FURTHER CHARACTERIZATION OF THE THROMBASTHENIA-RELATED IDIOTYPE OG - ANTIIDIOTYPE DEFINES A NOVEL EPITOPE(S) SHARED BY FIBRINOGEN B-BETA CHAIN, VITRONECTIN, AND VON-WILLEBRAND-FACTOR AND REQUIRED FOR BINDING TO BETA(3)

A patient (OG) with Glanzmann thrombasthenia became refractory to plat elet transfusion after the production of an immunoglobulin G (IgG) iso antibody (Ab1) specific for the integrin subunit beta(3). To determine the frequency at which the OG idiotype is found in the general popula tion and in immune-mediated disease states, we developed a rabbit poly clonal antibody (Ab2) specific for affinity-puritied OG anti-beta(3) F ab. The binding of Ab2 to Ab1 is inhibited by purified alpha(IIb)beta( 3). Ab2 also binds to IgG specific for alpha(IIb)beta(3) obtained from one nonrelated Glanzmann thrombasthenia patient ES who has developed isoantibodies of similar specificity. On the other hand, Ab2 does not recognize alpha(IIb)beta(3)-specific antibodies produced by two Glanzm ann thrombasthenia patients, AF and LUC, who have developed isoantibod ies with specificities distinct from that of the OG isoantibody. Moreo ver, Ab2 does not recognize alpha(IIb)beta(3)-specific antibodies deve loped by three representative patients with (autoimmune) thrombocytope nic purpura or six representative patients with alloimmune thrombocyto penias, nor does it bind to IgG from any of 13 nonimmunized individual s. We have found that Ab2 also binds to selected protein ligands of al pha(IIb)beta(3) namely, fibrinogen, vitronectin, and von Willebrand fa ctor, but not to other protein ligands or control proteins, such a fib ronectin, type I collagen, and albumin. The epitope(s) recognized by A b2 on each adhesive protein are either very similar or identical since each protein can inhibit the binding of Ab2 to any of the other prote ins. The epitope on fibrinogen recognized by Ab2 resides in the B beta chain, and is likely contained within the first 43 amino acids from t he NH2 terminus. Since OG IgG inhibits fibrinogen binding to alpha(IIb )beta(3), the specificity of the OG idiotype defines a novel binding m otif for the integrin alpha(IIb)beta(3) that is shared by fibrinogen, vitronectin, and von Willebrand factor, but distinct from previously d escribed RGD-containing sites on the fibrinogen, A alpha chain or the fibrinogen gamma chain COOH-terminal decapeptide site. Our findings re ported here represent an excellent example of molecular mimicry in whi ch an antigen-selected, IgG inhibitor of alpha(IIb)beta(3) function sh ares a novel recognition sequence common to three physiologic protein ligands of that receptor.