The biology of immunoglobulin free light chains in kidney disease: a study of Monoclonal and Polyclonal light chains

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http://eprints.org/relation/isVersionOf http://etheses.bham.ac.uk/id/document/15444 http://eprints.org/relation/isVolatileVersionOf http://etheses.bham.ac.uk/id/document/15444 http://eprints.org/relation/isIndexCodesVersionOf http://etheses.bham.ac.uk/id/document/15444 archive 4031 disk0/00/00/28/62 2011-10-25 10:56:10 2019-01-23 09:54:59 2011-10-25 10:56:10 thesis show 0 Basnayake Kolitha Indika Cockwell Paul University of Birmingham The biology of immunoglobulin free light chains in kidney disease: a study of Monoclonal and Polyclonal light chains unpub RC 10col_mede Monoclonal immunoglobulin free light chains (FLCs) cause a range of disorders in the kidney. In multiple myeloma, FLCs can activate the proximal tubule to release MCP-1, an important cytokine in renal fibrosis. Distal tubular cast formation can also occur when FLCs co-precipitate with uromodulin. However a pathogenic role for the elevated polyclonal FLC concentrations seen in chronic kidney disease has not been assessed to date. This thesis explores the biology of monoclonal FLCs as well as polyclonal FLCs. Detailed histological analyses demonstrated that in multiple myeloma, interstitial fibrosis can progress rapidly in situ and indicated that intratubular cast numbers might be linked to potential for renal recovery. The functional basis of this fibrosis was explored by in vitro studies, which showed that upon endocytosis of FLCs, oxidative stress activated redox signalling, resulting in MCP-1 production. Further in situ analyses showed that in chronic kidney disease, polyclonal FLCs co-localised with uromodulin in distal tubular casts. Relationships between these casts and markers of progression of chronic kidney disease were demonstrated. In vitro analyses then showed that polyclonal FLCs bind to uromodulin and promote aggregation. These findings: (i) further delineate the pathways for proximal tubular injury in myeloma and (ii) indicate a potential pathogenic role for polyclonal FLCs in the distal nephron. 2012-07 2011-01 graduation eng This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. public 301 University of Birmingham School of Immunity and Infection d_ph na 2012-07 graduation