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Factor I autoantibodies are associated with atypical haemolytic uraemic syndrome

Lookup NU author(s): Professor David Kavanagh, Dr Isabel Marchbank, Dr John Tapson, Dr Iain Moore, Dr Lisa Turnbull, Simon Lea, Professor Tim Goodship, Dr Kevin Marchbank

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Abstract

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.


Publication metadata

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

ISSN: 0161-5890

Publisher: Pergamon

URL: http://dx.doi.org/10.1016/j.molimm.2010.05.275

DOI: 10.1016/j.molimm.2010.05.275

Library holdings: Search Newcastle University Library for this item

ISBN: 18729142


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