title: Network Analysis Identifies Proinflammatory Plasma Cell Polarization for Secretion of ISG15 in Human Autoimmunity.
abstract: Plasma cells (PCs) as effectors of humoral immunity produce Igs to match pathogenic insult. Emerging data suggest more diverse roles exist for PCs as regulators of immune and inflammatory responses via secretion of factors other than Igs. The extent to which such responses are preprogrammed in B-lineage cells or can be induced in PCs by the microenvironment is unknown. In this study, we dissect the impact of IFNs on the regulatory networks of human PCs. We show that core PC programs are unaffected, whereas PCs respond to IFNs with distinctive transcriptional responses. The IFN-stimulated gene 15 (ISG15) system emerges as a major transcriptional output induced in a sustained fashion by IFN-α in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active systemic lupus erythematosus. Thus, ISG15-secreting PCs represent a distinct proinflammatory PC subset providing an Ig-independent mechanism of PC action in human autoimmunity.
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom; Bioinformatics Group, Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom;
authors.forename: Matthew A
authors.identifier: 0000-0001-6584-5889
authors.initials: MA
authors.lastname: Care
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom;
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Stephenson
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom;
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Barnes
authors.affiliation: Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals National Health Service Trust, Leeds LS9 7TF, United Kingdom;
authors.forename: Im
authors.initials: I
authors.lastname: Fan
authors.affiliation: Section of Oncology and Clinical Research, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom;
authors.forename: Alexandre
authors.identifier: 0000-0002-7168-1339
authors.initials: A
authors.lastname: Zougman
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom; and National Institute for Health Research Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals National Health Service Trust, Leeds LS9 7TF, United Kingdom.
authors.forename: Yasser M
authors.identifier: 0000-0003-4791-3475
authors.initials: YM
authors.lastname: El-Sherbiny
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom; and National Institute for Health Research Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals National Health Service Trust, Leeds LS9 7TF, United Kingdom.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Vital
authors.affiliation: Bioinformatics Group, Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom;
authors.forename: David R
authors.identifier: 0000-0002-0519-3820
authors.initials: DR
authors.lastname: Westhead
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom; Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals National Health Service Trust, Leeds LS9 7TF, United Kingdom;
authors.forename: Reuben M
authors.identifier: 0000-0003-2915-7119
authors.initials: RM
authors.lastname: Tooze
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, United Kingdom; g.m.doody@leeds.ac.uk.
authors.forename: Gina M
authors.identifier: 0000-0003-0665-6759
authors.initials: GM
authors.lastname: Doody
mesh_terms: D015551:Autoimmunity / Q000276:immunology*; D015153:Blotting, Western; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome; D014452:Ubiquitins / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D014452:Ubiquitins; C074034:ISG15 protein, human