Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA

Chetna Soni, Oriana A. Perez, William N. Voss, Joseph N. Pucella, Lee Serpas, Justin Mehl, Krystal L. Ching, Jule Goike, George Georgiou, Gregory C. Ippolito, Vanja Sisirak, Boris Reizis

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Class-switched antibodies to double-stranded DNA (dsDNA) are prevalent and pathogenic in systemic lupus erythematosus (SLE), yet mechanisms of their development remain poorly understood. Humans and mice lacking secreted DNase DNASE1L3 develop rapid anti-dsDNA antibody responses and SLE-like disease. We report that anti-DNA responses in Dnase1l3−/− mice require CD40L-mediated T cell help, but proceed independently of germinal center formation via short-lived antibody-forming cells (AFCs) localized to extrafollicular regions. Type I interferon (IFN-I) signaling and IFN-I-producing plasmacytoid dendritic cells (pDCs) facilitate the differentiation of DNA-reactive AFCs in vivo and in vitro and are required for downstream manifestations of autoimmunity. Moreover, the endosomal DNA sensor TLR9 promotes anti-dsDNA responses and SLE-like disease in Dnase1l3−/− mice redundantly with another nucleic acid-sensing receptor, TLR7. These results establish extrafollicular B cell differentiation into short-lived AFCs as a key mechanism of anti-DNA autoreactivity and reveal a major contribution of pDCs, endosomal Toll-like receptors (TLRs), and IFN-I to this pathway.

Original languageEnglish (US)
Pages (from-to)1022-1038.e7
JournalImmunity
Volume52
Issue number6
DOIs
StatePublished - Jun 16 2020

Keywords

  • DNASE1L3
  • TLR7
  • TLR9
  • anti-DNA antibodies
  • extrafollicular B cell response
  • plasmacytoid dendritic cells
  • systemic lupus erythematosus
  • type I interferon

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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