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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2828-2834
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Two classes of germline genes both derived from the
VH1 family direct the formation of human antibodies
that recognize distinct antigenic sites in the C2 domain of
factor VIII
Edward N. van den Brink,
Wendy S. Bril,
Ellen A. M. Turenhout,
Marleen Zuurveld,
Niels Bovenschen,
Marjolein Peters,
Thynn Thynn Yee,
Koen Mertens,
Deborah A. Lewis,
Thomas L. Ortel,
Pete Lollar,
Dorothea Scandella, and
Jan Voorberg
From the Department of Plasma Proteins, CLB; Laboratory
for Experimental and Clinical Immunology, Academic Medical Center,
University of Amsterdam; and Department of Pediatrics, Emma Children's
Hospital AMC; all of Amsterdam, The Netherlands; Haemophilia Centre and
Haemostasis Unit, Royal Free Hospital, London, United Kingdom;
Department of Pharmaceutics, Utrecht University for Pharmaceutical
Sciences (UIPS), Utrecht University, The Netherlands;
Departments of Medicine and Pathology, Duke University Medical Center,
Durham, NC; Emory University, Atlanta, GA; and Holland Laboratories,
American Red Cross, Rockville, MD.
Most plasmas from patients with inhibitors contain antibodies that
are reactive with the C2 domain of factor VIII. Previously, we have
shown that the variable heavy chain (VH) regions of
antibodies to the C2 domain are encoded by the closely related germline
gene segments DP-10, DP-14, and DP-88, which all belong to the
VH1 gene family. Here, we report on the isolation and
characterization of additional anti-C2 antibodies that are derived from
VH gene segments DP-88 and DP-5. Competition experiments
using murine monoclonal antibodies CLB-CAg 117 and ESH4 demonstrated
that antibodies derived from DP-5 and DP-88 bound to different sites
within the C2 domain. Epitope mapping studies using a series of factor
VIII/factor V hybrids revealed that residues 2223 to 2332 of factor
VIII are required for binding of the DP-10-, DP-14-, and
DP-88-encoded antibodies. In contrast, binding of the DP-5-encoded
antibodies required residues in both the amino- and
carboxy-terminus of the C2 domain. Inspection of the reactivity of the
antibodies with a series of human/porcine hybrids yielded similar data.
Binding of antibodies derived from germline gene segments DP-10, DP-14, and DP-88 was unaffected by replacement of residues 2181 to 2243 of
human factor VIII for the porcine sequence, whereas binding of the
DP-5-encoded antibodies was abrogated by this replacement. Together
these data indicate that antibodies assembled from VH gene
segments DP-5 and the closely related germline gene segments DP-10,
DP-14, and DP-88 target 2 distinct antigenic sites in the C2 domain of
factor VIII.
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