@article{96eb8dbb00514d28a71ec8ae9cae0ea7,
title = "Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA",
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.",
keywords = "DNASE1L3, TLR7, TLR9, anti-DNA antibodies, extrafollicular B cell response, plasmacytoid dendritic cells, systemic lupus erythematosus, type I interferon",
author = "Chetna Soni and Perez, {Oriana A.} and Voss, {William N.} and Pucella, {Joseph N.} and Lee Serpas and Justin Mehl and Ching, {Krystal L.} and Jule Goike and George Georgiou and Ippolito, {Gregory C.} and Vanja Sisirak and Boris Reizis",
note = "Funding Information: This work was supported by NIH grants AI072571 (B.R.), AR071703 (B.R. and G.C.I.), AR070591 (B.R.), CA232666 (O.A.P.), AI100853 (O.A.P. and L.S.), AR069515 (L.S.), HL145997 (J.N.P), CA009161 (J.N.P.), CA110624 (G.C.I.), and AR071703 (G.C.I.); and by the Lupus Research Alliance (B.R.), the Colton Center for Autoimmunity (B.R.), the Idex Junior Chair program from Bordeaux University (V.S.), and a Cancer Research Institute CLIP grant (V.S.). V.S. initiated, performed, and analyzed experiments. C.S. O.A.P. L.S. J.N.P. K.L.C. J.M. W.N.V. and J.G. performed and analyzed experiments. G.G. and G.C.I. supervised the analysis of B cell repertoire. B.R. analyzed the results and supervised the project. C.S. and B.R. wrote the manuscript with input from all coauthors. The authors declare no competing interests. Funding Information: This work was supported by NIH grants AI072571 (B.R.), AR071703 (B.R. and G.C.I.), AR070591 (B.R.), CA232666 (O.A.P.), AI100853 (O.A.P. and L.S.), AR069515 (L.S.), HL145997 (J.N.P), CA009161 (J.N.P.), CA110624 (G.C.I.), and AR071703 (G.C.I.); and by the Lupus Research Alliance (B.R.), the Colton Center for Autoimmunity (B.R.), the Idex Junior Chair program from Bordeaux University (V.S.), and a Cancer Research Institute CLIP grant (V.S.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = jun,
day = "16",
doi = "10.1016/j.immuni.2020.04.015",
language = "English (US)",
volume = "52",
pages = "1022--1038.e7",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "6",
}