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Localization of epitopes for human factor VIII inhibitor antibodies by
immunoblotting and antibody neutralization
D Scandella, M Mattingly, S de Graaf and CA Fulcher
Jerome H. Holland Laboratory for the Biomedical Sciences, American Red
Cross Blood Services, Rockville, MD.
Human factor VIII(FVIII) inhibitors are pathologic, circulating antibodies
that inactivate FVIII. We have examined the location of epitopes on the
FVIII protein for inhibitors from hemophilia A and nonhemophilic
individuals. The inhibitors were of type I or type II in the kinetics of
their inactivation of FVIII. A cDNA clone of human FVIII was used to
express defined FVIII protein fragments in Escherichia coli for
immunoblotting with inhibitor plasma. An epitope for 18 heavy-chain
inhibitors was localized to the aminoterminal 18.3 Kd of the A2 domain. Two
of these inhibitors also recognized an epitope located between A1 and A2
domains. Similarly, an epitope for 23 light- chain inhibitors was localized
to the C2 domain. Weaker epitopes for 13 of the same inhibitors within the
C1 and C2 domains were also observed. Four of the 23 inhibitors in addition
bound strongly to the A3 domain. Most inhibitors (22 of 23) were
neutralized in vitro only by the FVIII fragments to which they bound on
immunoblots; however, one inhibitor that was neutralized by a fragment
containing the A1 domain did not bind to it on immunoblots. Conversely, 3
of 3 inhibitors that bound to the A3 domain and 5 of 15 that bound to the
A2 domain were not neutralized by the corresponding fragments. The epitope
specificity of an inhibitor did not depend on its source or type. Our
results show that FVIII inhibitors bind to limited areas within the heavy
and light chains of FVIII. Some inhibitor plasmas contain additional
antibodies that may not be inhibitory.
Volume 74,
Issue 5,
pp. 1618-1626,
10/01/1989
Copyright © 1989 by The American Society of Hematology
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