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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1516-1518.
Prepublished online as a Blood First Edition Paper on May 10, 2007; DOI 10.1182/blood-2007-02-071472.
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Submitted February 1, 2007
Accepted April 17, 2007
Anti-factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome
Mihaly Jozsi*, Stefanie Strobel, Hans-Martin Dahse, Wei-shih Liu, Peter F Hoyer, Martin Oppermann, Christine Skerka, and Peter F Zipfel
Junior Research Group Cellular Immunobiology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
Department of Pediatric Nephrology, University Clinic Essen, University Duisburg-Essen, Essen, Germany
Department of Cellular and Molecular Immunology, University of Gottingen, Gottingen, Germany
Friedrich Schiller University, Jena, Germany
* Corresponding author; email: mihaly.jozsi{at}hki-jena.de.
The atypical form of the kidney disease hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. In addition to mutations in complement regulators, factor H (FH)-specific autoantibodies have been reported for aHUS patients. The aim of the present study was to understand the role of these autoantibodies in aHUS. First, the binding site of FH-autoantibodies from five unrelated aHUS patients were mapped using recombinant FH fragments and competitor antibodies. For all five autoantibodies the binding site was localized to the FH C-terminus. In a functional assay, isolated patient IgG inhibited FH binding to C3b. In addition, autoantibody positive patient's plasma caused enhanced hemolysis of sheep erythrocytes, which was reversed by adding FH in excess. These results suggest that aHUS-associated FH-autoantibodies mimick the effect of C-terminal FH mutations, as they inhibit the regulatory function of FH at cell surfaces by blocking its C-terminal recognition region.
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