Molecular insight into human platelet antigens: structural and evolutionary conservation analyses offer new perspective to immunogenic disorders

Abstract

BACKGROUND:Human platelet antigens (HPAs) are polymorphisms in platelet membrane glycoproteins (GPs) that can stimulate production of alloantibodies once exposed to foreign platelets (PLTs) with different HPAs. These antibodies can cause neonatal alloimmune thrombocytopenia, posttransfusion purpura, and PLT transfusion refractoriness. Most HPAs are localized on the main PLT receptors: 1) integrin αIIbβ3, known as the fibrinogen receptor; 2) the GPIb-IX-V complex that functions as the receptor for von Willebrand factor; and 3) integrin α2β1, which functions as the collagen receptor.STUDY DESIGN AND METHODS:We analyzed the structural location and the evolutionary conservation of the residues associated with the HPAs to characterize the features that induce immunologic responses but do not cause inherited diseases.RESULTS:We found that all HPAs reside in positions located on the protein surface, apart from the ligand-binding site, and are evolutionary variable.CONCLUSION:Disease-causing mutations often reside in highly conserved and buried positions. In contrast, the HPAs affect residues on the protein surface that were not conserved throughout evolution; this explains their naive effect on the protein function. Nonetheless, the HPAs involve substitutions of solvent-exposed positions that lead to altered interfaces on the surface of the protein and might present epitopes foreign to the immune system.

Human Platelet Antigen Alleles in 998 Taiwanese Blood Donors Determined by Sequence-Specific Primer Polymerase Chain Reaction

“…The frequency of HPA-1a/4a/6b on GPIIIa glycoprotein was about 0.023, which is higher than that (0.013) reported in Chinese Han population [23] and similar to that (0.027) in Japanese [24]. It should be kept in mind that allele frequency is only one of the factors involved in the risks of platelet antigen alloimmunization [25]. Indeed, while the likelihood of antigen incompatibility between mother and fetus is high in HPA-3 and HPA-15 systems, considering the high heterozygosity rate, they may actually be less likely to cause FNAIT compared to other systems.…”

“…Indeed, while the likelihood of antigen incompatibility between mother and fetus is high in HPA-3 and HPA-15 systems, considering the high heterozygosity rate, they may actually be less likely to cause FNAIT compared to other systems. We found that 0.5% of individuals are HPA-4b positive (compared to 0% in Caucasians) and 3.01% are HPA-5b positive; the potential for HPA-4b and HPA-5b to induce alloimmunization cannot be ignored since these alleles are known to be immunogenic [20, 25]. They may therefore be responsible for more FNAIT cases than HPA-3a or HPA-15b.…”

Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody‐mediated immune suppression and prevention of severe clinical complications in a murine model

“…A variety of HPA alloantigens are known to be implicated in FNAIT 18‐20 . Eleven (HPA‐1a/b, ‐4a/b, ‐6w, ‐7w, ‐8w, ‐10w, ‐11w, ‐14w, and ‐16w) of the HPAs are located throughout the extracellular part of the β3 integrin subunit (GPIIIa) on the most abundant PLT receptor, αIIbβ3 (GPIIbIIIa) 21 . The HPA‐1 antigen epitope consists of a polymorphism of Residue 33 on the β3 subunit.…”

Genetic polymorphisms of human platelet antigens in the Asian population: implications in the establishment of platelet donor registries

“…Two families of glycoproteins are particularly important with regard to HPA polymorphisms. The first being integrins which are the most abundant platelet membrane glycoprotein . Integrins are characterized as heterodimeric molecules that interact with ligands and mediate cell–cell and cell–adhesive protein interactions.…”

“…Among these surface molecules are the platelet membrane glycoproteins. Apart from their functional importance, these molecules may also confer immunogenicity due to subtle conformational changes induced by single amino acid changes in their sequence without significant alteration of functional response, resulting in the development of antibodies in certain homozygous individuals exposed to the antithetical antigen . The human platelet antigens (HPA) are immunogenic polymorphic forms of some of these platelet membrane glycoproteins, characterized by virtue of antibodies found in allo‐immunized individuals .…”