Our goal is to combine advanced genomic and proteomic tools with innovative experimental models to study the regulation of the immune response in health and disease. In order to achieve this goal, our group is organized around the following research programs:
- Role of environmental factors in disease susceptibility and pathogenesis. Complex interactions between genes and the environment control the development of immune-mediated diseases. Significant advances have been made in the study of genetic variants, but our understanding of the role of the environment on immune disease pathogenesis is limited. To address this point we developed novel zebrafish models, which identified the aryl hydrocarbon receptor (AHR), a transcription factor whose activity is regulated by pollutants, the diet, the commensal flora and endogenous metabolites as an important regulator of the immune response (Quintana et al, Nature 2008). We have also identified an important role for nightlenght/melatonin in immunoregulation (Farez et al, Cell 2015). We are currently using new zebrafish models, together with mouse, humanized mouse and human experimental systems, to identify additional mechanisms by which the environment regulates the immune response.
Figure by CC and Maisa
- Regulation of the adaptive immune response. A dysregulated immune response against self-proteins causes autoimmunity. Dendritic cells (DCs) control the immune response. Using transcriptional, epigenetic and proteomic data we defined molecular pathways that regulate DC and T cell activity and identified potential targets for therapeutic intervention (Mascanfroni et al, Nature Immunology 2013; Mascanfroni et al, Nature Medicine 2015). Based on these findings we developed nanoparticles to control DCs in vivo and arrest autoimmunity (Yeste et al, PNAS 2012; Yeste et al, Science Signaling 2016). Additional nanoparticle-based approaches for the regulation of the adaptive immune response are currently being developed.
- Regulation of the local immune response in the CNS. Astrocytes play a central role in controlling CNS inflammation and neurodegeneration. However, the mechanisms controlling astrocyte activity are mostly unknown, and no therapies are available to modulate astrocyte activity. We developed new human, mouse and zebrafish experimental models to study astrocytes and identify potential targets for therapeutic intervention (Mayo et al, Nature Medicine 2014; Covacu et al, Cell Reports 2016; Rothhammer et al, Nature Medicine 2016, Rothhammer et al, PNAS 2017). These studies have recently identified a new gut-brain axis through which the diet and commensal bacteria control CNS local innate immunity in MS.
Gut microbiota and local cytokine signaling influence autoimmune responses in the central nervous system (CNS). We have demonstrated that Type I interferons and gut flora metabolites regulate CNS inflammation by activating the Aryl hydrocarbon receptor.
Figure by CC and Mike
- Control of tumor infiltrating macrophages and T cells in glioblastoma. Tumor-associated macrophages (TAMs) play an important role in the immune response to cancer, but the mechanisms by which the tumor microenvironment controls TAMs and T-cell immunity are not completely understood. Glioblastoma (GBM) is the most common primary brain tumor in adults. GBM is also one of the most aggressive cancers with a median survival of around 15 months despite aggressive treatment. GBM achieves fast growth and dissemination in the brain parenchyma through several mechanisms that include rapid proliferation, the promotion of angiogenesis and the induction of immunosuppression. TAMs derived from microglia and peripheral monocytes constitute more than 30 percent of infiltrating cells in GBM. Interestingly, GBM progression is associated with TAM infiltration, showing a better correlation than infiltration by FoxP3+ regulatory T cells (Tregs). In support of crucial role for TAMs in tumor pathogenesis, the modulation of TAM activity has beneficial effects on GBM. In some tumors including GBM, the acquisition of a phenotype resembling M2 macrophages by TAMs has been linked with tumor progression and the suppression of tumor-specific immunity. We are currently investigating the mechanisms that control TAMs in GBM, with the goal to identify new targets for therapeutic intervention.
- Biomarkers for patient stratification and monitoring. We have developed antigen arrays to study the immune response in MS and other immune-mediated disorders. Using antigen microarrays we found patterns of serum autoantibodies that distinguish MS from healthy controls and other neurologic or autoimmune diseases. We also found unique antibody patterns linked to clinical types or stages of MS, or to disease pathology as determined by biopsy. These serum immune signatures provide a new tool for the individualized management of the disease. We are currently investigating the association of antibody patterns, as detected with antigen arrays, with magnetic resonance imaging (MRI) measures of disease progression, genetic determinants of disease and the response to specific therapeutic agents.
Autoantibodies in sera from patients with Multiple Sclerosis. This heatmap shows the correlation of serum autoantibodies with magnetic resonance tomography criteria.
We have developed bioassays to determine the presence of ligands to the Aryl hydrocarbon receptor (AHR) in biological samples. In this way, we are able to determine quantitative alterations in AHR ligand levels in autoimmune diseases of the CNS. Left, measurement of AHR activating activity in MS patients at different disease stages, or healthy controls. Right, schematic of modulation of AHR agonistic activity during the course of MS.