Periodic Reporting for period 3 - INSPIRE (IN-depth SPatiotemporal dissection of autoimmunity-induced Inflammation in RhEumatoid arthritis)
Periodo di rendicontazione: 2023-04-01 al 2024-09-30
Rheumatoid arthritis (RA) belongs to the most common immune-mediated inflammatory diseases. RA results in an impaired quality of life for patients and high socioeconomic costs for our society. Although autoreactive T cells and B cell-derived autoantibodies have been considered to act as major drivers of this disease, underlying mechanisms that control onset of autoimmunity and inflammation have been incompletely understood. Current therapeutic strategies aim at inhibiting inflammation, but do not allow a curative treatment approach.
Within the current project, we seek to understand the early pathogenesis of RA and to decipher molecular pathways that promote the onset of synovial inflammation. During the present funding period, we could further define the molecular characteristics of autoreactive T cells during the murine model of collagen-induced arthritis and human RA. We have identified a set of T cell-derived cytokines that act on synovial macrophages thereby fostering a priming of the synovial microenvironment and lowering the threshold of autoantibody induced inflammation during early stages of autoimmune arthritis. In addition, we were able to define an alternative set of cytokines that derives from synovial macrophages and which is able to promote resolution of inflammation and restoration of tissue homeostasis.
Our findings might thus help to better understand disease-relevant molecular pathways and to design future treatment strategies that will potentially allow to prevent onset of RA and foster resolution of this otherwise chronic inflammatory disease.
Within the current project, we seek to understand the early pathogenesis of RA and to decipher molecular pathways that promote the onset of synovial inflammation. During the present funding period, we could further define the molecular characteristics of autoreactive T cells during the murine model of collagen-induced arthritis and human RA. We have identified a set of T cell-derived cytokines that act on synovial macrophages thereby fostering a priming of the synovial microenvironment and lowering the threshold of autoantibody induced inflammation during early stages of autoimmune arthritis. In addition, we were able to define an alternative set of cytokines that derives from synovial macrophages and which is able to promote resolution of inflammation and restoration of tissue homeostasis.
Our findings might thus help to better understand disease-relevant molecular pathways and to design future treatment strategies that will potentially allow to prevent onset of RA and foster resolution of this otherwise chronic inflammatory disease.
Using scRNAseq together with repertoire analysis, we have identified pathogenic T cell clones and their recptor sequences within the inflamed synovial tissue in RA patients and in RA mouse models. These clones show a characteristic gene expression signature that suggests the involvement of cytotoxic CD4+T cells and GM-CSF in the early pathogenesis of RA.
Using scRNAseq and a bioinformatical niche net approach, we identified novel pro- and ani-inflammatory cytokines that mediate the crosstalk between synovial fibroblasts and macrophages during onset and resolution of arthritis.
Using scRNAseq and a bioinformatical niche net approach, we identified novel pro- and ani-inflammatory cytokines that mediate the crosstalk between synovial fibroblasts and macrophages during onset and resolution of arthritis.
Identification of pathogenic T cell and B cell clones as well as the respective autoantigens that are responsible for the pathogenesis of RA. Characterization of the profile and effector molecules that drive T cell-mediated inflammation during RA.