Structural basis of HPA-1a alloimmunization in FNAIT and allosteric regulation of integrin conformation. Blood 2026 May 28;147(22):2569-2581
Date
02/11/2026Pubmed ID
41671508Pubmed Central ID
PMC13389798DOI
10.1182/blood.2025032546Scopus ID
2-s2.0-105035750196 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) can be caused by maternal immunoglobulin G alloantibodies against the human platelet antigen 1a (HPA-1a), a Leu33Pro polymorphism at the plexin-semaphorin-integrin (PSI) domain of the β3 subunit shared by integrins αIIbβ3 and αVβ3. Although serologic detection of anti-HPA-1a alloantibodies has long aided FNAIT diagnosis, the disease remains a major clinical challenge due to unpredictable severe outcomes, particularly intracranial hemorrhage and fetal loss. To define the molecular basis of HPA-1a immunogenicity and antibody pathogenicity, we determined crystal structures of the HPA-1a antigen bound to Fabs from 4 anti-HPA-1a monoclonal antibodies, including 3 clinically relevant maternal alloantibodies (26.4, D-204, and M-204) and 1 murine antibody (SZ21). The structures reveal that all antibodies recognize an HPA-1a epitope centered on Leu33, spanning both PSI and integrin-epidermal growth factor (I-EGF) 1 domains of β3 integrin. Variations in antibody-binding interfaces account for differential affinities to both αIIbβ3 and αVβ3, whereas distinct binding orientations determine whether antibody engagement stabilizes the bent inactive β3 conformation. Functional assays demonstrated antibody-dependent inhibition of αIIbβ3-mediated platelet aggregation, thrombus formation, and clot retraction, as well as αVβ3-mediated endothelial adhesion and spreading. These results establish the structural framework of HPA-1a alloantigenicity, explain the conformational selectivity of anti-HPA-1a antibodies, and elucidate how they block integrin activation. The findings provide mechanistic insight into FNAIT pathogenesis and suggest that antibody heterogeneity in affinity and function may contribute to clinical variability. Furthermore, these findings demonstrate antibody-mediated stabilization of the PSI/I-EGF1 domain as a potential strategy for allosteric modulation of integrin structure and function.
Author List
Zhang H, Paddock C, Oosterhoff JJ, Nguyen HTT, Zhi H, Wang Z, Sheridan D, Stuge TB, Ghevaert C, Newman DK, Vidarsson G, Newman PJ, Zhu JAuthors
Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of WisconsinDebra K. Newman PhD Professor in the Research Office department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Allosteric RegulationAnimals
Antibodies, Monoclonal
Antigens, Human Platelet
Crystallography, X-Ray
Female
Humans
Integrin beta3
Isoantibodies
Mice
Models, Molecular
Protein Conformation
Thrombocytopenia, Neonatal Alloimmune
