2013 Dendritic Cells, Human Lupus Biology, Target Identification
2016 Environmental Triggers, DNA, Biomarkers, Genetics
Can bacterial infections cause lupus and trigger flares?
The study and what it means to patients
“Our study will explore whether infections affecting the entire body caused by bacteria that typically live harmoniously on the skin, gut, respiratory tract, etc., can trigger lupus initially and if they cause flares as the disease progresses. If so, the next step will be to explore implications for treating and possibly preventing this devastating disease.”
Bacterial biofilms are bacterial communities that are abundant in the human microbiome but also found in chronic infections such as ear or urinary tract infections. We propose that protein fragments known as curli, which are produced by bacterial biofilm infections, may trigger the onset of lupus (as well as subsequent flares in the disease) and the production of anti- curli antibodies by immune system may participate and be a measure of disease activity.
Using mice with lupus and samples from lupus patients, our study will research whether: 1) exposure to curli-expressing bacteria stimulate the development of lupus symptoms, 2) these bacterial infections can be used as therapeutic targets to decrease inflammation and prevent flares, 3) curli antibodies can be used as biomarkers for the disease.
Bacterial biofilms are bacterial communities, abundant in the human microbiome, and also important in chronic infections by pathogens. No study has yet addressed whether components of biofilms contribute to SLE progression. We have found that bacterial and eukaryotic DNA are incorporated into curli fibers, functional bacterial amyloids present in biofilms. We found that curli/DNA complexes in biofilms activate dendritic cells, T and B cells, production of pro- inflammatory cytokines, including Type I-Interferons. Administration of curli/DNA complexes triggered autoantibodies production in lupus-prone NZBxW/F1 mice and also in wild type mice, suggesting curli/DNA complexes can break tolerance in lupus. We propose to study how curli affect two major pathogenic steps in lupus: 1) the IFN Signature by pDCs and 2) the activation of autoreactive B cells. Supported by Preliminary results that infection by commensals induces autoAbs when bacteria expressed curli, we will study in mice the role of curli in accelerating lupus onset and inducing flares. Moreover, we will determine 3) whether SLE patients are exposed to curli differently than healthy controls, in correlation with disease activity. These studies may suggest commensal biofilms and bacterial amyloids as new therapeutic targets and anti-curli Abs as new biomarker of flares in lupus.
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.