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Autoimmune rheumatic disease IgG has differential effects upon neutrophil integrin activation that is modulated by the endothelium

Title: Autoimmune rheumatic disease IgG has differential effects upon neutrophil integrin activation that is modulated by the endothelium
Authors: Khawaja, AA
Pericleous, C
Ripoll, VM
Porter, JC
Giles, IP
Item Type: Journal Article
Abstract: The importance of neutrophils in the pathogenesis of autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), is increasingly recognised. Generation of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs) by activated neutrophils are both thought to contribute to pathology; although the underlying mechanisms, particularly the effects of IgG autoantibodies upon neutrophil function, are not fully understood. Therefore, we determined whether purified IgG from patients with SLE or RA have differential effects upon neutrophil activation and function. We found that SLE- and RA-IgG both bound human neutrophils but differentially regulated neutrophil function. RA- and SLE-IgG both increased PMA-induced β1 integrin-mediated adhesion to fibronectin, whilst only SLE-IgG enhanced αMβ2 integrin-mediated adhesion to fibrinogen. Interestingly, only SLE-IgG modulated neutrophil adhesion to endothelial cells. Both SLE- and RA-IgG increased ROS generation and DNA externalisation by unstimulated neutrophils. Only SLE-IgG however, drove DNA externalisation following neutrophil activation. Co-culture of neutrophils with resting endothelium prevented IgG-mediated increase of extracellular DNA, but this inhibition was overcome for SLE-IgG when the endothelium was stimulated with TNF-α. This differential pattern of neutrophil activation has implications for understanding SLE and RA pathogenesis and may highlight avenues for development of novel therapeutic strategies.
Issue Date: 4-Feb-2019
Date of Acceptance: 24-Oct-2018
URI: http://hdl.handle.net/10044/1/67300
DOI: https://dx.doi.org/10.1038/s41598-018-37852-5
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 9
Issue: 1
Copyright Statement: © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre-ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per-mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
SYSTEMIC-LUPUS-ERYTHEMATOSUS
B-LYMPHOCYTE HYPERACTIVITY
BLOOD MONONUCLEAR-CELLS
REGULATORY T-CELLS
EXTRACELLULAR TRAPS
PERIPHERAL-BLOOD
ELEVATED LEVELS
DENDRITIC CELLS
SYNOVIAL-FLUID
SOLUBLE CD14
Publication Status: Published
Article Number: ARTN 1283
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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