Project Details
Projekt
P1: Dissecting the role of CXCR3/4 expression and interaction with autoantibodies in atherosclerosis
Subject Area
Rheumatology
Cardiology, Angiology
Clinical Immunology and Allergology
Cardiology, Angiology
Clinical Immunology and Allergology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 552470287
Atherosclerosis and its complications are major determinants of morbidity and mortality worldwide. In addition to classical risk factors, systemic chronic inflammation and autoimmunity are also crucial for its prognosis. The chemokine receptors CXCR3 and CXCR4 have been identified as central players in the pathogenesis of atherosclerosis. Our research group demonstrated that CXCR3 autoantibodies (Abs) enable the prediction of overall mortality and cardiovascular morbidity in the population-based Gutenberg Health Study. Furthermore, ApoE-/- mice immunized against CXCR3 exhibited increased levels of CXCR3 Abs and a higher burden of atherosclerosis, correlating with Ab concentrations in the passive transfer model. The project's hypothesis is that sustained overexpression of CXCR3 and CXCR4 under inflammatory stimuli, such as diet-induced inflammation, leads to antigen presentation and the formation of tertiary lymphoid structures. Increased antigen exposure enhances local antibody production, affinity maturation, and class switching, promoting the emergence of pathogenic CXCR3/CXCR4 Abs. These Abs contribute to the progression of atherosclerosis by facilitating immune cell recruitment, endothelial dysfunction, and persistent vascular inflammation. The aim is to i) investigate the impact of distinct epitopes and receptor expression levels on Ab generation under inflammatory conditions, and ii) unravel the significance of CXCR3 and CXCR4 expression in the emergence of respective Abs in the context of atherosclerosis. Our interdisciplinary team, composed of a Clinician Scientist and a basic researcher, integrates translational and mechanistic approaches to study CXCR3/4 expression and its interactions with Abs in atherosclerosis. Using immunohistochemistry and RNAscope, we analyse receptor expression in plaques. Co-culture and organ-on-chip models allow us to examine Ab-mediated effects on endothelial and smooth muscle cells. Structural characterization focuses on identifying atherosclerosis-associated epitopes through MHCI/II immunopeptidome analysis, epitope mapping, and antigen-specific T-cell investigations. Functional validation employs adeno associated virus vectors for targeted receptor expression in endothelial cells of different vascular regions and smooth muscle cells, enabling the study of tissue-specific receptor overexpression on antibody formation and plaque development. This integrative approach combines clinical and experimental expertise to identify novel therapeutic strategies for the targeted modulation of immunological processes in vascular diseases.
DFG Programme
Research Units
