Faculty Collaboration Database

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 01;101(3):937-42

Date

10/24/2002

Pubmed ID

12393510

DOI

10.1182/blood-2002-07-2336

Scopus ID

2-s2.0-0037307118 (requires institutional sign-in at Scopus site)   26 Citations

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.

Author List

Peterson JA, Nyree CE, Newman PJ, Aster RH

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Antibodies
Antibody Affinity
Epitopes
Humans
Integrin beta3
Molecular Sequence Data
Mutation
Quinine
Rats
Recombinant Fusion Proteins
Sequence Homology, Amino Acid
Species Specificity
Thrombocytopenia