Abstract
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 sites of FH autoantibodies from 5 unrelated aHUS patients were mapped using recombinant FH fragments and competitor antibodies. For all 5 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 patients' plasma caused enhanced hemolysis of sheep erythrocytes, which was reversed by adding FH in excess. These results suggest that aHUS-associated FH autoantibodies mimic 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.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoantibodies / chemistry
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Autoantibodies / immunology*
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology*
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Autoimmune Diseases / pathology
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Binding Sites, Antibody / genetics
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Binding Sites, Antibody / immunology*
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Child
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Child, Preschool
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Complement Activation / genetics
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Complement Activation / immunology*
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Complement C3b / genetics
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Complement C3b / immunology
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Complement Factor H / genetics
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Complement Factor H / immunology*
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Erythrocytes / chemistry
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Erythrocytes / immunology
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Female
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Genetic Diseases, Inborn / genetics
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Genetic Diseases, Inborn / immunology
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Genetic Diseases, Inborn / pathology
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Hemolysis / immunology
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Hemolytic-Uremic Syndrome / genetics
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Hemolytic-Uremic Syndrome / immunology*
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Hemolytic-Uremic Syndrome / pathology
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Humans
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Immunoglobulin G / genetics
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Immunoglobulin G / immunology
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Male
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Molecular Mimicry / genetics
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Molecular Mimicry / immunology*
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Mutation / immunology
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Peptide Mapping
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Protein Binding / genetics
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Protein Binding / immunology
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Protein Structure, Tertiary / genetics
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Recombinant Proteins / chemistry
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Recombinant Proteins / immunology
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Sheep
Substances
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Autoantibodies
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Immunoglobulin G
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Recombinant Proteins
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Complement C3b
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Complement Factor H