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

• Published in: Scientific reports Vol. 9; no. 1; p. 1283
• Main Authors: Khawaja, Akif A., Pericleous, Charis, Ripoll, Vera M., Porter, Joanna C., Giles, Ian P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2019; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/31; 692/4023/1670/1613; 692/4023/1670/498; Adhesion; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Autoantibodies; Autoantibodies - immunology; Autoimmune diseases; Cell activation; Cell culture; Deoxyribonucleic acid; DNA; Endothelial cells; Endothelium; Fibrinogen; Fibronectin; Human Umbilical Vein Endothelial Cells - immunology; Human Umbilical Vein Endothelial Cells - pathology; Humanities and Social Sciences; Humans; Immunoglobulin G; Immunoglobulin G - immunology; Integrin beta1 - immunology; Leukocytes (neutrophilic); Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; multidisciplinary; Neutrophil Activation; Neutrophils; Neutrophils - immunology; Neutrophils - pathology; Pathogenesis; Reactive oxygen species; Rheumatic diseases; Rheumatoid arthritis; Science; Science (multidisciplinary); Systemic lupus erythematosus; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-37852-5

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 β 1 integrin-mediated adhesion to fibronectin, whilst only SLE-IgG enhanced α M β 2 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.