PMID- 27784538 OWN - NLM STAT- MEDLINE DCOM- 20171222 LR - 20210109 IS - 1095-9157 (Electronic) IS - 0896-8411 (Linking) VI - 77 DP - 2017 Feb TI - Phenotyping and auto-antibody production by liver-infiltrating B cells in primary sclerosing cholangitis and primary biliary cholangitis. PG - 45-54 LID - S0896-8411(16)30226-8 [pii] LID - 10.1016/j.jaut.2016.10.003 [doi] AB - Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are immune-mediated biliary diseases that demonstrate prominent and restricted genetic association with human leukocyte antigen (HLA) alleles. In PBC, anti-mitochondrial antibodies (AMA) are specific and used as diagnostic biomarkers. PSC-relevant auto-antibodies remain controversial despite a distinct HLA association that mirrors archetypical auto-antigen driven disorders. Herein, we compared antibody-secreting B cells (ASCs) in PSC and PBC liver explants to determine if liver-infiltrating ASCs represent an opportune and novel source of disease-relevant auto-antibodies. Using enzymatic digestion and mechanical disruption, liver mononuclear cells (LIMCs) were isolated from fresh PSC and PBC explants and plasmablast (CD19+CD27+CD38(hi)CD138-) and plasma cell (CD19+CD27+CD38(hi)CD138+) ASCs were enumerated by flow cytometry. We observed 45-fold fewer plasma cells in PSC explants (n = 9) compared to PBC samples (n = 5, p < 0.01) and 10-fold fewer IgA-, IgG- and IgM-positive ASCs (p < 0.05). Liver-infiltrating ASCs from PSC and PBC explants were functional and produced similar concentrations of IgA, IgG and IgM following 2 weeks of culture. Antibody production by PBC ASCs (n = 3) was disease-specific as AMA to pyruvate dehydrogenase complex E2 subunit (PDC-E2) was detected by immunostaining, immunoblotting and ELISA. Antibody profiling of PSC supernatants (n = 9) using full-length recombinant human protein arrays (Cambridge Protein Arrays) revealed reactivities to nucleolar protein 3 (5/9) and hematopoietic cell-specific Lyn substrate 1 (3/9). Array analysis of PBC supernatants (n = 3) detected reactivities to PDC-E2 and hexokinase 1 (3/3). In conclusion, we detected unique frequencies of liver-infiltrating ASCs in PSC and PBC and in so doing, highlight a feasible approach for understanding disease-relevant antibodies in PSC. CI - Copyright (c) 2016. Published by Elsevier Ltd. FAU - Chung, Brian K AU - Chung BK AD - Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Birmingham Health Partners, Institute of Translational Medicine, University Hospitals Birmingham, Birmingham, UK; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. FAU - Guevel, Bardia T AU - Guevel BT AD - Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Birmingham Health Partners, Institute of Translational Medicine, University Hospitals Birmingham, Birmingham, UK. FAU - Reynolds, Gary M AU - Reynolds GM AD - Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Birmingham Health Partners, Institute of Translational Medicine, University Hospitals Birmingham, Birmingham, UK. FAU - Gupta Udatha, D B R K AU - Gupta Udatha DB AD - Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. FAU - Henriksen, Eva Kristine Klemsdal AU - Henriksen EK AD - Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. FAU - Stamataki, Zania AU - Stamataki Z AD - Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Birmingham Health Partners, Institute of Translational Medicine, University Hospitals Birmingham, Birmingham, UK. FAU - Hirschfield, Gideon M AU - Hirschfield GM AD - Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Birmingham Health Partners, Institute of Translational Medicine, University Hospitals Birmingham, Birmingham, UK. Electronic address: g.hirschfield@bham.ac.uk. FAU - Karlsen, Tom Hemming AU - Karlsen TH AD - Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: t.h.karlsen@medisin.uio.no. FAU - Liaskou, Evaggelia AU - Liaskou E AD - Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Birmingham Health Partners, Institute of Translational Medicine, University Hospitals Birmingham, Birmingham, UK. LA - eng GR - MC_PC_13057/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20161024 PL - England TA - J Autoimmun JT - Journal of autoimmunity JID - 8812164 RN - 0 (Antigens, CD20) RN - 0 (Autoantibodies) RN - 0 (Biomarkers) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Antibody Formation/immunology MH - Antigens, CD20/metabolism MH - Autoantibodies/blood/*immunology MH - Autoimmunity MH - B-Lymphocytes/*immunology/pathology MH - Biomarkers MH - Cholangitis, Sclerosing/*diagnosis/*immunology/metabolism MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - Fluorescent Antibody Technique MH - Humans MH - Immunophenotyping MH - Liver/immunology/metabolism/pathology MH - Liver Cirrhosis, Biliary/*diagnosis/*immunology/metabolism MH - Lymphocyte Count MH - Male MH - Middle Aged MH - *Phenotype MH - Plasma Cells/immunology/metabolism MH - Young Adult OTO - NOTNLM OT - Antibody-secreting B cells OT - Auto-antibodies OT - Autoimmunity OT - Biomarkers OT - Primary biliary cholangitis OT - Primary sclerosing cholangitis OT - Protein arrays EDAT- 2016/10/30 06:00 MHDA- 2017/12/23 06:00 CRDT- 2016/10/30 06:00 PHST- 2016/07/13 00:00 [received] PHST- 2016/10/05 00:00 [revised] PHST- 2016/10/10 00:00 [accepted] PHST- 2016/10/30 06:00 [pubmed] PHST- 2017/12/23 06:00 [medline] PHST- 2016/10/30 06:00 [entrez] AID - S0896-8411(16)30226-8 [pii] AID - 10.1016/j.jaut.2016.10.003 [doi] PST - ppublish SO - J Autoimmun. 2017 Feb;77:45-54. doi: 10.1016/j.jaut.2016.10.003. Epub 2016 Oct 24.