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Involvement of the cysteine-rich domain of glycoprotein IIIa in the
expression of the human platelet alloantigen, PlA1: evidence for
heterogeneity in the humoral response
N Valentin, GP Visentin and PJ Newman
Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee
53201, USA.
To assess the potential contribution of the cysteine-rich domain of human
platelet glycoprotein (GP) IIIa to the structure of the PlA1 epitope, we
used site-directed mutagenesis to substitute alanines for cysteines at key
positions potentially involved in PlA1 alloantigen formation. One of these
GPIIIa isoforms in which alanine replaced Cys435 reacted normally with a
series of well-characterized murine MoAbs directed against the 250
amino-terminal residues of GPIIIa, whereas binding of MoAbs specific for
residues 348-692 was diminished or lost. Interestingly, of eight
PlA1-specific antibodies tested, two recognized Ala435GPIIIa, two did not,
and four bound to it less well than to wild-type (WT) GPIIIa. However,
disruption of disulfide bonds located at or near the N-terminus of GPIIIa
abolished the binding of all the anti-PlA1 alloantibodies tested. These
findings provide evidence that the humoral response to the PlA1 antigen is
(1) heterogenous, ie, the binding site on GPIIIa for human anti-PlA1
antibodies differs from one individual to another and (2) complex--
although some anti-PlA1 alloantibodies bind to an epitope comprised solely
of the amino-terminus of GPIIIa, others combine most efficiently with a
more complex determinant that involves the cysteine-rich domain of GPIIIa.
These findings may have implications for diagnostic and therapeutic use of
synthetic or recombinant PlA1 mimetics.
Volume 85,
Issue 11,
pp. 3028-3033,
06/01/1995
Copyright © 1995 by The American Society of Hematology
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