RESUMO
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.
Assuntos
Anticorpos Antinucleares/sangue , Doenças Cardiovasculares/imunologia , DNA/imunologia , Células Endoteliais/imunologia , Imunoglobulina G/sangue , Leucócitos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Apoptose , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/genética , Células Cultivadas , Técnicas de Cocultura , Estudos Transversais , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Leucócitos/metabolismo , Lipídeos/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Estresse Oxidativo , Estudos Retrospectivos , Medição de Risco , Transdução de SinaisRESUMO
OBJECTIVE: Our aim was to characterize distinctive clinical antiphospholipid syndrome phenotypes and identify novel microRNA (miRNA)-mRNA-intracellular signaling regulatory networks in monocytes linked to cardiovascular disease. Approach and Results: Microarray analysis in antiphospholipid syndrome monocytes revealed 547 differentially expressed genes, mainly involved in inflammatory, cardiovascular, and reproductive disorders. Besides, this approach identified several genes related to inflammatory, renal, and dermatologic diseases. Functional analyses further demonstrated phosphorylation of intracellular kinases related to thrombosis and immune-mediated chronic inflammation. miRNA profiling showed altered expression of 22 miRNAs, enriched in pathways related to immune functions, cardiovascular disease, and autoimmune-associated pathologies. Unbiased integrated mRNA-miRNA analysis identified a signature of 9 miRNAs as potential modulators of 17 interconnected genes related to cardiovascular disease. The altered expression of that miRNA-mRNA signature was proven to be stable along time and distinctive of nonautoimmune thrombotic patients. Transfection studies and luciferase assays established the relationship between specific miRNAs and their identified target genes and proteins, along with their involvement in the regulation of monocytes procoagulant activity and cell adhesion. Correlation analyses showed relationship among altered miRNAs and their interconnected genes with aPL (antiphospholipid antibodies)-titers, along with microvascular endothelial dysfunction. In vitro studies demonstrated modulation in healthy monocytes by IgG-aPLs of several genes/miRNAs, which further intermediated downstream effects on endothelial function. The identified transcriptomic signature allowed the unsupervised division of three clusters of patients with antiphospholipid syndrome showing distinctive clinical profiles, mainly associated with their prothrombotic risk (thrombosis, autoantibody profile, cardiovascular risk factors, and atherosclerosis). CONCLUSIONS: Extensive molecular profiling of monocytes in patients with primary antiphospholipid syndrome might help to identify distinctive clinical phenotypes, thus enabling new patients' tailored treatments.
Assuntos
Síndrome Antifosfolipídica/genética , Perfilação da Expressão Gênica , MicroRNAs/genética , Monócitos/metabolismo , Trombose/genética , Transcriptoma , Aprendizado de Máquina não Supervisionado , Adulto , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/complicações , Estudos de Casos e Controles , Células Cultivadas , Análise por Conglomerados , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Mapas de Interação de Proteínas , Medição de Risco , Fatores de Risco , Transdução de Sinais , Trombose/sangue , Trombose/etiologiaRESUMO
La aterotrombosis en el síndrome antifosfolípido primario (SAF) y el lupus eritematoso sistémico (LES) constituye una enfermedad de carácter sistémico, en cuyo desarrollo interviene una compleja red de mediadores inmunológicos, procoagulantes, componentes inflamatorios y el estrés oxidativo, todos ellos conducentes a la activación del complemento, el daño endotelial y la activación leucocitaria. Estudios genómicos y epigenéticos han contribuido asimismo a identificar nuevos biomarcadores que, junto a factores de riesgo tradicionales, han permitido delinear nuevos mecanismos patogénicos implicados en el desarrollo de trombosis y enfermedad cardiovascular (CV) en estos pacientes. Actualmente se están estudiando nuevas herramientas terapéuticas para la prevención de la enfermedad CV, tales como las estatinas, los inhibidores del interferón α o la coenzima Q10, entre otros. Los nuevos anticoagulantes orales pueden suponer también avances importantes en el tratamiento de estos pacientes. El presente estudio examina aspectos moleculares y terapéuticos asociados al diagnóstico y el seguimiento de la enfermedad CV en SAF y LES (AU)
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are 2 highly related autoimmune-rheumatic diseases associated with an increased risk of developing cardiovascular (CV) diseases. Despite the great progresses made in understanding the pathological mechanisms leading to CV diseases in those pathologies, there is still the unmet need to improve long term prognosis. CV diseases in SLE and APS is thought to happen as the result of a complex interaction between traditional CV risk factors, immune deregulation and disease activity, including the synergic effect of cytokines, chemokines, adipokines, proteases, autoantibodies, adhesion receptors, oxidative stress and a plethora of intracellular signalling molecules. Genomic and epigenomic analyses have further allowed the identification of specific signatures explaining the proathero-thrombotic profiles of APS and SLE patients. This review examines the complex role of these heterogeneous factors, and analyses new therapeutic approaches under study to reduce the CV risk in these autoimmune disorders (AU)
Assuntos
Humanos , Síndrome Antifosfolipídica/fisiopatologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Biomarcadores/análise , Fatores de Risco , Trombose Venosa/prevenção & controle , Coenzimas/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêuticoRESUMO
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are 2 highly related autoimmune-rheumatic diseases associated with an increased risk of developing cardiovascular (CV) diseases. Despite the great progresses made in understanding the pathological mechanisms leading to CV diseases in those pathologies, there is still the unmet need to improve long term prognosis. CV diseases in SLE and APS is thought to happen as the result of a complex interaction between traditional CV risk factors, immune deregulation and disease activity, including the synergic effect of cytokines, chemokines, adipokines, proteases, autoantibodies, adhesion receptors, oxidative stress and a plethora of intracellular signalling molecules. Genomic and epigenomic analyses have further allowed the identification of specific signatures explaining the proathero-thrombotic profiles of APS and SLE patients. This review examines the complex role of these heterogeneous factors, and analyses new therapeutic approaches under study to reduce the CV risk in these autoimmune disorders.