Autoimmune rheumatic disease IgG has differential effects upon neutrophil integrin activation that is modulated by the endothelium
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Scientific reports - 9(2019), 1 vom: 04. Feb., Seite 1283 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Khawaja, Akif A [VerfasserIn] |
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| Links: |
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| Themen: |
Autoantibodies |
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| Anmerkungen: |
Date Completed 19.08.2020 Date Revised 09.01.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41598-018-37852-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM293454604 |
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| 245 | 1 | 0 | |a Autoimmune rheumatic disease IgG has differential effects upon neutrophil integrin activation that is modulated by the endothelium |
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| 500 | |a Date Revised 09.01.2021 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Autoantibodies |2 NLM | |
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| 700 | 1 | |a Ripoll, Vera M |e verfasserin |4 aut | |
| 700 | 1 | |a Porter, Joanna C |e verfasserin |4 aut | |
| 700 | 1 | |a Giles, Ian P |e verfasserin |4 aut | |
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