Plasmacytoid dendritic cells promote extrafollicular anti-DNA responses in lupus through type I interferon

Class-switched antibodies to double-stranded DNA (dsDNA) are prevalent and pathogenic in systemic lupus erythematosus (SLE), yet the mechanisms of their development remain poorly understood. Humans and mice lacking the secreted DNase DNASE1L3 develop rapid and specific anti-dsDNA antibody responses and SLE-like disease. We report that anti-DNA response in Dnase1l3-deficient mice required CD40L-mediated T cell help but was largely independent of germinal center formation. Rather, anti-DNA reactivity was mediated by short-lived plasmablasts localized to extrafollicular regions. Blockade of type I interferon (IFN-I) signaling or impairment of interferon-producing plasmacytoid dendritic cells (pDCs) did not prevent anti-DNA response but reduced DNA-reactive plasmablast differentiation and ameliorated downstream manifestations of autoimmunity. Moreover, IFN-I produced by pDCs directly promoted B cell differentiation into antibody-secreting cells. These results establish extrafollicular B cell differentiation into short-lived plasmablasts as a key mechanism of anti-DNA autoreactivity, and reveal a major role of IFN-I production by pDCs in the maintenance of this pathway.