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Generierung und Charakterisierung eines Antikörper-basierten Mausmodells für die systemische Sklerose

Fachliche Zuordnung Rheumatologie
Förderung Förderung von 2015 bis 2023
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 272606465
 
Erstellungsjahr 2022

Zusammenfassung der Projektergebnisse

In this study, we aimed to determine contributions and functions of autoantibodies (abs) directed to the angiotensin receptor type 1 (AT1R), which have been suggested to be involved in the pathogenesis of systemic sclerosis (SSc). For this purpose, C57BL/6J mice were immunized with membrane extract from human AT1R overexpressing cells or that from control cells. The induced phenotype was examined by histology, immunohistochemistry, immunofluorescence and ELISA. In addition, a monoclonal antibody against AT1R was generated by hybridoma technique and transferred into C57BL/6J mice. We could show that i) AT1R-immunized mice, but not control mice, generated anti-AT1R abs and developed pulmonary inflammation, skin inflammation and skin fibrosis; ii) Both CD4+ T and B cells are indispensable for the AT1R-induced immunological and histopathological phenotypes in mice; iii) application of monoclonal antibody against AT1R induced skin and lung inflammation in wildtype mice but not in the AT1R-deficient mice; and iv) AT1R Abs activated rat cardiomyocytes and human monocytes and enhanced Ang II-mediated AT1R activation in AT1R-transfected HEK293 cells via AT1R binding. Taken together, our immunization strategy successfully induced AT1R Abs, contributing to inflammation and, most likely, to fibrosis via activation of AT1R. Our study has proven, for the first time, the role of anti-AT1R abs in lung and skin inflammation, which is present in SSc, but also in other diseases. Based on these data and on novel published data, novel concepts for diseases can be generated. Anti-AT1R abs as well as other antibodies directed to G protein-coupled receptors might be valuable targets for future therapies of SSc and possibly other AT1R Ab-related diseases. In this project, we also have shown that anti-AT1R abs are also present in healthy donors and correlate with other abs. The correlations depend on age, sex, but also on diseases and symptoms of diseases. Therefore, anti-AT1R abs should be seen in the context of diseases and of the ab network, which also induced signalling in various cells and a cytokine response. The latter can be used to identify therapeutic targets. Anti-AT1R abs are present in all individuals. In some, acute vascular diseases, the ab levels are lower compared to healthy donors. In addition, we have shown that not only the ab levels are important. Anti-AT1R abs correlate with several other abs in a disease-and symptomspecific manner. This is of high relevance and could explain the heterogeneity of AT1R- mediated effects. Further, IgG from patients transfer disease mechanisms present in their donors into monocytes, which express a high number of GPCR. Analyses of the supernatants could be used to identify pathways.

Projektbezogene Publikationen (Auswahl)

 
 

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