Functional mapping of anti-factor IX inhibitors developed in patients with severe hemophilia B.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Christophe OD,Lenting PJ,Cherel G,Boon-Spijker M,Lavergne JM,Boertjes R,Briquel ME,de Goede-Bolder A,Goudemand J,Gaillard S,d'Oiron R,Meyer D,Mertens K

doi

10.1182/blood.v98.5.1416

subject

Has Abstract

pub_date

2001-09-01 00:00:00

pages

1416-23

issue

5

eissn

0006-4971

issn

1528-0020

journal_volume

98

pub_type

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