Autoantibodies and extracellular vesicles as driver for organ-specific tissue damage in connective tissue diseases
Principal Investigators
Prof. Dr. med. Gabriela Riemekasten (PI)
Xinhua Yu, PhD (Co-PI)
PD Dr. med. Tanja Lange (Co-PI)
Dr. rer. nat. Lars-Oliver Tykocinski (PI)
Dr. rer. nat. Theresa Tretter (Co-PI)
Prof. Dr. med. Hanns-Martin Lorenz (Co-PI)
Additional Partners
LysatPharma GmbH c/o Kyra de Miroschedji
Abstract
Systemic sclerosis (SSc) is a severe systemic autoimmune disease that can affect various organs such as the skin, lungs, muscles, heart, gastrointestinal tract or kidneys. SSc is characterized by the increased occurrence of autoantibodies (AAB) directed against G protein-coupled receptors (GPCRs) such as the angiotensin II type 1 receptor (AT1R) and the endothelin 1 type A receptor (ETAR), as well as extracellular vesicles (EVs). Both AABs and EVs play an important role in SSc and related inflammatory fibrotic processes. Since GPCRs are secreted via EVs, an interaction of anti-GPCR AABs and EVs is likely, but has not yet been investigated. Therefore, the aim of our subproject is to determine the role of an interaction of anti-GPCR AABs and EVs in the pathogenesis of SSc and other inflammatory musculoskeletal diseases. To this end, we will investigate the levels of anti-GPCR AABs and EVs, GPCRs on EVs, the expression of GPCRs on immune cells and fibroblasts, and the functional impact of anti-GPCR AABs and EVs on the phenotype of these cells in healthy donors, SSc patients and in SSc mouse models. The results will be correlated with clinical patient data as well as with disease expression in the mouse model. To characterize the effects of GPCR-AAB/ EV interaction on SSc symptoms in vivo, we will transfer anti-GPCR AABs and/or isolated human and murine EVs into mice. We suspect that the interaction of anti-GPCR AABs and GPCR-bearing EVs plays a regulatory role in organ specificity of inflammation and fibrosis and influences the expression of a fibrotic phenotype and the recruitment of leukocytes into the tissue. It is can be assumed that the interaction of anti-GPCR AABs and EVs also plays a role in the pathogenesis of other inflammatory musculoskeletal diseases. Therefore, together with our partners from this consortium we will investigate the role of anti-GPCR AABs and EVs in rheumatoid arthritis (Kamradt/Müller-Ladner (P3)) and idiopathic inflammatory myopathies (Ruck (P4)). In collaboration with our partner LysatPharma GmbH, we will test the effect of therapeutic EVs in our SSc animal models. Using the joint Clinical Translational Platform (CTP (P7)), anti-GPCR AABs and EVs will also be characterized in patients with granulomatosis with polyangiitis (GPA), chronic osteomyelitis and periodontal disease. In this way, the data of this project will improve the understanding of inflammatory and fibrotic processes in musculoskeletal diseases and open new avenues for targeted therapies.