Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus

• Type of Material: Article
• Authors: Christopher M. Tipton, Emory University; Christopher F. Fucile, University of Rochester; Jamie Darce, Cell Signaling Technol; Asiya Chida, Emory University; Travis Ichikawa, Emory University; Ivan Gregoretti, Cell Signaling Technol; Sandra Schieferl, Cell Signaling Technol; Jennifer R. Hom, Emory University; Scott A. Jenks, Emory University; Ron J. Feldman, Emory University; Ramit Mehr, Bar Ilan University; Chungwen Wei, Emory University; Frances Eun-Hyung Lee, Emory University; Wan Cheung Cheung, Cell Signaling Technol; Alexander F. Rosenberg, University of Rochester; Ignacio Sanz, Emory University
• Language: English
• Date: 2015-07-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015, Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/ni.3175
• Title of Journal or Parent Work: Nature Immunology
• ISSN: 1529-2908
• Volume: 16
• Issue: 7
• Start Page: 755
• End Page: +
• Grant/Funding Information: Supported by grants U19 AI110483 (Autoimmunity Center of Excellence), 5P01AI078907, 5R37AI049660.
• Keywords: AUTOIMMUNITY; MONOCLONAL-ANTIBODIES; ACTIVATION; Immunology; GERMINAL CENTER; RESPONSES; AFFINITY MATURATION; SLE; ANTIGEN; Science & Technology; MEMORY B-CELLS; PERIPHERAL-BLOOD; Life Sciences & Biomedicine

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 V<inf>H</inf>4-34 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.