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Complement activity influences glomerular inflammation and clinical severity in IgA nephropathy and C3 glomerulopathy

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Title: Complement activity influences glomerular inflammation and clinical severity in IgA nephropathy and C3 glomerulopathy
Authors: Medjeral-Thomas, Nicholas
Item Type: Thesis or dissertation
Abstract: The mechanisms that link complement activation and glomerular injury are not understood. Recently, novel mechanisms of complement dysregulation mediated by factor H related protein (FHR)1 and FHR5 have been described. IgA nephropathy (IgAN) is important and poorly understood. Exciting recent evidence suggests FHR proteins and lectin complement pathways contribute to IgAN pathogenesis. C3 glomerulopathy (C3G) demonstrates the potential for alternative complement pathway dysregulation to drive glomerular injury. However, in the majority of C3G cases, precise pathogenesis is not understood. I hypothesised IgAN and C3G pathogenesis were dependent on imbalances of FHR1, FHR5 and lectin complement pathway proteins. I demonstrated circulating FHR1 levels and the ratio of FHR1 to factor H (FH) were increased in patients with IgAN compared to healthy controls and in patients with progressive compared to stable IgAN. I found IgAN patients had higher circulating FHR5 levels than healthy controls and higher circulating FHR5 levels associated with histology markers of IgAN severity. Glomerular FHR5 deposition associated with both clinical and histologic markers of IgAN severity and immunohistolgical markers of complement activation. Glomerular FHR5 deposition also associated with clinical and histology markers of C3G severity and co-localised with glomerular complement (C)3 deposits in C3G. Glomerular FHR5 deposition co-localised with markers of both ongoing (C3b/iC3b/C3c) and previous (C3dg) alternative complement activation in C3G and IgAN. I detected FHR5 in Immunoglobulin (Ig)A containing immune complexes. With regards to the lectin complement pathway, I found IgAN patients had higher circulating levels of M-ficolin, L-ficolin, mannan binding lectin (MBL) associated serine protease (MASP)-1 and MBL associated protein (MAp)19 than healthy controls, and lower circulating levels of MASP-3 than healthy controls. Lower circulating MASP-3 levels also associated with markers of IgAN severity. My research addresses fundamental gaps in our understanding of glomerular complement activation and IgAN pathogenesis. The results are limited by a number of important confounding factors that need to be addressed. However, they justify researching the mechanisms by which FHR5 contributes to complement activation and disease severity in IgAN and C3G and could contribute to novel and exciting diagnostic tools and therapeutic targets for IgAN, C3G and other complement dependent glomerulopathies.
Content Version: Open Access
Issue Date: Apr-2019
Date Awarded: Jul-2020
URI: http://hdl.handle.net/10044/1/91770
DOI: https://doi.org/10.25560/91770
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Pickering, Matthew
Cook, Herbert Terence
Sponsor/Funder: Kidney Research UK
Funder's Grant Number: TF14/2015
Department: Department of Immunology and Inflammation
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Department of Immunology and Inflammation PhD Theses



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