Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Ankylosing Spondylitis (AS) is a chronic inflammatory disease associated with the development of atherosclerosis. Our aims were: 1) To evaluate the involvement of immune system cells and NETosis in the atherosclerosis process in AS patients. 2) To analyze in vitro the role of leukocyte subsets in the endothelial function.
Methods: Thirty four AS patients and 34 healthy donors (HDs) were included in the study. Endothelial function was determined by the post occlusive hyperaemia test using Laser-Doppler. The expression of 84 genes related to atherosclerosis was determined in pooled RNA samples from peripheral blood mononuclear cells (PBMCs) of patients and HDs (n=3 each) by PCR array. Validation of several differentially expressed genes in PBMCs and the expression of various markers of oxidative stress and inflammation was quantified in leukocyte subsets. In neutrophils, NETosis markers and cell death by Sytox staining were also analyzed. Plasma DNA was quantified by fluorimetry. In vitro co-cultures of endothelial cells (HUVEC) with PBMCs or neutrophils from AS patients were performed.
Results: AS patients showed a prominent endothelial dysfunction, along with a significant alteration (fold change ≥ 2) in the expression of 50 genes related to atherosclerosis in PBMCs. Validation and expression studies showed that lymphocytes of AS patients exhibited an increase of inflammatory markers (STAT3, TNFα, IL1α, IL1β, IL6, IL23, IL2, ERAP1, IL10, IL5 mRNA), nitric oxide synthase (NOS) enzymes (NOS3 mRNA), and genes involved in adhesion (SELL, CDH5, THBS4 mRNA). In turn, monocytes displayed an augmented expression of inflammatory markers (STAT3, IFNγ, IL5, SPP1) and adhesion molecules (VCAM1, SELL), as well as a decrease in mRNA for IL6 and adhesive glycoprotein trombospondin 4 (THBS4). Neutrophils from AS patients showed a significant increase in NETosis and extruded plasma DNA levels, the latter associated with endothelial dysfunction present in AS. In addition, an increase of inflammatory markers (STAT3, TNFα, IL1β, IL1α, IL5 mRNA), adhesion molecules (ICAM1, SELL mRNA) and NOS3 mRNA was also found in this cell type. Oxidative status-related analyses demonstrated that leukocyte subsets from AS patients displayed an increase in oxidative stress and mitochondrial membrane potential, along with an alteration of TAC and NO at plasma levels. In vitro treatment of HUVECs with PBMCs or neutrophils from AS patients promoted an altered activity of the endothelial cells, which displayed altered expression of adhesion molecules, oxidative stress markers, cytokines and NOS enzymes, all of them associated to the pro-atherogenic profile of these patients.
Conclusion: 1) Leukocyte subsets from AS patients display an altered expression profile of key genes involved in the development of atherosclerosis. 2) NETosis is a cellular death mechanism occurring in AS, whose induction may act a key mediator of endothelial dysfunction in these patients. 3) That highly inflammatory PBMCs and neutrophils are responsible, at least partially, for the endothelial alteration displayed by AS patients. Funded by JA PI-0314-2012, SER
To cite this abstract in AMA style:Jiménez-Gómez Y, Font-Ugalde P, Ruiz-Limon P, Abalos-Aguilera MC, Castro-Villegas MC, Barbarroja N, Perez-Sanchez C, Arias de la Rosa I, Arias I, Ortega-Castro R, Calvo-Gutierrez J, Lopez-Pedrera C, Escudero-Contreras A, Collantes-Estévez E. Role of Immune System Cells and Induction of Netosis-Mediated Cell Death in the Development of Atherosclerosis in Ankylosing Spondylitis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/role-of-immune-system-cells-and-induction-of-netosis-mediated-cell-death-in-the-development-of-atherosclerosis-in-ankylosing-spondylitis/. Accessed November 29, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-immune-system-cells-and-induction-of-netosis-mediated-cell-death-in-the-development-of-atherosclerosis-in-ankylosing-spondylitis/