2013 Dendritic Cells, Human Lupus Biology, Target Identification
Sex Hormones, Dendritic cells, and the IFN Signature in Lupus
The Study and What It Means to Patients
"Nine out of 10 people with lupus are women. We are testing our novel idea that female sex hormones might be the cause by triggering certain cells of the immune system to overproduce inflammation-driving chemicals known as interferons. If we are correct our work could identify new drug targets in lupus."
Female sex hormones (estrogens) are suspected to contribute to the development of lupus by unbalancing the immune system and tipping it towards self-destruction. But how this happens is unclear. We are testing our novel idea that estrogens promote lupus by causing the immune system to over-produce inflammation-driving chemicals known as interferons that are known to fuel the development of lupus disease. We are studying the intricate chain of molecular interactions triggered by estrogen acting on the immune cells, focusing on cells known as dendritic cells. This project may explain the different susceptibilities of women and men to lupus and identify new therapeutic targets.
Dendritic cells (DCs) are pivotal immune regulators and require Type I Interferons (I-IFNs) to become activated. Both DCs and I-IFNs are important in systemic lupus erythematosus (SLE). DCs from lupus-prone mice constitutively over-express 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 F1) and by Fulvestrant, an estrogen selective receptor inhibitor.