Faculty Collaboration Database

High-resolution mapping of the polyclonal immune response to the human platelet alloantigen HPA-1a (Pl^A1). Blood Adv 2018 Nov 13;2(21):3001-3011

Date

11/11/2018

Pubmed ID

30413435

Pubmed Central ID

PMC6234362

DOI

10.1182/bloodadvances.2018023341

Scopus ID

2-s2.0-85067320916 (requires institutional sign-in at Scopus site)   19 Citations

Abstract

Antibodies to platelet-specific antigens are responsible for 2 clinically important bleeding disorders: posttransfusion purpura and fetal/neonatal alloimmune thrombocytopenia (FNAIT). The human platelet-specific alloantigen 1a/1b (HPA-1a/1b; also known as Pl^A1/A2) alloantigen system of human platelet membrane glycoprotein (GP) IIIa is controlled by a Leu33Pro polymorphism and is responsible for ∼80% of the cases of FNAIT. Local residues surrounding polymorphic residue 33 are suspected to have a profound effect on alloantibody binding and subsequent downstream effector events. To define the molecular requirements for HPA-1a alloantibody binding, we generated transgenic mice that expressed murine GPIIIa (muGPIIIa) isoforms harboring select humanized residues within the plexin-semaphorin-integrin (PSI) and epidermal growth factor 1 (EGF1) domains and examined their ability to support the binding of a series of monoclonal and polyclonal HPA-1a-specific antibodies. Humanizing the PSI domain of muGPIIIa was sufficient to recreate the HPA-1a epitope recognized by some HPA-1a-specific antibodies; however, humanizing distinct amino acids within the linearly distant but conformationally close EGF1 domain was required to enable binding of others. These results reveal the previously unsuspected complex heterogeneity of the polyclonal alloimmune response to this clinically important human platelet alloantigen system. High-resolution mapping of this alloimmune response may improve diagnosis of FNAIT and should facilitate the rational design and selection of contemplated prophylactic and therapeutic anti-HPA-1a reagents.

Author List

Zhi H, Ahlen MT, Thinn AMM, Weiler H, Curtis BR, Skogen B, Zhu J, Newman PJ

Authors

Brian Curtis PhD Director in the Platelet & Neutrophil Immunology Laboratory department at BloodCenter of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Jieqing Zhu PhD Assistant Professor, Associate Investigator in the Biochemistry department at BloodCenter of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Amino Acid Substitution
Animals
Antibodies
Antigen-Antibody Reactions
Antigens, Human Platelet
Epitope Mapping
Humans
Integrin beta3
Mice
Mice, Transgenic
Protein Domains
Protein Isoforms
Protein Structure, Tertiary
Thrombocytopenia, Neonatal Alloimmune