Autoantibodies against the chemokine receptor 3 predict cardiovascular risk
Authors: Müller Felix S , Aherrahrou Zouhair , Grasshoff Hanna , Heidorn Marc W , Humrich Jens Y , Johanson Laurence , Aherrahrou Redouane , Reinberger Tobias , Schulz Andreas , ten Cate Vincent , Robles Alejandro Pallares , Koeck Thomas , Rapp Steffen , Lange Tanja , Brachaczek Lukas , Luebber Finn , Erdmann Jeanette , Heidecke Harald , Schulze-Forster Kai , Dechend Ralf , Lackner Karl J , Pfeiffer Norbert , Ghaemi Kerahrodi Jasmin , Tüscher Oliver , Schwarting Andreas , Strauch Konstantin , Münzel Thomas , Prochaska Jürgen H , Riemekasten Gabriela , Wild Philipp S 
Published: November 2023

Abstract

Background and Aims
Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear.

Methods
Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(−/−) mice for preclinical validation.

Results
The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima–media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine–cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(−/−) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model.

Conclusions
In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.