Alloimmunization to Platelet antigen HPA-1a (PIA1) is strongly associated with both HLA-DRB3∗0101 and HLA-DQB1∗0201

doi:10.1016/0198-8859(92)90036-M

Human Immunology

Volume 34, Issue 2, June 1992, Pages 107-114

https://doi.org/10.1016/0198-8859(92)90036-M Get rights and content

Abstract

Antibodies to the platelet HPA-1a antigen can elicit in the newborn a condition known as neonatal alloimmune thrombocytopenic purpura (NAITP). Previous studies based on RFLP analysis showed that 100% of HPA-1a-negative women who produced anti-HPA-1a antibodies (responders) were HLA-DRw52a (DRB3^∗0101). However, this specificity could also be found in some HPA-1a-negative women not producing anti-HPA-1a antibodies (nonresponders). We have analyzed in detail by PCR-SSOP the HLA-DR, -DQ, and -DP loci of 36 responders and 10 nonresponders. We found that while the allele DRB3^∗0101 was present in the vast majority of responders (91%), there were exceptions. Furthermore, the DQB1^∗0201 allele was found to be present in almost all responders (94%), but again was also found in nonresponders. The risk of alloimmunization to HPA-1a in an HPA-1b homozygous mother significantly increases with the presence of either allele, the odds ratio being 39.7 for DQB1^∗0201 and 24.9 for DRB3^∗0101. Sequencing of exon 2 of these two alleles from responders indicated no sequence difference when compared with the consensus sequences. This indicates that they do not represent variants when compared with the same alleles found in some nonresponders.

