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Title: Neutrophil involvement in autoimmune rheumatic disease : the modulatory roles of hypoxia and autoimmune immunoglobulin G
Author: Khawaja, A. A.
ISNI:       0000 0004 8498 3402
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Neutrophil dysfunction has been described in various inflammatory and autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). These ARDs are typically characterised by circulating autoantibodies, which contribute to immunopathology. Studies have also reported low oxygen levels, or hypoxia, in association with disease manifestations. One mechanism of neutrophil activation, results in the release of a meshwork of chromatin fibres decorated with antimicrobial proteins, called neutrophil extracellular traps (NETs), which promote pathogen killing. Whilst NETs are important in fighting infection, if unchecked severe damage to host organs can be caused. Aberrant NETosis has been described in ARDs. Integrin engagement modulates several aspects of neutrophil activation including NETosis, cytokine production and reactive oxygen species (ROS) generation, which are associated with pathology in certain ARDs. Therefore, my PhD aimed to examine the effects of hypoxia and purified ARD-IgG on integrin activation, ROS generation and NETosis. Isolated neutrophils were cultured under normoxia (21% oxygen) or hypoxia (1% oxygen) and integrin expression, adhesion, ROS generation and NETosis examined. Hypoxic neutrophils had higher αM and αX expression and increased adhesion to endothelial cells. Trans-endothelial migration was also enhanced under hypoxia. Whilst hypoxia did not have an effect on ROS generation, NETosis was higher in hypoxic cells. IgG was purified from the serum of RA, SLE and APS patients. The effects of purified IgG upon neutrophil adhesion, ROS generation and NETosis were examined. ARD-IgG had a differential effect upon integrin activation, with RA- and SLE-IgG promoting αMβ2 (Mac-1)-mediated adhesion whilst APS-IgG enhanced β1-integrin mediated adhesion. Moreover, RA- and SLE-IgG increased rates of hydrogen peroxide generation and NETosis. The results obtained in this thesis demonstrate that hypoxia modulates neutrophil function. Purified ARD-IgG was also identified as having differential effects on neutrophil integrin activation, ROS generation and NETosis.
Supervisor: Porter, J. C. ; Giles, I. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available