title: A site involving the "hybrid" and PSI homology domains of GPIIIa (beta 3-integrin subunit) is a common target for antibodies associated with quinine-induced immune thrombocytopenia.
abstract: Drug-dependent antibodies (DDAbs) can cause the precipitous destruction of platelets if a patient is exposed to the drug for which the antibodies 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 group of quinine-dependent antibodies that react with human glycoprotein IIIa (GPIIIa; beta3-integrin subunit) but fail to recognize rat GPIIIa, despite close homology between the 2 proteins. By characterizing reactions of these antibodies with human/rat GPIIIa chimeras and selected GPIIIa mutants, we found that each of 3 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 the 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 may provide a basis for further studies to elucidate the molecular basis of glycoprotein-drug-antibody interaction.
authors.affiliation: Blood Research Institute, the Blood Center of Southeastern Wisconsin, and the Department of Cellular Biology, Medical College of Wisconsin, Milwaukee 53201-2178, USA. japeterson@bcsew.edu
authors.forename: Julie A
authors.initials: JA
authors.lastname: Peterson
authors.forename: Contessa E
authors.initials: CE
authors.lastname: Nyree
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Newman
authors.forename: Richard H
authors.initials: RH
authors.lastname: Aster
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000915:Antibody Affinity; D000939:Epitopes / Q000235:genetics* / Q000276:immunology; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation; D011803:Quinine / Q000009:adverse effects* / Q000276:immunology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology
chemical_list: D000906:Antibodies; D000939:Epitopes; D039661:Integrin beta3; D011993:Recombinant Fusion Proteins; D011803:Quinine