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Preclinical evaluation of immunotherapeutic regimens for fetal/neonatal alloimmune thrombocytopenia
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Citation Excerpt :
Whether milk-derived anti-HPA-1a alloantibodies are able to mediate persistent postnatal thrombocytopenia in this animal model of FNAIT is an important, and perhaps clinically relevant, area for future investigation. The development of an immune response to HPA-1a is one of the most MHC-restricted examples of alloimmunity in humans4,45-49; >92% of HPA-1b/b mothers who develop anti-HPA-1a antibodies express at least 1 HLA DRB3*01:01 class II allele. It is worth noting that BALB/c mice (H-2 I-Ad, I-Ed) dependably developed a robust response to the APLDQ humanized form of murine GPIIIa (Figure 2), but C57BL/6 mice (H-2 I-Ab, I-Enull) barely responded at all (not shown).
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies directed against paternally inherited antigens present on the surface of fetal platelets. The human platelet alloantigen HPA-1a (formerly known as the Pl^A1 alloantigen), is the most frequently implicated HPA for causing FNAIT in Whites. A single Leu33Pro amino acid polymorphism residing within the ∼50-amino-acid plexin-semaphorin-integrin domain near the N-terminus of the integrin β3 subunit (platelet membrane glycoprotein IIIa [GPIIIa]) is responsible for generating the HPA-1a and HPA-1b epitopes in human GPIIIa and serves as the central target for alloantibody-mediated platelet destruction. To simulate the etiology of human FNAIT, wild-type female mice were pre-immunized with platelets derived from transgenic mice engineered to express the human HPA-1a epitope on a murine GPIIIa backbone. These mice developed a strong alloimmune response specific for HPA-1a, and when bred with HPA-1a⁺ males, gave birth to severely thrombocytopenic pups that exhibited an accompanying bleeding phenotype. Administering either polyclonal intravenous immunoglobulin G or a human monoclonal blocking antibody specific for the HPA-1a epitope into pregnant female mice resulted in significant elevation of the neonatal platelet count, normalized hemostasis, and prevented bleeding. The establishment of an alloantigen-specific murine model that recapitulates many of the clinically important features of FNAIT should pave the way for the preclinical development and testing of novel therapeutic and prophylactic modalities to treat or prevent FNAIT in humans.
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Human platelet antibody (HPA) detection is necessary for the diagnosis and therapeutic decisions for refractoriness to platelet transfusions, post transfusion purpura and fetal and neonatal alloimmune thrombocytopenia. In the last four to five decades many new developments, both in knowledge and methods, have increased the quality of platelet serology. However, the quest for the optimal antibody detection method(s) encountered, sometimes unexpected, difficulties. In this review the various aspects concerning platelet antibody test methods and detection of platelet antibodies both for the diagnostic and screening setting are discussed.
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2020, Immunologic Concepts in Transfusion Medicine
Fetal and neonatal cytopenias are a heterogeneous group of disorders with unique and sometimes multifaceted origins. In some cases, abnormalities of fetal hematopoiesis may be the cause; whereas, in others, placental or maternal factors may contribute to the underlying pathology. Immune-mediated cytopenias have been described in the fetus and/or neonate for red blood cells, platelets, and neutrophils. This chapter will focus on those entities attributed to a fetal–maternal incompatibility for platelets (FNAIT) and neutrophils (NAIN).
Alloantibodies and Platelets
2020, Immunologic Concepts in Transfusion Medicine
Platelets are a vital part of the hemostatic system, providing the physical basis of primary hemostasis and the surface for formation of the secondary hemostatic fibrin clot, in addition to important roles in inflammatory and immune signaling and response. Platelets express antigens from several important antigen systems: blood group ABO, human leukocyte antigen (HLA), and human platelet antigen (HPA). Antibodies to all of these systems can cause immune clearance of incompatible platelets. We discuss the various alloimmune thrombocytopenia syndromes: posttransfusion purpura, passive alloimmune thrombocytopenia, fetal/neonatal alloimmune thrombocytopenia, transplantation-associated alloimmune thrombocytopenia, and alloimmune platelet transfusion refractoriness. Platelet transfusion refractoriness is the most commonly encountered alloimmune thrombocytopenia condition, with the others being less common (though likely underrecognized). Antibodies to all three antigen systems (ABO, HLA, and HPA) are associated with immune platelet transfusion refractoriness, with HLA generally being the most important. In contrast, fetal/neonatal alloimmune thrombocytopenia, posttransfusion purpura (PTP), passive alloimmune thrombocytopenia, and transplantation-associated alloimmune thrombocytopenia are all caused by antibodies to the HPA system. PTP is unique among the alloimmune thrombocytopenia syndromes in its combined immune attack against allogeneic platelets and autologous platelets.
Foetal and neonatal alloimmune thrombocytopenia
2019, Best Practice and Research: Clinical Obstetrics and Gynaecology
Foetal or neonatal thrombocytopenia results from alloimmunisation during pregnancy. Maternal alloantibodies can be formed following exposure to paternally derived human platelet antigens (HPAs) on foetal platelets, in case of incompatible HPA type. These alloantibodies are of the immunoglobulin G subclass and can therefore enter the foetal circulation through active placental transport mediated by the neonatal Fc-receptor. After entering the foetal circulation, these alloantibodies can cause destruction of foetal platelets and potentially damage other foetal cells containing the specific antigen. Subsequent clinical presentation in foetuses or neonates can vary widely, from an asymptomatic thrombocytopenia to a broad spectrum of bleeding complications. Most frequently encountered are minor skin haemorrhages, such as hematomas or petechiae, but also more devastating haemorrhages can occur. Of these, an intracranial haemorrhage is the most feared complication because of its high risk of life-long major neurological handicaps or perinatal death.
HLA-DRB3*01:01 exhibits a dose-dependent impact on HPA-1a antibody levels in HPA-1a–immunized women
2019, Blood Advances
HLA-DRB3*01:01 is a predisposing factor for human platelet antigen 1a (HPA-1a) immunization, which is responsible for most cases of fetal and neonatal alloimmune thrombocytopenia. The aim of this study was to investigate if the HLA-DRB3*01:01 allele imposes a dose-dependent effect on anti-HPA-1a levels and neonatal platelet counts. One hundred and thirty HPA-1a–immunized women were divided into 3 groups: HLA-DRB3*01:01 negative, HLA-DRB3*01:01 hemizygous or heterozygous, and HLA-DRB3*01:01 homozygous. The dose of the HLA-DRB3*01:01 allele was determined by sequencing exon 2 of the HLA-DRB3 gene followed by HLA-DRB3 and HLA-DRB1 typing of selected samples. Anti-HPA-1a levels at time of delivery and neonatal platelet counts were compared among groups. There was a significant dose-dependent effect of the HLA-DRB3*01:01 allele on anti-HPA-1a levels (global P value [P_global] = .0032). Median (range) anti-HPA-1a levels were 1.5 IU/mL (0.0-19.0 IU/mL), 21.1 IU/mL (0.0-1967 IU/mL), and 43.7 IU/mL (1.0-980 IU/mL) in women with 0, 1, and 2 copies of the HLA-DRB3*01:01 allele, respectively. There was also a significant, but opposite, dose-dependent effect of the mother's HLA-DRB3*01:01 allele on the platelet count of the newborn (P_global = .0155). Median (range) neonatal platelet counts were 241 × 10⁹/L (59 × 10⁹/L to 393 × 10⁹/L), 107 × 10⁹/L (4 × 10⁹/L to 387 × 10⁹/L) and 32 × 10⁹/L (4 × 10⁹/L to 352 × 10⁹/L) for newborns of mothers with 0, 1, and 2 copies of the HLA-DRB3*01:01 allele, respectively. Thus, the HLA-DRB3*01:01 allele exhibits a dose-dependent impact on maternal anti-HPA-1a levels in HPA-1a–immunized women.

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Alloimmunization to Platelet antigen HPA-1a (PIA1) is strongly associated with both HLA-DRB3∗0101 and HLA-DQB1∗0201

Abstract

Blood Rev

Mol Immunol

Human Immunol

Hum Immunol

Blood

Hum Immunol

Hum Immunol

Immunol Today

Hum Immunol

Hum Immunol

Platelet antigens

Plasma Ther Transfus Technol

An immune response gene linked to HLA in man

Tissue Antigens

Immunogenicity of and immune response to human platelet antigen Zwa is strongly associated with HLA-B8 and DR3

Tissue Antigens

Is HLA-DR3 a risk factor in PIA1 negative women?

The immune response to the HPa-1a antigen: association with HLA-DR152a

Transfus Med

Alloimmunization to the PIA1 antigen: results of a prospective study

Br J Haematol

Alloimmunization to Platelet antigen HPA-1a (PI^A1) is strongly associated with both HLA-DRB3^∗0101 and HLA-DQB1^∗0201

Immunogenicity of and immune response to human platelet antigen Zw^a is strongly associated with HLA-B8 and DR3

Is HLA-DR3 a risk factor in PI^A1 negative women?

Alloimmunization to the PI^A1 antigen: results of a prospective study