Recognition of highly restricted regions in the beta -propeller domain of alpha IIb by platelet-associated anti- alpha IIb beta 3 autoantibodies in primary immune thrombocytopenia

Platelet-associated (PA) IgG autoantibodies play an essential role in primary immune thrombocytopenia (ITP). However, little is known about the epitopes of these Abs. This study aimed to identify critical binding regions for PA anti- alpha IIb beta 3 Abs. Because PA anti- alpha IIb beta 3 Abs bound...

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Bibliographic Details
Published in:Blood 2012-08, Vol.120 (7), p.1499-1509
Main Authors: Kiyomizu, Kazunobu, Kashiwagi, Hirokazu, Nakazawa, Tsuyoshi, Tadokoro, Seiji, Honda, Shigenori, Kanakura, Yuzuru, Tomiyama, Yoshiaki
Format: Article
Language:English
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Summary:Platelet-associated (PA) IgG autoantibodies play an essential role in primary immune thrombocytopenia (ITP). However, little is known about the epitopes of these Abs. This study aimed to identify critical binding regions for PA anti- alpha IIb beta 3 Abs. Because PA anti- alpha IIb beta 3 Abs bound poorly to mouse alpha IIb beta 3, we created human-mouse chimera constructs. We first examined 76 platelet eluates obtained from patients with primary ITP. Of these, 26 harbored PA anti- alpha IIb beta 3 Abs (34%). Further analysis of 15 patients who provided sufficient materials showed that the epitopes of these Abs were mainly localized in the N-terminal half of the beta -propeller domain in alpha IIb (L1-W235). We could identify 3 main recognition sites in the region; 2 eluates recognized a conformation formed by the W1:1-2 and W2:3-4 loops, 5 recognized W1:2-3, and 4 recognized W3:4-1. The remaining 4 eluates could not be defined by the binding sites. Within these regions, we identified residues critical for binding, including S29 and R32 in W1:1-2; G44 and P45 in W1:2-3; and P135, E136, and R139 in W2:3-4. Of 11 eluates whose recognition sites were identified, 5 clearly showed restricted Kappa / lambda -chain usage. These results suggested that PA anti- alpha IIb beta 3 Abs in primary ITP tended to recognize highly restricted regions of alpha IIb with clonality.
ISSN:1528-0020
DOI:10.1182/blood-2012-02-409995