IN-depth SPatiotemporal dissection of autoimmunity-induced Inflammation in RhEumatoid arthritis

Informazioni relative al progetto

INSPIRE

ID dell’accordo di sovvenzione: 101001866

DOI

10.3030/101001866

Data della firma CE 16 Febbraio 2021

Data di avvio 1 Luglio 2021

Data di completamento 31 Dicembre 2026

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 2 000 000,00

Contributo UE

€ 2 000 000,00

Coordinato da

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany

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

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.