Reduced circulating anti-CXCR3 antibodies as a common hallmark bridging systemic autoimmunity and atherosclerosis

Introduction immune dysregulation underlies cardiovascular risk excess in systemic autoimmune diseases, such as rheumatoid arthritis (RA) and Sjögren disease (SjD). However, exact mediators are unknown. Regulatory autoantibodies targeting G protein–coupled receptors, including CXCR3, have emerged as modulators of immune and vascular homeostasis, but their role in autoimmunity remains ill-defined. Our aim was to evaluate anti-CXCR3 levels in systemic autoimmunity and their potential value as biomarkers. Methods anti-CXCR3 IgG serum levels were quantified in early RA (n=84), clinically-suspect arthralgia (n=14), and controls (n=65). Established RA (n=103) and SjD (n=44) were recruited for validation. Atherosclerosis was assessed by carotid ultrasound. Cytokines were measured by multiplex immunoassays. Cardiometabolic-related proteins were evaluated using high-throughput targeted proteomics. Publicly available datasets were used for validation. Results anti-CXCR3 antibodies were significantly reduced in early RA and clinically-suspect arthralgia compared with controls, independently of disease activity, autoantibodies, or systemic inflammation. This finding was confirmed in the validation cohort. Equivalent results were also observed in SjD. Anti-CXCR3 were negatively associated with good therapeutic outcomes upon csDMARD at 6 and 12 months in early RA. Lower anti-CXCR3 levels were independently associated with atherosclerosis occurrence and extent across conditions. Incorporating anti-CXCR3 into mSCORE improved risk stratification. Anti-CXCR3 were related to proteomic signatures linked to immune activation and to apoptosis, chemotaxis, and cell adhesion in an atherosclerosis-dependent manner in RA and SjD. Transcriptomic analyses indicated compartment-specific CXCR3 dysregulation both in RA and SjD. Conclusion reduced anti-CXCR3 antibodies represent a shared hallmark bridging systemic autoimmunity and atherosclerosis burden, shaping our understanding on the regulatory role of antibodies at the vascular–immune interface. Clinical translation of anti-CXCR3 antibodies hold promise to improve risk stratification.