title: Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus.
abstract: Acute systemic lupus erythematosus (SLE) courses with surges of antibody-secreting cells (ASCs) whose origin, diversity and contribution to serum autoantibodies remain unknown. Here, deep sequencing, proteomic profiling of autoantibodies and single-cell analysis demonstrated highly diversified ASCs punctuated by clones expressing the variable heavy-chain region VH4-34 that produced dominant serum autoantibodies. A fraction of ASC clones contained autoantibodies without mutation, a finding consistent with differentiation outside the germinal centers. A substantial ASC segment was derived from a distinct subset of newly activated naive cells of considerable clonality that persisted in the circulation for several months. Thus, selection of SLE autoreactivities occurred during polyclonal activation, with prolonged recruitment of recently activated naive B cells. Our findings shed light on the pathogenesis of SLE, help explain the benefit of agents that target B cells and should facilitate the design of future therapies.
authors.affiliation: Department of Medicine, Division of Rheumatology, Emory University, Atlanta, Georgia, USA.
authors.forename: Christopher M
authors.identifier: 0000000250492571
authors.initials: CM
authors.lastname: Tipton
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Fucile
authors.affiliation: Cell Signaling Technology, Danvers, Massachusetts, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Darce
authors.affiliation: Department of Medicine, Division of Rheumatology, Emory University, Atlanta, Georgia, USA.
authors.forename: Asiya
authors.initials: A
authors.lastname: Chida
authors.affiliation: Department of Medicine, Division of Rheumatology, Emory University, Atlanta, Georgia, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Ichikawa
authors.affiliation: Cell Signaling Technology, Danvers, Massachusetts, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Gregoretti
authors.affiliation: Cell Signaling Technology, Danvers, Massachusetts, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schieferl
authors.affiliation: Department of Medicine, Division of Rheumatology, Emory University, Atlanta, Georgia, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hom
authors.affiliation: Department of Medicine, Division of Rheumatology, Emory University, Atlanta, Georgia, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Jenks
authors.affiliation: Department of Dermatology, Emory University, Atlanta, Georgia, USA.
authors.forename: Ron J
authors.initials: RJ
authors.lastname: Feldman
authors.affiliation: Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Ramit
authors.initials: R
authors.lastname: Mehr
authors.affiliation: Department of Medicine, Division of Rheumatology, Emory University, Atlanta, Georgia, USA.
authors.forename: Chungwen
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Pulmonology, Emory University, Atlanta, Georgia, USA.
authors.forename: F Eun-Hyung
authors.initials: FE
authors.lastname: Lee
authors.affiliation: Cell Signaling Technology, Danvers, Massachusetts, USA.
authors.forename: Wan Cheung
authors.initials: WC
authors.lastname: Cheung
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Rosenberg
authors.affiliation: Department of Medicine, Division of Rheumatology, Emory University, Atlanta, Georgia, USA.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Sanz
mesh_terms: D000208:Acute Disease; D000595:Amino Acid Sequence; D000916:Antibody Diversity / Q000235:genetics / Q000276:immunology*; D000921:Antibody-Producing Cells / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D049109:Cell Proliferation; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007252:Influenza Vaccines / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D020543:Proteome / Q000032:analysis / Q000276:immunology; D040901:Proteomics / Q000379:methods; D017386:Sequence Homology, Amino Acid; D059010:Single-Cell Analysis / Q000379:methods; D053719:Tandem Mass Spectrometry; D013745:Tetanus Toxoid / Q000276:immunology
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007252:Influenza Vaccines; D020543:Proteome; D013745:Tetanus Toxoid