Use of Single Point Mutations in Domain I of β2-Glycoprotein I to Determine Fine Antigenic Specificity of Antiphospholipid Autoantibodies
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- G. Michael Iverson
- *La Jolla Pharmaceutical Co., San Diego, CA 92121;
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- Stephen Reddel
- †Departments of Medicine and Immunology and Infectious Disease, St. George Hospital, University of New South Wales, Sydney, Australia; and
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- Edward J. Victoria
- *La Jolla Pharmaceutical Co., San Diego, CA 92121;
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- Keith A. Cockerill
- *La Jolla Pharmaceutical Co., San Diego, CA 92121;
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- Ying-Xia Wang
- †Departments of Medicine and Immunology and Infectious Disease, St. George Hospital, University of New South Wales, Sydney, Australia; and
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- Marc A. Marti-Renom
- ‡Laboratory of Molecular Biophysics, Rockefeller University, New York, NY 10012
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- Andrej Sali
- ‡Laboratory of Molecular Biophysics, Rockefeller University, New York, NY 10012
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- David M. Marquis
- *La Jolla Pharmaceutical Co., San Diego, CA 92121;
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- Steven A. Krilis
- †Departments of Medicine and Immunology and Infectious Disease, St. George Hospital, University of New South Wales, Sydney, Australia; and
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- Matthew D. Linnik
- *La Jolla Pharmaceutical Co., San Diego, CA 92121;
抄録
<jats:title>Abstract</jats:title><jats:p>Autoantibodies against β2-glycoprotein I (β2GPI) 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 β2GPI. In this study the fine detail of the domain I epitope has been examined using 10 selected mutants of whole β2GPI containing single point mutations in the first domain. The binding to β2GPI 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-β2GPI in a competitive inhibition ELISA and with whole serum in a direct binding ELISA. This study confirms that anti-β2GPI autoantibodies bind to domain I, and that the charged surface patch defined by residues 40–43 contributes to a dominant target epitope.</jats:p>
収録刊行物
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- The Journal of Immunology
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The Journal of Immunology 169 (12), 7097-7103, 2002-12-15
The American Association of Immunologists