Abstract
Alloimmunization against human platelet antigen (HPA)-1a during pregnancy can cause foetal/neonatal alloimmune thrombocytopenia (FNAIT) and severe bleeding in the foetus or newborn and likely depends on several factors. HPA-1a alloimmunization is associated with DRB3*01:01, which is associated with several DR-DQ haplotypes. However, it is not known to what extent these haplotypes contribute to the prevalence of HPA-1a alloimmunization. HPA-1a-alloimmunized women, identified in a prospective study, and random donors were typed for selected DRB3, DRB4, DRB1, DQA1 and DQB1 alleles to determine allele and DR-DQ haplotype frequencies. DRB3*01:01 was carried by 94% HPA-1a-immunized women compared to 27% in the general population. In the first population, the DR3-DQ2 haplotype was overrepresented (P<.003). The prevalence of HPA-1a alloimmunization was estimated to be about twice as frequent with DR3-DQ2 compared to DR13-DQ6, together accounting for about 90% of DRB3*01:01-positive individuals. Further, we examined DQB1*02 and DRB4*01:01 alleles for their reported association with HPA-1a alloimmunization, in the context of DR-DQ haplotypes. Since~80% of DQB1*02 alleles are linked to the DR3-DQ2 haplotype, the association might be coincidental. However, the DQB1*02:02-associated DR7-DQ2 haplotype was also overrepresented in alloimmunized women, suggesting a role for this allele or haplotype in HPA-1a alloimmunization. As DRB4*01:01 is predominantly associated with the DR7-DQ2 haplotype in HPA-1a-alloimmunized individuals, the reported association with FNAIT may be coincidental. Typing for DR-DQ haplotypes revealed important genetic associations with HPA-1a alloimmunization not evident from typing individual alleles, and the presence of different DRB3-associated DR-DQ haplotypes showed different prevalence of HPA-1a alloimmunization.
Highlights
foetal/neonatal alloimmune thrombocytopenia (FNAIT) is a rare condition that can cause severe complications such as intracranial haemorrhage in the foetus or newborn due to the transfer of platelet-depleting alloantibodies from the mother to the foetus during pregnancy
The MHC class II allele HLA-DRB3*01:01 is strongly associated with human platelet antigen (HPA)-1a alloimmunization; more than 90% of immunized women carry this MHC allele,[4,5,6] which shows a dose-dependent association to the severity of HPA-1a immunization.[7]. This strong genetic association suggests that HPA-1a immunization is dependent on T cells restricted by the MHC class II molecule encoded by the HLA-DRA/DRB3*01:01 alleles
We aimed to examine the impact of DRB3*01:01–associated DR-DQ haplotypes on HPA-1a alloimmunization, and to determine the haplotype associations and relative importance in HPA-1a alloimmunization for HLA-DQB1*02:01/*02:02 and HLA-DRB4*01:01 alleles
Summary
FNAIT is a rare condition that can cause severe complications such as intracranial haemorrhage in the foetus or newborn due to the transfer of platelet-depleting alloantibodies from the mother to the foetus during pregnancy. There is support for this notion: HPA-1a– but not HPA-1b–derived peptides bind this molecule, and the allogeneic residue Leu[33] serves to anchor the peptide.[8,9] HPA-1a–specific CD4+ T cell clones have been isolated from alloimmunized women,[10,11,12] and these T cell clones are restricted by DRA/DRB3*01:01.10 it is possible that there exist additional genetic factors that predispose for immunization. In that respect, both DQB1*02 and DRB4*01 have been shown to be associated with FNAIT.1314. The DRB3*01:01 allele is known to be in linkage disequilibrium with several different DR-DQ haplotypes, and one of these contains a DQB1*02 allele.[15,16]
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