title: Follicular Dendritic Cell Activation by TLR Ligands Promotes Autoreactive B Cell Responses.
abstract: A hallmark of autoimmunity in murine models of lupus is the formation of germinal centers (GCs) in lymphoid tissues where self-reactive B cells expand and differentiate. In the host response to foreign antigens, follicular dendritic cells (FDCs) maintain GCs through the uptake and cycling of complement-opsonized immune complexes. Here, we examined whether FDCs retain self-antigens and the impact of this process in autoantibody secretion in lupus. We found that FDCs took up and retained self-immune complexes composed of ribonucleotide proteins, autoantibody, and complement. This uptake, mediated through CD21, triggered endosomal TLR7 and led to the secretion of interferon (IFN) α via an IRF5-dependent pathway. Blocking of FDC secretion of IFN-α restored B cell tolerance and reduced the amount of GCs and pathogenic autoantibody. Thus, FDCs are a critical source of the IFN-α driving autoimmunity in this lupus model. This pathway is conserved in humans, suggesting that it may be a viable therapeutic target in systemic lupus erythematosus.
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Das
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Balthasar A
authors.initials: BA
authors.lastname: Heesters
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Bialas
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Flynn
authors.affiliation: Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Rifkin
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ochando
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity (RIA), MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Nanette
authors.initials: N
authors.lastname: Mittereder
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity (RIA), MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Carlesso
authors.affiliation: Department of Cancer Biology, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbst
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: michael.carroll@childrens.harvard.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D020566:Dendritic Cells, Follicular / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D051199:Toll-Like Receptor 7 / Q000276:immunology; D059467:Transcriptome
chemical_list: D001324:Autoantigens; D016898:Interferon-alpha; D008024:Ligands; D051199:Toll-Like Receptor 7
keywords: CD21; CD35; DAMP; TLR7; autoimmunity; follicular dendritic cells; immune complex; interferon-α; systemic lupus erythematosus