Catalytic IgG from Patients with Hemophilia A Inactivate Therapeutic Factor VIII

Lacroix-Desmazes, Sebastien and Bharath, Wootla and Dasgupta, Suryasarathi and Sandrine, Delignat and Bayry, Jagadeesh and Reinbolt, Joseph and Hoebeke, Johan and Saenko, Evgueni and Kazatchkine, Michel D and Alain, Friboulet and Christophe, Olivier and Nagaraja, Valakunja and Kaveri, Srini V (2006) Catalytic IgG from Patients with Hemophilia A Inactivate Therapeutic Factor VIII. In: Journal Of Immunology, 177 (2). pp. 1355-1363.

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Abstract

Factor VIII (FVIII) inhibitors are anti-FVIII IgG that arise in up to 50% of the patients with hemophilia A, upon therapeutic administration of exogenous FVIII. Factor VIII inhibitors neutralize the activity of the administered FVIII by sterically hindering its interaction with molecules of the coagulation cascade, or by forming immune complexes with FVIII and accelerating its clearance from the circulation. We have shown previously that a subset of anti-factor VIII IgG hydrolyzes FVIII. FVIII-hydrolyzing IgG are detected in over 50% of inhibitor-positive patients with severe hemophilia A, and are not found in inhibitor-negative patients. Although human proficient catalytic Abs have been described in a number of inflammatory and autoimmune disorders, their pathological relevance remains elusive. We demonstrate here that the kinetics of FVIII degradation by FVIII-hydrolyzing IgG are compatible with a pathogenic role for IgG catalysts. We also report that FVIII-hydrolyzing IgG from each patient exhibit multiple cleavage sites on FVIII and that, while the specificity of cleavage varies from one patient to another, catalytic IgG preferentially hydrolyze peptide bonds containing basic amino acids.

Item Type:	Journal Article
Publication:	Journal Of Immunology
Publisher:	American Association Of Immunologists
Additional Information:	Copyright of this article belongs to American Association Of Immunologists.
Keywords:	Immunology;Antibody Light-Chain; Activated Protein-C; Procoagulant Activity; Factor-Ixa; Factor Xa; Vonwillebrand-Factor; Monoclonal-Antibody; Heavy-Chain; Inhibitor; Thrombin
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	10 Dec 2008 13:00
Last Modified:	19 Sep 2010 04:54
URI:	http://eprints.iisc.ac.in/id/eprint/16948

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