Drug-induced
immune thrombocytopenia is caused by
drug-dependent
antibodies (DDAbs) that bind tightly to
platelet glycoproteins only when
drug is present. How drugs mediate this interaction is not yet resolved. Several studies indicate that sites recognized by DDAbs tend to cluster in specific structural domains, suggesting they may recognize a limited number of distinct
epitopes. To address this issue, we characterized the binding sites for 16
quinine-dependent
antibodies thought on the basis of preliminary studies to be possibly specific for a single
epitope on
glycoprotein IIIa (
GPIIIa). Fourteen of the
antibodies reacted with a 29-kDa
GPIIIa fragment comprising only the
GPIIIa hybrid and plextrin-
semaphorin-
integrin homology domains. However, studies with mutant
GPIIIa and the blocking
monoclonal antibody AP3 showed that the 14 DDAbs recognize at least 6 and possibly more distinct, but overlapping, structures involving
GPIIIa residues 50 to 66. The findings suggest that even
antibodies specific for restricted domains on a target
glycoprotein may each have a slightly different fine specificity; ie, "unique"
epitopes recognized by DDAbs may be rare or nonexistent. The observations are consistent with a recently proposed model in which
drug reacts noncovalently with both target
protein and antibody to promote binding of an otherwise nonreactive
immunoglobulin.