title: Environmental factor and inflammation-driven alteration of the total peripheral T-cell compartment in granulomatosis with polyangiitis.
abstract: Autoimmune diseases are initiated by a combination of predisposing genetic and environmental factors resulting in self-perpetuating chronic inflammation and tissue damage. Autoantibody production and an imbalance of effector and regulatory T-cells are hallmarks of autoimmune dysregulation. While expansion of circulating effector memory T-cells is linked to disease pathogenesis and progression, the causes driving alterations of the peripheral T-cell compartment have remained poorly understood so far. In granulomatosis with polyangiitis (GPA), a prototypical autoimmune disorder of unknown aetiology, we performed for the first time a combined approach using phenotyping, transcriptome and functional analyses of T-cell populations to evaluate triggers of memory T-cell expansion. In more detail, we found increased percentages of circulating CD4+CD28-, CD8+CD28- and CD4+CD161+ single-positive and CD4+CD8+ double-positive T-cells in GPA. Transcriptomic profiling of sorted T-cell populations showed major differences between GPA and healthy controls reflecting antigen- (bacteria, viruses, fungi) and cytokine-driven impact on T-cell populations in GPA. Concomitant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) - positivity was associated with a significant increase in the percentage of CD28- T-cells in GPA-patients compared to sole CMV- or EBV-positivity or CMV- and EBV-negativity. T-cells specific for other viruses (influenza A virus, metapneumovirus, respiratory syncytial virus) and the autoantigen proteinase 3 (PR3) were infrequently detected in GPA. Antigen-specific T-cells were not specifically enriched in any of the T-cell subsets. Altogether, on a genetic and cellular basis, here we show that alterations of the peripheral T-cell compartment are driven by inflammation and various environmental factors including concomitant CMV and EBV infection. Our study provides novel insights into mechanisms driving autoimmune disease and on potential therapeutic targets.
authors.affiliation: Department of Rheumatology & Vasculitis Center UKSH, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Electronic address: anja.kerstein@uksh.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Kerstein
authors.affiliation: Department of Rheumatology & Vasculitis Center UKSH, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Electronic address: silke-schueler@gmx.de.
authors.forename: Silke
authors.initials: S
authors.lastname: Schüler
authors.affiliation: Department of Rheumatology & Vasculitis Center UKSH, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Electronic address: Otavio.Marques@uksh.de.
authors.forename: Otávio
authors.initials: O
authors.lastname: Cabral-Marques
authors.affiliation: Institute of Immunology, Christian-Albrechts-University of Kiel, Michaelmass 5, 24105 Kiel, Germany. Electronic address: juliane_fazio@web.de.
authors.forename: Juliane
authors.initials: J
authors.lastname: Fazio
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts University Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany. Electronic address: r.haesler@mucosa.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.affiliation: Department of Rheumatology & Vasculitis Center UKSH, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Electronic address: antje.mueller@uksh.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Müller
authors.affiliation: Department of Rheumatology & Vasculitis Center UKSH, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Electronic address: silke.pitann@uksh.de.
authors.forename: Silke
authors.initials: S
authors.lastname: Pitann
authors.affiliation: Rheumatology Center Schleswig-Holstein Mitte, Kuhberg 5a, 24534 Neumünster, Germany. Electronic address: moosig@rheuma-sh.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Moosig
authors.affiliation: Section Maritime Medicine, Institute of Experimental Medicine, Christian-Albrechts-University of Kiel, c/o German Naval Medical Institute, Kopperpahler Allee 120, 24119 Kronshagen, Germany. Electronic address: s.klapa@iem.uni-kiel.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Klapa
authors.affiliation: Division of Nephrology, Department of Internal Medicine 1, UKSH Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Electronic address: christian.haas@uksh.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Haas
authors.affiliation: Institute of Immunology, Christian-Albrechts-University of Kiel, Michaelmass 5, 24105 Kiel, Germany. Electronic address: dietrich.kabelitz@uksh.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.affiliation: Department of Rheumatology & Vasculitis Center UKSH, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Electronic address: gabriela.riemekasten@uksh.de.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
authors.affiliation: Department of Rheumatology & Vasculitis Center UKSH, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Electronic address: wolters.steffen@googlemail.com.
authors.forename: Steffen
authors.initials: S
authors.lastname: Wolters
authors.affiliation: Department of Rheumatology & Vasculitis Center UKSH, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Electronic address: peter.lamprecht@uksh.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Lamprecht
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers; D016000:Cluster Analysis; D019295:Computational Biology; D003586:Cytomegalovirus Infections / Q000150:complications; D004777:Environment; D020031:Epstein-Barr Virus Infections / Q000150:complications; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014890:Granulomatosis with Polyangiitis / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D015415:Biomarkers
keywords: ANCA; ANCA associated vasculitis; CD28− effector memory T-cells; Granulomatosis with polyangiitis; T-cell; Transcriptome profile