Molecular mechanisms of IgA nephropathy

McDonald, Kenneth John (2006) Molecular mechanisms of IgA nephropathy. PhD thesis, University of Glasgow.

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IgA nephropathy is the most common form of glomerulonephritis and is the underlying cause of renal failure in up to 10% of patients in dialysis and renal transplantation programmes. The condition has a variable natural history, leading over a period of several years to end stage renal failure in approximately one third of those affected. The pathogenesis of IgA nephropathy, and the factors determining susceptibility and disease progression are incompletely understood, but abnormalities have been described in both the systemic and mucosal limbs of the immune system. Although circulating levels of IgA may be increased in patients, and the IgA is abnormally glycosylated, the characteristic diagnostic feature is the presence of IgA-containing immune complexes in the glomerular mesangium. However, the mechanism by which these complexes are deposited in the mesangium, and the nature of their pathophysiological role, is unknown. Human mesangial cells (HMCs) cultured in vitro can bind monomeric and polymeric IgA in a dose-dependent, specifically inhibitable manner but do not express classical IgA receptors such as the Fc alpha receptor (FcalphaRI), the polymeric immunoglobulin receptor or the asialoglycoprotein receptor. This evidence has led several authors to suggest that HMCs possess a novel IgA receptor, but its identity has remained elusive. Mesangial cell activation following IgA binding and receptor signalling could underlie the mesangial cellular proliferation and extracellular matrix accumulation seen in IgA nephropathy. A better understanding of these potentially receptor mediated events is an important step toward defining the pathophysiology of IgA nephropathy more clearly. Initial reports of FcalphaRI expression by HMCs had yielded conflicting results. In accordance with work subsequently published by other authors we failed to detect FcalphaRI message or protein expression by HMCs using a variety of techniques. Another report had suggested that HMCs expressed a novel FcalphaRI variant that perhaps mediated mesangial deposition of IgA. We examined HMCs for expression of such a variant using real time polymerase chain reaction to provide relative quantification of FcalphaRI exons. These investigations provided no evidence for expression of an FcalphaRI variant by cultured HMCs. Mesangial cells were then assessed for expression of the human homologue of a novel IgA and IgM-binding receptor described on murine macrophages and B lymphocytes. We hypothesised that this Fcalpha/muR could be involved in the mesangial deposition of IgA if it were expressed in human kidney. Fcalpha/muR gene expression was detected in human renal cortex, isolated glomeruli and in primary cultures of HMCs.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Alan Jardine
Keywords: Immunology, Molecular biology, Pathology
Date of Award: 2006
Depositing User: Enlighten Team
Unique ID: glathesis:2006-74073
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Sep 2019 15:33
Last Modified: 23 Sep 2019 15:33

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