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

Blood. 2003 Feb 1;101(3):937-42. doi: 10.1182/blood-2002-07-2336. Epub 2002 Sep 19.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies / immunology*
  • Antibody Affinity
  • Epitopes / genetics*
  • Epitopes / immunology
  • Humans
  • Integrin beta3 / genetics
  • Integrin beta3 / immunology*
  • Molecular Sequence Data
  • Mutation
  • Quinine / adverse effects*
  • Quinine / immunology
  • Rats
  • Recombinant Fusion Proteins / immunology
  • Sequence Homology, Amino Acid
  • Species Specificity
  • Thrombocytopenia / chemically induced*
  • Thrombocytopenia / immunology

Substances

  • Antibodies
  • Epitopes
  • Integrin beta3
  • Recombinant Fusion Proteins
  • Quinine