Affinity maturation generates pathogenic antibodies with dual reactivity to DNase1L3 and dsDNA in systemic lupus erythematosus

• Type of Material: Article
• Authors: Eduardo Gomez-Banuelos, Johns Hopkins University; Yikai Yu, Huazhong University of Science & Technology; Jessica Li, Johns Hopkins University; Kevin S Cashman, Emory University; Merlin Paz, Johns Hopkins University; Maria I Trejo-Zambrano, Johns Hopkins University; Regina Bugrovsky, Emory University; Youliang Wang, Emory University; Asiay Seema Chida, Emory University; Cheryl A Sherman-Baust, National Institute on Aging, Baltimore; Dylan P Ferris, Johns Hopkins University; Daniel W Goldman, Johns Hopkins University; Erika Darrah, Johns Hopkins University; Michelle Petri, Johns Hopkins University; Iñaki Sanz, Emory University; Felippe Andrade, Johns Hopkins University
• Language: English
• Date: 2023-03-20
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-37083-x
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 14
• Issue: 1
• Start Page: 1388
• End Page: 1388
• Keywords: AUTOIMMUNE; Science & Technology; 9G4 IDIOTOPE; MONOCLONAL-ANTIBODIES; ANTI-DNA ANTIBODIES; Science & Technology - Other Topics; BINDING; AUTOANTIBODIES; CELLS; Multidisciplinary Sciences; AUTOREACTIVITY; DISEASE-ACTIVITY; ALPHA-ACTININ
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Anti-dsDNA antibodies are pathogenically heterogeneous, implying distinct origins and antigenic properties. Unexpectedly, during the clinical and molecular characterization of autoantibodies to the endonuclease DNase1L3 in patients with systemic lupus erythematosus (SLE), we identified a subset of neutralizing anti-DNase1L3 antibodies previously catalogued as anti-dsDNA. Based on their variable heavy-chain (VH) gene usage, these antibodies can be divided in two groups. One group is encoded by the inherently autoreactive VH4-34 gene segment, derives from anti-DNase1L3 germline-encoded precursors, and gains cross-reactivity to dsDNA – and some additionally to cardiolipin – following somatic hypermutation. The second group, originally defined as nephritogenic anti-dsDNA antibodies, is encoded by diverse VH gene segments. Although affinity maturation results in dual reactivity to DNase1L3 and dsDNA, their binding efficiencies favor DNase1L3 as the primary antigen. Clinical, transcriptional and monoclonal antibody data support that cross-reactive anti-DNase1L3/dsDNA antibodies are more pathogenic than single reactive anti-dsDNA antibodies. These findings point to DNase1L3 as the primary target of a subset of antibodies classified as anti-dsDNA, shedding light on the origin and pathogenic heterogeneity of antibodies reactive to dsDNA in SLE.