Immunity (Cambridge, Mass.), 2020-06, Vol.52 (6), p.1022-1038.e7
2020
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- Autor(en) / Beteiligte
- Titel
- Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA
- Ist Teil von
- Immunity (Cambridge, Mass.), 2020-06, Vol.52 (6), p.1022-1038.e7
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2020
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. [Display omitted] •Anti-DNA antibody response is driven by T-dependent extrafollicular plasmablasts•IFN-I signaling propagates anti-DNA responses and SLE-like disease•IFN-I produced by pDCs promotes plasmablast proliferation and differentiation•TLR9 drives anti-DNA responses and autoimmunity redundantly with TLR7 Autoantibodies to self-DNA are a defining feature of systemic lupus erythematosus (SLE), yet the mechanisms of their development remain poorly understood. Soni et al. show that anti-DNA autoreactivity is driven by extrafollicular B cell differentiation into short-lived plasmablasts, which is facilitated by plasmacytoid dendritic cells, type I interferon, and endosomal Toll-like receptors 7 and 9.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1074-7613eISSN: 1097-4180DOI: 10.1016/j.immuni.2020.04.015Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7306002
- Format
- –
- Schlagworte
- Adaptive immunology, Animals, Anti-DNA antibodies, Antibodies, Antibodies, Antinuclear - immunology, Antigens, Autoantigens - immunology, Autoimmune diseases, Autoimmunity, B-Lymphocytes - immunology, B-Lymphocytes - metabolism, Biomarkers, CD40 Ligand - deficiency, CD40L protein, Cell Communication - genetics, Cell Communication - immunology, Cell differentiation, Chronic conditions, Dendritic cells, Dendritic Cells - immunology, Dendritic Cells - metabolism, Deoxyribonuclease, Deoxyribonucleic acid, Differentiation (biology), Disease Models, Animal, Disease Susceptibility, DNA, DNA - immunology, DNASE1L3, Endodeoxyribonucleases - deficiency, extrafollicular B cell response, Fluorescent Antibody Technique, Germinal Center - immunology, Germinal Center - metabolism, Germinal Center - pathology, Immunology, Innate immunity, Interferon, Interferon Type I - metabolism, Life Sciences, Lupus, Lupus Erythematosus, Systemic - etiology, Lupus Erythematosus, Systemic - metabolism, Lymphocytes, Lymphocytes T, Mice, Mice, Knockout, Nucleic acids, plasmacytoid dendritic cells, Receptors, Spleen, Systemic lupus erythematosus, TLR7, TLR7 protein, TLR9, TLR9 protein, Toll-Like Receptor 7 - metabolism, Toll-Like Receptor 9 - metabolism, Toll-like receptors, type I interferon