1. Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA
- Author
-
Jule Goike, Vanja Sisirak, Joseph Pucella, Krystal L. Ching, Justin Mehl, George Georgiou, William N. Voss, Oriana A. Perez, Boris Reizis, Chetna Soni, Lee Serpas, Gregory C. Ippolito, New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of Texas at Austin [Austin], Immunology from Concept and Experiments to Translation (ImmunoConcept), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)
- Subjects
0301 basic medicine ,Fluorescent Antibody Technique ,Autoimmunity ,Cell Communication ,medicine.disease_cause ,TLR7TLR9 ,Autoantigens ,extrafollicular B cell response ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Mice ,0302 clinical medicine ,systemic lupus erythematosus ,Interferon ,immune system diseases ,Immunology and Allergy ,Lupus Erythematosus, Systemic ,Receptor ,skin and connective tissue diseases ,Mice, Knockout ,B-Lymphocytes ,3. Good health ,Cell biology ,Infectious Diseases ,medicine.anatomical_structure ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,plasmacytoid dendritic cells ,030220 oncology & carcinogenesis ,Antibodies, Antinuclear ,Interferon Type I ,type I interferon ,Disease Susceptibility ,Antibody ,medicine.drug ,Immunology ,CD40 Ligand ,Biology ,Article ,03 medical and health sciences ,medicine ,Animals ,B cell ,Endodeoxyribonucleases ,TLR9 ,Germinal center ,TLR7 ,DNA ,Dendritic Cells ,Germinal Center ,Disease Models, Animal ,030104 developmental biology ,Toll-Like Receptor 7 ,Toll-Like Receptor 9 ,anti-DNA antibodies ,biology.protein ,DNASE1L3 ,Biomarkers - Abstract
International audience; 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.
- Published
- 2020
- Full Text
- View/download PDF