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Prepublished online as a Blood First Edition Paper on September 19, 2002; DOI 10.1182/blood-2002-07-2336.
Submitted July 31, 2002
Accepted September 12, 2002
A site involving the "hybrid" and PSI homology domains of GPIIIa (ß3 integrin subunit) is a common target for antibodies associated with quinine-induced immune thrombocytopenia
Julie A Peterson*, Contessa E Nyree, Peter J Newman, and Richard H Aster
The Blood Researc Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA
The Blood Researc Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA; Department of Cellular Biology, The Medical College of Wisconsin, Milwaukee, WI, USA; Department of Pharmacology, The Medical College of Wisconsin, Milwaukee, WI, USA
The Blood Researc Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA; Department of Medicine, The Medical College of Wisconsin, Milwaukee, WI, USA; Department of Pathology, The Medical College of Wisconsin, Milwaukee, WI, USA
* Corresponding author; email: japeterson{at}bcsew.edu.
Drug-dependent antibodies (DDAbs) can cause precipitous destruction of platelets when a patient is exposed to the drug for which they are specific. The molecular character of the epitopes recognized is poorly understood and the mechanism by which drugs promote tight binding of these antibodies to platelet glycoproteins without linking covalently to protein or antibody is not yet known. We studied a family of quinine-dependent antibodies that reacts with human glycoprotein IIIa (ß3 integrin subunit) but fails to recognize rat GPIIIa, despite close homology between the two proteins. By characterizing reactions of these antibodies with human/rat GPIIIa chimeras and selected GPIIIa mutants, we found that each of three quinine-dependent antibodies requires a 17 amino acid sequence in the newly recognized "hybrid" and PSI homology domains of GPIIIa for drug-dependent binding. Disulfide bonds are required to stabilize the target epitope. Monoclonal antibody AP3, which blocks binding of these DDAbs to GPIIIa, was found to require a more limited stretch of the same peptide for its reaction with the glycoprotein. The findings suggest this region of GPIIIa may be a favored target for quinine-dependent antibodies and provide a basis for further studies to elucidate the molecular basis of glycoprotein-drug-antibody interaction.
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