Title: Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA
Author: 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
Abstract: Class-switched antibodies to double-stranded DNA (dsDNA) are prevalent and pathogenicin systemic lupus erythematosus (SLE), yet mechanisms of their development remainpoorly understood. Humans and mice lacking secreted DNase DNASE1L3 develop rapid anti-dsDNAantibody 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 centerformation via short-lived antibody-forming cells (AFCs) localized to extrafollicularregions. Type I interferon (IFN-I) signaling and IFN-I-producing plasmacytoid dendriticcells (pDCs) facilitate the differentiation of DNA-reactive AFCs in vivo and in vitro and are required for downstream manifestations of autoimmunity. Moreover, the endosomalDNA sensor TLR9 promotes anti-dsDNA responses and SLE-like disease in Dnase1l3/ mice redundantly with another nucleic acid-sensing receptor, TLR7. These resultsestablish extrafollicular B cell differentiation into short-lived AFCs as a key mechanismof anti-DNA autoreactivity and reveal a major contribution of pDCs, endosomal Toll-likereceptors (TLRs), and IFN-I to this pathway.