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 language | English (US) |
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Pages (from-to) | 1022-1038.e7 |
Journal | Immunity |
Volume | 52 |
Issue number | 6 |
DOIs | |
State | Published - Jun 16 2020 |
Keywords
- DNASE1L3
- TLR7
- TLR9
- anti-DNA antibodies
- extrafollicular B cell response
- plasmacytoid dendritic cells
- systemic lupus erythematosus
- type I interferon
- Autoimmunity
- CD40 Ligand/deficiency
- Endodeoxyribonucleases/deficiency
- Toll-Like Receptor 9/metabolism
- Toll-Like Receptor 7/metabolism
- Cell Communication/genetics
- DNA/immunology
- Lupus Erythematosus, Systemic/etiology
- Germinal Center/immunology
- Disease Models, Animal
- Disease Susceptibility
- Autoantigens/immunology
- Mice, Knockout
- B-Lymphocytes/immunology
- Animals
- Antibodies, Antinuclear/immunology
- Fluorescent Antibody Technique
- Biomarkers
- Interferon Type I/metabolism
- Dendritic Cells/immunology
- Mice
ASJC Scopus subject areas
- Infectious Diseases
- Immunology and Allergy
- Immunology