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Title: The role of complement and monocytes in antineutrophil cytoplasmic antibody associated vasculitis
Author: Popat, Reena Jayantilal
ISNI:       0000 0004 5994 505X
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a multi-systemic disease with autoantibody generation to myeloperoxidase (MPO) and proteinase 3 (PR3), components of neutrophils and monocytes. It is widely believed that ANCA are pathogenic. The most convincing evidence for this comes from the ability to induce crescentic glomerulonephritis in mice with passive transfer of MPO-ANCA. Studies have also shown with limited numbers of ANCA, the autoantibodies can activate neutrophils in vitro. The role of monocytes in pathogenesis though is scarcely explored. The alternative pathway of complement has also been implicated as vital to the pathogenesis of AAV, but the activating factors of complement are unknown. Contrary to previous studies we failed to consistently activate neutrophils with a large panel of randomly selected ANCA. We investigated the effect of these ANCA on peripheral blood monocytes. Interestingly, we found that MPO-ANCA derived from AAV patients cause a reduction in IL6 and IL10 production from lipopolysaccharide treated monocytes, which is Fc dependent and MPO enzyme dependent. Using gene expression microarrays we show that MPO-ANCA cause a widespread reduction in toll-like receptor (TLR) 4 signalling. We show using mass spectrometry analysis that MPO-ANCA leads to the production of a subset of oxidised phospholipids that can inhibit TLR4. We also demonstrate that MPO-ANCA lead to an increase in survival of macrophages differentiated in vitro from monocytes, which is dependent on colony stimulating factor-1. The differentiated macrophages have an M2-like phenotype that induce IL10 and TGFβ production from CD4 T cells, which would have a potential role in fibrosis. Secondly, we address potential triggers for complement activation during disease and show that there is a redundancy between the classical and alternative pathway. C3 deficient mice are protected from disease, but factor B deficient and C4 deficient mice are not. We also demonstrate cross talk between the coagulation and complement cascade. Using bone marrow chimeras, we demonstrate a role for circulating and not bone marrow-derived C5 in disease pathogenesis, which may help refine complement-targeted therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available