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

Immunity 2020 Jun 16

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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. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

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. Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA. Immunity. 2020 Jun 16;52(6):1022-1038.e7