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Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis

Lookup NU author(s): Dr David Adams, Dr Jess Dyson

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. BACKGROUND AND AIMS: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.


Publication metadata

Author(s): Taubert R, Engel B, Diestelhorst J, Hupa-Breier KL, Behrendt P, Baerlecken NT, Suhs K-W, Janik MK, Zachou K, Sebode M, Schramm C, Londono M-C, Habes S, Oo YH, Lalanne C, Pape S, Schubert M, Hust M, Dubel S, Thevis M, Jonigk D, Beimdiek J, Buettner FFR, Drenth JPH, Muratori L, Adams DH, Dyson JK, Renand A, Graupera I, Lohse AW, Dalekos GN, Milkiewicz P, Stangel M, Maasoumy B, Witte T, Wedemeyer H, Manns MP, Jaeckel E

Publication type: Article

Publication status: Published

Journal: Hepatology (Baltimore, Md.)

Year: 2022

Volume: 75

Issue: 1

Pages: 13-27

Online publication date: 02/09/2021

Acceptance date: 16/08/2021

Date deposited: 21/02/2022

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: Wiley Periodicals LLC

URL: https://doi.org/10.1002/hep.32134

DOI: 10.1002/hep.32134

PubMed id: 34473365


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Funding

Funder referenceFunder name
“Else-Kröner-Fresenius-Stiftung” as part of the M.D. dissertation program (KlinStrucMed)
European Consolidator Grant (ERC; reference no.: 771883)
Institute of Health Research (NIHR) Birmingham Biomedical Research Centre (BRC; Ye Oo and David Adams)
EU research consortium RESHAPE
German Research Foundation (KFO250 projects 3, 7, and Z1; FOR2953 projects 432218849 and project P9; and BU 2920/4-1)
NIHR Newcastle Biomedical Research Centre
NIHR Rare Diseases Translational Research Collaboration and LiverNorth (a national patient support group)
Sir Jules Thorn Biomedical Research Charitable Trust (Ye Oo)
young clinician scientist program (Practis) from Hannover Medical School
Young Faculty program and from Core 100 advanced clinician scientist from the Hannover Medical School

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