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2-Glycoprotein I to Determine Fine Antigenic Specificity of Antiphospholipid Autoantibodies1
* La Jolla Pharmaceutical Co., San Diego, CA 92121;
Departments of Medicine and Immunology and Infectious Disease, St. George Hospital, University of New South Wales, Sydney, Australia; and
Laboratory of Molecular Biophysics, Rockefeller University, New York, NY 10012
Autoantibodies against 
2-glycoprotein I
(2GPI) appear to be a critical feature of the
antiphospholipid syndrome (APS). As determined using domain deletion
mutants, human autoantibodies bind to the first of five domains present
in 2GPI. In this study the fine detail of the domain I
epitope has been examined using 10 selected mutants of whole
2GPI containing single point mutations in the first
domain. The binding to 2GPI was significantly affected
by a number of single point mutations in domain I, particularly by
mutations in the region of aa 40–43. Molecular modeling predicted
these mutations to affect the surface shape and electrostatic charge of
a facet of domain I. Mutation K19E also had an effect, albeit one less
severe and involving fewer patients. Similar results were obtained in
two different laboratories using affinity-purified
anti-2GPI in a competitive inhibition ELISA and with
whole serum in a direct binding ELISA. This study confirms that
anti-2GPI autoantibodies bind to domain I, and that
the charged surface patch defined by residues 40–43 contributes to a
dominant target epitope.
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