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Title: Autoantibody in the pathogenesis of systemic lupus erythematosus
Author: Lou, Hantao
ISNI:       0000 0004 9350 1583
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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SLE is an autoimmune disease characterized by the production of autoantibodies against self-antigens. Anti-dsDNA antibodies are found to correlate with SLE disease activity and it is believed that they bind to nuclear antigens to form immune complex and mediate tissue damage. The observation that serum from a subset of SLE patients impairs the neutrophil extracellular traps (NET) degradation, further suggested that autoantibodies can cause additional damage by binding to NETs. The aim of my PhD project is to study the pathogenic mechanism of the anti-dsDNA antibodies. To achieve this I cloned 200 monoclonal antibodies from two active SLE patients and characterized their reactivity to a panel of nuclear antigens including histones, chromatin, dsDNA and extractable nuclear antigens. In order to identify the pathogenic group of anti-dsDNA antibodies, their reactivity against apoptotic cells, neutrophil extracellular traps were tested by immunofluorescence and Western Blot. In addition to this, their potential binding to autoantigens in the kidney were studied by intraperitoneal injection of these mAb mice followed by immunofluorescence of the kidney specimens. Only one group of mAbs (which are histone 1 and naked dsDNA positive) deposit in the nephritic mouse kidney and they show high reactivity to both apoptotic cells and NET. Furthermore, this group of mAbs are able to stabilize the NET, prevent it from nuclease digestion. The stabilized NET-anti-dsDNA antibody immune complex enhance the type I IFN expression in monocytes. Interestingly, this mAb also facilitates apoptotic cell engulfment to suppress type I IFN expression. In summary, these findings indicate only a subgroup of anti-dsDNA antibodies are pathogenic, they deposit in diseased kidney tissue and fuel inflammation. These anti-dsDNA antibodies also stabilize NET and enhance type I IFN expression from monocytes.
Supervisor: Mongkolsapaya, Juthathip ; Screaton, Gavin ; Pickering, Matthew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral