Functional mapping of anti-factor IX inhibitors developed in patients with severe hemophilia B
| Autor: | Ghislaine Cherel, M. E. Briquel, Koen Mertens, Peter J. Lenting, Dominique Meyer, Mariëtte Boon-Spijker, Jenny Goudemand, Ria C. Boertjes, Arja de Goede-Bolder, Olivier D. Christophe, Roseline d'Oiron, Solange Gaillard, Jean-Maurice Lavergne |
|---|---|
| Přispěvatelé: | Pediatrics |
| Rok vydání: | 2001 |
| Předmět: |
Protein Conformation
Recombinant Fusion Proteins Immunology Antigen-Antibody Complex Biochemistry Hemophilia B Epitope Immunoglobulin G Factor IXa Factor IX chemistry.chemical_compound Epitopes Membrane Lipids Epidermal growth factor Antibody Specificity Isoantibodies medicine Humans Factor VIIIa Phospholipids Gla domain biology business.industry Factor X Cell Biology Hematology Virology Molecular biology Peptide Fragments Protein Structure Tertiary Enzyme Activation chemistry biology.protein Antibody business medicine.drug Protein Binding |
| Zdroj: | Blood, 98(5), 1416-1423. American Society of Hematology |
| ISSN: | 0006-4971 |
| Popis: | Development of inhibitory antibodies is a serious complication of treatment with repeated factor IX infusions in a minority of patients with hemophilia B. Such antibodies detected in 8 patients have been characterized. Typing studies revealed that patients' immune response toward factor IX is highly heterogeneous and involves immunoglobulin G (IgG) antibodies, preferentially IgG1 and IgG4. The preservation of the sequence and the 3-dimensional orientation of the amino acids constituting one epitope are highly important for the assembly of an antibody-antigen complex. To localize the epitopes on the factor IX molecule, an original approach was designed using a set of factor X chimeras carrying regions of factor IX. Results showed that some patients' antibodies were directed against both the domain containing the gamma-carboxy glutamic acid residues (Gla domain) and the protease domain of factor IX. In contrast, no binding was observed to the epidermal growth factor-like domains or to the activation peptide. Functional characterization showed that the purified IgG from patients' serum inhibited the factor VIIIa-dependent activation of factor X. Moreover, patients' IgG directed against the Gla domain inhibited the binding of factor IX to phospholipids as well as the binding of factor VIII light chain to factor IXa. These data demonstrate that inhibitors appearing in patients with severe hemophilia B display specificity against restricted functional domains of factor IX. |
| Databáze: | OpenAIRE |
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