O-linked sialic acid residues on platelet membrane glycoprotein IIb mask the human HPA-9b alloepitope.

Autor:	Zhang N; Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI., Sullivan MJ; Platelet and Neutrophil Immunology Laboratory, Versiti Blood Center of Wisconsin, Milwaukee, WI., Curtis BR; Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI.; Platelet and Neutrophil Immunology Laboratory, Versiti Blood Center of Wisconsin, Milwaukee, WI., Newman PJ; Blood Research Institute, Versiti Blood Center of Wisconsin, Milwaukee, WI.; Department of Pharmacology, Medical College of Wisconsin, Milwaukee, WI.; Department of Cell Biology, Medical College of Wisconsin, Milwaukee, WI.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Nov 30; Vol. 142 (22), pp. 1909-1917.
DOI:	10.1182/blood.2023021122
Abstrakt:	Sialic acids occupy the terminal position of glycan chains and have the potential to influence the antigenicity of glycoproteins (GP). The polymorphisms of human platelet alloantigens (HPA)-3 and HPA-9, located near the C-terminus of the extracellular domain of platelet membrane GPIIb, are adjacent to sialyl-core 1 O-glycans emanating from serines 845 and 847. Whether the nearby O-glycans affect the antigenicity of HPA-9b or influence the binding of anti-HPA-9b alloantibodies in clinically significant cases of neonatal alloimmune thrombocytopenia is unknown. To address this issue, we generated a series of O-glycan mutant HPA-9 allele-specific induced pluripotent stem cell lines, differentiated them to megakaryocytes (MKs), and examined their ability to bind HPA-9b-specific alloantibodies. We found that both wild-type MKs treated with neuraminidase and those genetically modified to lack the sialidases ST3GAL1 and ST3GAL2 dramatically increased anti-HPA-9b alloantibody binding, indicating that the HPA-9b epitope is partially masked by terminal sialic acids on nearby O-glycans of GPIIb. Interestingly, mutating the serine residues that carry these glycan chains to alanine actually reduced the binding of anti-HPA-9b alloantibodies, indicating that these 2 O-glycan chains contribute to the presentation of the HPA-9b epitope-perhaps by stabilizing the conformation of the GP in this region. Collectively, our data suggest that detection of anti-HPA-9b alloantibodies may be enhanced through the use of HPA-9b-specific MKs that have been genetically altered to lack nearby terminal sialic acid residues but retain the glycan chains to which they are attached. (© 2023 by The American Society of Hematology.)
Databáze:	MEDLINE
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