title: Overexpression of Fkbp11, a feature of lupus B cells, leads to B cell tolerance breakdown and initiates plasma cell differentiation.
abstract: Systemic Lupus Erythematosus (SLE) is a severe systemic autoimmune disease, characterized by multi-organ damages, triggered by an autoantibody-mediated inflammation, and with a complex genetic influence. It is today accepted that adult SLE arises from the building up of many subtle gene variations, each one adding a new brick on the SLE susceptibility and contributing to a phenotypic trait to the disease. One of the ways to find these gene variations consists in comprehensive analysis of gene expression variation in a precise cell type, which can constitute a good complementary strategy to genome wide association studies. Using this strategy, and considering the central role of B cells in SLE, we analyzed the B cell transcriptome of quiescent SLE patients, and identified an overexpression of FKBP11, coding for a cytoplasmic putative peptidyl-prolyl cis/trans isomerase and chaperone enzyme. To understand the consequences of FKBP11 overexpression on B cell function and on autoimmunity's development, we created lentiviral transgenic mice reproducing this gene expression variation. We showed that high expression of Fkbp11 reproduces by itself two phenotypic traits of SLE in mice: breakdown of B cell tolerance against DNA and initiation of plasma cell differentiation by acting upstream of Pax5 master regulator gene.
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Ruer-Laventie
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Simoni
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France ; Université de Strasbourg, UFR Médecine Strasbourg, F-67085, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Soley
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Duval
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France ; Université de Strasbourg, UFR Médecine Strasbourg, F-67085, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Knapp
authors.affiliation: Department of Anatomopathology, H, ô, pitaux Universitaires de Strasbourg F-67085, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Marcellin
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Lamon
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France ; Université de Strasbourg, UFR Médecine Strasbourg, F-67085, France ; Department of Clinical Immunology, Hôpitaux Universitaires de Strasbourg F-67085, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Korganow
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France ; Université de Strasbourg, UFR Médecine Strasbourg, F-67085, France ; Department of Clinical Immunology, Hôpitaux Universitaires de Strasbourg F-67085, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Martin
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France ; Université de Strasbourg, UFR Médecine Strasbourg, F-67085, France ; Department of Clinical Immunology, Hôpitaux Universitaires de Strasbourg F-67085, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pasquali
authors.affiliation: CNRS UPR3572, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis Strasbourg, F-67084, France ; Department of Clinical Immunology, Hôpitaux Universitaires de Strasbourg F-67085, France ; Université de Strasbourg, UFR Sciences Pharmaceutiques Illkirch, F-67401, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Soulas-Sprauel
keywords: B cells; Fkbp11; lupus; mouse models