title: OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response.
abstract: Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS(+) blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4(+) T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Jacquemin
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schmitt
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Contin-Bordes
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Narayanan
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Seneschal
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
authors.forename: Typhanie
authors.initials: T
authors.lastname: Maurouard
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dougall
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
authors.forename: Emily Spence
authors.initials: ES
authors.lastname: Davizon
authors.affiliation: CNRS, Immunopathology and therapeutic chemistry/Laboratory of excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire;University of Strasbourg, F-67081 Strasbourg, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Dumortier
authors.affiliation: CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Douchet
authors.affiliation: CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Raffray
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Richez
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Lazaro
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Duffau
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Marie-Elise
authors.initials: ME
authors.lastname: Truchetet
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France.
authors.forename: Liliane
authors.initials: L
authors.lastname: Khoryati
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mercié
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Couzi
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Merville
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Schaeverbeke
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Viallard
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Pellegrin
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Moreau
authors.affiliation: CNRS, Immunopathology and therapeutic chemistry/Laboratory of excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire;University of Strasbourg, F-67081 Strasbourg, France; University of Strasbourg Institute for Advanced Study, F-67081 Strasbourg, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Muller
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Zurawski
authors.affiliation: Dynavax Technologies Corporation, Berkeley, CA 94710, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204, USA. Electronic address: hidekiu@baylorhealth.edu.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ueno
authors.affiliation: University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; Baylor Institute for Immunology Research, Dallas, TX 75204, USA; CHU de Bordeaux, F-33076 Bordeaux, France. Electronic address: patrick.blanco@chu-bordeaux.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Blanco
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D022423:Myeloid Cells / Q000276:immunology*; D053278:OX40 Ligand / Q000378:metabolism*; D012313:RNA / Q000276:immunology; D053262:Receptors, OX40 / Q000378:metabolism*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D053278:OX40 Ligand; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; D051199:Toll-Like Receptor 7; D012313:RNA