Projektbeschreibung
Die Mechanismen der Autoimmunität bei rheumatoider Arthritis
Schätzungen zufolge leidet etwa 1 % der Weltbevölkerung an rheumatoider Arthritis, einer entzündlichen Autoimmunerkrankung, die mit der Bildung von Autoantikörpern (wie Antikörpern gegen citrullinierte Proteine) und schweren Entzündungen einhergeht. Die Krankheit schädigt die peripheren Gelenke und stellt für die betroffene Person eine schwere Belastung dar. Die Mechanismen, die die Gewebeentzündung bei rheumatoider Arthritis ursprünglich auslösen, sind leider bisher ungeklärt. Behandlung und Prävention stoßen dadurch schnell an Grenzen. Das EU-finanzierte Projekt INSPIRE wird daher eine umfassende, tiefgründige räumlich-zeitliche Analyse der bei rheumatoider Arthritis durch Autoimmunität erzeugten Entzündungen durchführen. Mithilfe von aktuellsten technologischen Entwicklungen wie Einzelzell-RNA-Sequenzierung und ATAC-Sequenzierung in Kombination mit MHC-Dextrameren und Antigenen mit DNA-Barcodes, räumlicher Transkriptomik sowie hochmoderner Bildgebung sollen die Mechanismen der rheumatoiden Arthritis erklärt und neue Behandlungsoptionen gefunden werden.
Ziel
Rheumatoid Arthritis (RA) is a prototypic T cell- and B cell-driven inflammatory autoimmune disease that affects around 1% of the population worldwide and creates a severe burden for patients as well as substantial socioeconomic costs for society. Hallmarks of RA are a destructive inflammation of peripheral joints as well as the presence of autoantibodies such as anti-citrullinated protein antibodies (ACPA). Although ACPA are considered to represent major drivers of RA pathology, they can be also found in otherwise healthy “individuals at risk” where they emerge decades before the eventual onset of RA. Factors and mechanisms that promote onset of tissue inflammation in such autoantibody-positive individuals still remain elusive. Due to this gap of knowledge, current therapies are primarily designed to suppress later stages of joint inflammation, rather than targeting the underlying processes of autoimmunity or the initial onset of inflammatory disease. RA patients thus still lack effective preventive or curative therapeutic concepts. Here we aim to exploit recent technical breakthroughs such as single-cell RNA- and ATAC-sequencing in conjunction with DNA bar-coded MHC dextramers and antigens, spatial transcriptomics and cutting-edge imaging to perform a comprehensive and in-depth spatiotemporal analysis of the molecular events underlying the initial onset of inflammatory disease in autoantibody-positive individuals. We will additionally profit from the access to a large and well-characterized cohort of ACPA-positive “individuals at risk” and ACPA-positive RA patients as well as from corresponding biomaterial. In combination with preclinical animal models of RA, we thereby seek to delineate the sequences of events that promote the early transition from autoimmunity to inflammation. The obtained data will yield key insights into basic mechanisms of inflammatory autoimmune diseases such as RA and provide the basis for novel treatment concepts.
Wissenschaftliches Gebiet
- medical and health sciencesclinical medicinerheumatology
- medical and health scienceshealth sciencesinflammatory diseases
- medical and health sciencesbasic medicineimmunologyautoimmune diseases
- medical and health sciencesbasic medicinepathology
- engineering and technologyindustrial biotechnologybiomaterials
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
10117 Berlin
Deutschland