Mercado M, Sanchez-Orozco L, Pauley B, Chan J, Chan E, Panduro A . Autoantibodies to a miRNA-binding protein Argonaute2 (Su antigen) in patients with hepatitis C virus infection. Clin Exp Rheumatol. 2010; 28(6):842-8. View

14.

Satoh M, Chan J, Ceribelli A, Vazquez del-Mercado M, Chan E . Autoantibodies to Argonaute 2 (Su antigen). Adv Exp Med Biol. 2012; 768:45-59. DOI: 10.1007/978-1-4614-5107-5_4. View

15.

Sarin S, Kumar M, Lau G, Abbas Z, Chan H, Chen C . Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2015; 10(1):1-98. PMC: 4722087. DOI: 10.1007/s12072-015-9675-4. View

16.

Choudhury A, Jindal A, Maiwall R, Sharma M, Sharma B, Pamecha V . Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models. Hepatol Int. 2017; 11(5):461-471. DOI: 10.1007/s12072-017-9816-z. View

17.

Fagerberg L, Hallstrom B, Oksvold P, Kampf C, Djureinovic D, Odeberg J . Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2013; 13(2):397-406. PMC: 3916642. DOI: 10.1074/mcp.M113.035600. View

18.

Sarin S, Choudhury A, Sharma M, Maiwall R, Al Mahtab M, Rahman S . Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. Hepatol Int. 2019; 13(4):353-390. PMC: 6728300. DOI: 10.1007/s12072-019-09946-3. View

19.

Moritz C, Do L, Tholance Y, Vallayer P, Rogemond V, Joubert B . Conformation-stabilizing ELISA and cell-based assays reveal patient subgroups targeting three different epitopes of AGO1 antibodies. Front Immunol. 2022; 13:972161. PMC: 9630334. DOI: 10.3389/fimmu.2022.972161. View

20.

Li H, Xia Q, Zeng B, Li S, Liu H, Li Q . Submassive hepatic necrosis distinguishes HBV-associated acute on chronic liver failure from cirrhotic patients with acute decompensation. J Hepatol. 2015; 63(1):50-9. DOI: 10.1016/j.jhep.2015.01.029. View