Sex hormones, dendritic cells, and the IFN signature in lupus

Dendritic cells (DCs) are pivotal immune regulators and require type I Interferons (I-IFNs) to activate. Both DCs and I-IFNs are important in Systemic Lupus Erythematosus (SLE). DCs from lupus-prone mice constitutively overexpress I-IFN responsive genes resembling the IFN Signature found in SLE patients. Since this signature is present in pre-diseased mice, it may contribute to disease pathogenesis. We hypothesize that estrogens are required for the expression of the IFN signature by DCs from lupus-prone mice and aim to study the effects of estrogen on the I-IFN response in DC subsets from female and male lupus-prone mice, constitutively and upon I-IFN stimulators in vitro and in vivo. To understand the molecular mechanisms of estrogen regulation of I-IFNs, we will study expression and functions of the estrogen receptors, TLRs and pivotal transcription factors and signaling molecules downstream of I-IFN receptors. Finally, we hypothesize that in vivo DCs contribute to lupus pathogenesis primarily if they can respond to estrogens and by producing I-IFN. To this end, we will investigate disease outcome in lupus mouse models in which disease will be modulated by an I-IFN-producing adenovirus, by injection of DCs that lack ERalpha (NZBxNZW F 1) and by Fulvestrant, an estrogen selective receptor inhibitor.