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

Abstract

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.

Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and signs of neurodegeneration: a prospective cross-sectional study

“…Certainly, antibody production predominantly took place in the plasma, pointing to an ingress of peripherally activated B cells/antibodies. In line with recent findings identifying new onset autoantibodies in patients with COVID-19 (4), our identification of elevated anti-dsDNA IgG, which are associated with cardiovascular symptoms in systemic lupus (23), may provide a potential pathophysiological rationale for cardiovascular risk factors in severe COVID-19 (24). Indeed, two out of four class lll patients with vascular complications had increased levels of anti-dsDNA IgG in the CSF.…”

effects of toxoplasmosis infection on the levels of IL-18 and anti-ds-DNA antibodies in SLE patients

“…Anti-dsDNA antibodies are considered as a critical marker for the diagnosis and classification of SLE. Moreover, the fluctuating titers of these antibodies reflect the activity of disease of many patients; a rising titer could be predictive of disease relapse [25]. According to previous studies, higher levels of anti-dsDNA antibodies were detected in patients with active SLE [26].Another previous study, in line with ours, showed that anti-dsDNA antibodies levels appear to remain similar in sera of SLE patients after being infected with T. gondii [27].…”

The Causal Relationship Between Blood Lipids and Systemic Lupus Erythematosus Risk: A Bidirectional Two-Sample Mendelian Randomization Study

“…In addition, the parameters related to increased cardiovascular risk were associated with the presence and titer of anti-dsDNA antibodies, and the relationship was independent of the other cardiovascular risk factors ( Patiño-Trives et al, 2021 ). Certainly, glucocorticoid exposure may also play an important role in CVDs, for example, the high-dose of prednisolone promote carotid intima-media thickness progression in SLE ( Ajeganova et al, 2020 ; Lengton et al, 2021 ).…”