Lookup NU author(s): Professor David Kavanagh,
Dr Isabel Pappworth,
Dr John Tapson,
Dr Iain Moore,
Dr Lisa Turnbull,
Professor Tim Goodship,
Dr Kevin Marchbank
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Background: Atypical haemolytic uraemic syndrome (aHUS) is a disease of complement over activation. Mutations in the genes encoding both regulators (factor H, membrane cofactor protein and factor I) and activators (factor B and C3) are associated with aHUS. Factor H autoantibodies have also been demonstrated in around not, vert, similar10% of aHUS patients. These autoantibodies bind to the C-terminal recognition domain of factor H and impair complement regulation at the cell surface. In this study we have examined the hypothesis that factor I (fI) autoantibodies are associated with aHUS.Methods: We screened sera from 142 aHUS patients and 100 controls for fI autoantibodies using ELISA. We confirmed positive results by titration and western blotting. We screened CFH, CFI, MCP, CFB and C3 for mutations using direct fluorescent sequencing. We screened for genomic disorders using muliplex ligation-dependent probe amplification and assessed the functional significance of co-existing mutations in co-factor assays using recombinant proteins.Results: We detected IgG fI autoantibodies in the sera of three aHUS patients. One was strongly positive and two were moderately positive. We confirmed these results with western blotting, which also showed that the autoantibodies bind predominantly to the heavy chain of fI. In one individual, archived serum samples allowed serial measurements of autoantibody titre demonstrating an increased titre at the time of recurrence of aHUS in a renal transplant. In the same patient, we also detected functionally significant mutations in CFH (c.3468dupA) and CFI (−c.1657 C > T− Pro553Ser).Conclusions: We have found fI autoantibodies in three aHUS patients. In one patient we have found additional mutations in CFH and CFI and in this individual we observed an increased titre at the time of transplant recurrence. This observation provides further evidence that multiple concurrent risk factors may be necessary in individual patients for disease manifestation.
Author(s): Kavanagh D, Pappworth IY, Roversi P, Tapson JS, Moore I, Strain L, Lea S, Goodship THJ, Marchbank KJ
Publication type: Conference Proceedings (inc. Abstract)
Publication status: Published
Conference Name: Molecular Immunology: 23rd International National Complement Workshop
Year of Conference: 2010
Pages: 2291-2292 no. 92
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