Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells.

Autor:	Mulcahy V; Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.; Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Liaskou E; Centre for Liver and Gastrointestinal Research, National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, UK.; Institute of Immunology & Immunotherapy, University of Birmingham, Birmingham, UK., Martin JE; Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.; Cancer Molecular Diagnostic Laboratory, Oncology Department, University of Cambridge, Cambridge, UK., Kotagiri P; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Badrock J; Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK., Jones RL; Leeds Liver Unit, The Leeds Teaching Hospitals NHS Trust, Leeds, UK., Rushbrook SM; Department of Hepatology, Norwich Medical School, University of East Anglia, Norwich, UK., Ryder SD; NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK., Thorburn D; The Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK., Taylor-Robinson SD; Department of Surgery and Cancer, Imperial College London, St Mary's Campus, London, UK., Clark G; Stratified Medicine Core Laboratory (SMCL) Next Generation Sequencing Hub, NIHR Cambridge BRC, Cambridge, UK., Cordell HJ; Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, UK., Sandford RN; Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK., Jones DE; Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.; NIHR Newcastle BRC, Newcastle University, Newcastle-upon-Tyne, UK., Hirschfield GM; Toronto Centre for Liver Disease, University Health Network and Department of Medicine, University of Toronto, Toronto, Canada., Mells GF; Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.; Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Jazyk:	angličtina
Zdroj:	Hepatology communications [Hepatol Commun] 2023 Apr 04; Vol. 7 (4). Date of Electronic Publication: 2023 Apr 04 (Print Publication: 2023).
DOI:	10.1097/HC9.0000000000000110
Abstrakt:	Background Aims: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. Methods: We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets. Results: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. Conclusions: We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
Databáze:	MEDLINE
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