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.
Key Findings
Results
Anti-CXCR3 IgG serum levels were significantly reduced in early rheumatoid arthritis and clinically-suspect arthralgia compared with healthy controls.
Early RA cohort included n=84 patients, clinically-suspect arthralgia n=14, and controls n=65.
The reduction was independent of disease activity, autoantibodies, or systemic inflammation.
This finding was confirmed in a validation cohort of established RA (n=103).
Publicly available transcriptomic datasets were also used for validation.
Results
Reduced anti-CXCR3 antibody levels were also observed in Sjögren disease, suggesting a shared hallmark across systemic autoimmune diseases.
Sjögren disease cohort included n=44 patients.
Equivalent results to those observed in RA were found in SjD.
The finding bridges two distinct systemic autoimmune conditions, indicating a common immune dysregulation mechanism.
Results
Lower anti-CXCR3 levels were negatively associated with good therapeutic outcomes upon conventional synthetic DMARD treatment in early RA.
The association was observed at both 6 and 12 months of follow-up.
Anti-CXCR3 were negatively associated with good therapeutic outcomes upon csDMARD therapy.
This suggests potential utility of anti-CXCR3 as a prognostic biomarker for treatment response in early RA.
Results
Lower anti-CXCR3 levels were independently associated with both the occurrence and extent of atherosclerosis across conditions.
Atherosclerosis was assessed by carotid ultrasound.
The association was independent across RA and SjD conditions.
Incorporating anti-CXCR3 into the modified SCORE (mSCORE) improved cardiovascular risk stratification.
The association was observed for both atherosclerosis occurrence and extent, suggesting a dose-response relationship.
Results
Anti-CXCR3 antibodies were related to proteomic signatures linked to immune activation, apoptosis, chemotaxis, and cell adhesion in an atherosclerosis-dependent manner.
Cardiometabolic-related proteins were evaluated using high-throughput targeted proteomics.
Cytokines were measured by multiplex immunoassays.
The proteomic associations were observed in an atherosclerosis-dependent manner in both RA and SjD.
Signatures encompassed pathways related to immune activation as well as apoptosis, chemotaxis, and cell adhesion.
Results
Transcriptomic analyses indicated compartment-specific CXCR3 dysregulation in both RA and SjD.
Publicly available transcriptomic datasets were used for this analysis.
Dysregulation was described as compartment-specific, suggesting tissue- or cell-type-dependent differences.
This finding was observed in both RA and SjD, further supporting a shared mechanism.
Results
Anti-CXCR3 reduction was detectable at the clinically-suspect arthralgia stage, prior to established RA diagnosis.
Clinically-suspect arthralgia cohort included n=14 individuals.
This pre-diagnostic stage finding suggests anti-CXCR3 reduction is an early event in the autoimmune disease process.
The finding implies potential utility for early identification of individuals at risk.
What This Means
This research suggests that people with systemic autoimmune diseases — specifically rheumatoid arthritis (RA) and Sjögren disease — have notably lower blood levels of a type of antibody that targets a receptor called CXCR3, compared to healthy individuals. Importantly, this reduction was seen even in people with early-stage arthritis before a full RA diagnosis, and it was not explained by how active the disease was, other disease-related antibodies, or general inflammation markers. The finding held up across multiple independent patient groups, strengthening confidence in the result.
The study also found that these lower anti-CXCR3 antibody levels were linked to worse responses to standard arthritis treatment (conventional DMARDs) at both 6 and 12 months, and were independently associated with the presence and severity of hardening of the arteries (atherosclerosis), as measured by carotid ultrasound. Adding anti-CXCR3 measurements to an existing cardiovascular risk scoring tool improved the ability to identify who was at higher risk. The antibodies were also connected to protein patterns in the blood related to immune activation and processes involved in artery disease, such as cell adhesion and inflammation.
This research suggests that anti-CXCR3 antibodies may play an important regulatory role at the intersection of immune function and blood vessel health, and their reduction could be a shared biological feature connecting autoimmune disease with increased cardiovascular risk. If confirmed in further studies, measuring anti-CXCR3 levels could potentially help clinicians better predict treatment responses and identify autoimmune patients who are at higher risk for heart and vascular disease earlier than currently possible.
Miranda-Prieto D, Alperi-López M, Pérez-Álvarez &, Suárez-Díaz S, Alonso-Castro S, Heidecke H, et al.. (2026). Reduced circulating anti-CXCR3 antibodies as a common hallmark bridging systemic autoimmunity and atherosclerosis.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1937388