Anti-dsDNA Antibodies Increase the Cardiovascular Risk in Systemic Lupus Erythematosus Promoting a Distinctive Immune and Vascular Activation

• DOI: 10.1161/atvbaha.121.315928
• Publication Date: 2021-07-29T09:00:14Z
• Authors: Alejandra María P...; Carlos Pérez-Sánchez; Laura Pérez-Sánchez; María Luque-Tévar; M. Carmen Ábalos-...; Lourdes Alcaide-R...; Iván Arias-de la ...; Cristóbal Román-R...; Pedro Seguí; Mario Espinosa; Pilar Font; Nuria Barbarroja; Alejandro Escuder...; José Antonio Gonz...; José Manuel Villalba; Eduardo Collantes...; M. Ángeles Aguirr...; Chary López-Pedrera
• Keywords: Adult; Male; 0301 basic medicine; Endothelial Cells; Apoptosis; DNA; Extracellular Traps; Lipids; Coculture Techniques; 3. Good health; 03 medical and health sciences; Cross-Sectional Studies; Cardiovascular Diseases; Heart Disease Risk Factors; Antibodies, Antinuclear; Immunoglobulin G; Leukocytes; Cytokines; Humans; Lupus Erythematosus, Systemic; Female; Biomarkers; Cells, Cultured

Objective: Systemic lupus erythematosus (SLE) is associated to boosted atherosclerosis development and a higher cardiovascular disease risk. This study aimed to delineate the role of anti-double stranded DNA (anti-dsDNA) antibodies on the molecular profile and the activity of immune and vascular cells, as well as on their enhanced cardiovascular risk.

Approach and Results: Eighty SLE patients were included. Extensive clinical/analytical evaluation was performed, including cardiovascular disease parameters (endothelial function, proatherogenic dyslipidemia, and carotid intima-media thickness). Gene and protein expression profiles were evaluated in monocytes from patients diagnosed positive or negative for anti-dsDNA antibodies by using NanoString and cytokine arrays, respectively. NETosis and circulating inflammatory profile was assessed in both neutrophils and plasma. Positivity and persistence of anti-dsDNA antibodies in SLE patients were associated to endothelial dysfunction, proatherogenic dyslipidemia, and accelerated atherosclerosis. In parallel, anti-dsDNA antibodies were linked to the aberrant activation of innate immune cells, so that anti-dsDNA(+) SLE monocytes showed distinctive gene and protein expression/activity profiles, and neutrophils were more prone to suffer NETosis in comparison with anti-dsDNA(−) patients. Anti-dsDNA(+) patients further displayed altered levels of numerous circulating mediators related to inflammation, NETosis, and cardiovascular risk. In vitro, Ig-dsDNA promoted NETosis on neutrophils, apoptosis on monocytes, modulated the expression of inflammation and thrombosis-related molecules, and induced endothelial activation, at least partially, by FcR (Fc receptor)-binding mechanisms.

Conclusions: Anti-dsDNA antibodies increase the cardiovascular risk of SLE patients by altering key molecular processes that drive a distinctive and coordinated immune and vascular activation, representing a potential tool in the management of this comorbidity.