4 research outputs found
The prevalence of HPA-1a alloimmunization and the potential risk of FNAIT depend on both the DRB3*01:01 allele and associated DR-DQ haplotypes
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 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
Current perspectives on fetal and neonatal alloimmune thrombocytopenia - Increasing clinical concerns and new treatment opportunities
Differences in platelet type between the fetus and the mother can lead to maternal
immunization and destruction of the fetal platelets, a condition named fetal and neonatal
alloimmune thrombocytopenia (FNAIT). FNAIT is reported to occur in ~1 per 1,000 live born
neonates. The major risk is intracranial hemorrhage in the fetus or newborn, which is associated
with severe neurological complications or death. Since no countries have yet implemented a
screening program to detect pregnancies at risk, the diagnosis is typically established after the
birth of a child with symptoms. Reports on broader clinical impact have increased clinical concern and awareness. Along with new treatment options for FNAIT, the debate around antenatal
screening to detect pregnancies at risk of FNAIT has been revitalized
Storage-induced platelet apoptosis is a potential risk factor for alloimmunization upon platelet transfusion
Platelet transfusion can elicit alloimmune responses leading to alloantibody formation against donor-specific polymorphic residues, ultimately resulting in platelet transfusion refractoriness. Universal leukoreduction significantly reduced the frequency of alloimmunization after platelet transfusion, thereby showing the importance of white blood cells (WBCs) in inducing this alloresponse. It is, however, unknown if the residual risk for alloimmunization is caused by WBCs remaining after leukoreduction or if alloimmunization can be induced by platelets themselves. This study investigated the capacity of platelets to induce alloimmunization and identified potential product-related risk factors for alloimmunization. First, internalization of allogeneic platelets by dendritic cells (DCs) was demonstrated by confocal microscopy. Second, after internalization, presentation of platelet-derived peptides was shown by mass spectrometry analysis of human leukocytes antigen (HLA)-DR eluted peptides. Third, platelet-loaded DCs induced platelet-specific CD4 T cell responses. Altogether, this indicates a platelet-specific ability to induce alloimmunization. Therefore, factors enhancing platelet internalization may be identified as risk factor for alloimmunization by platelet concentrates. To investigate if storage of platelets is such a risk factor, internalization of stored platelets was compared with fresh platelets and showed enhanced internalization of stored platelets. Storage-induced apoptosis and accompanied phosphatidylserine exposure seemed to be instrumental for this. Indeed, DCs pre-incubated with apoptotic platelets induced the strongest IFN-γ production by CD4 T cells compared with pre-incubation with untreated or activated platelets. In conclusion, this study shows the capacity of platelets to induce platelet-specific alloimmune responses. Furthermore, storage-induced apoptosis of platelets is identified as potential risk factor for alloimmunization after platelet transfusions
Anti-human platelet antigen (HPA)-1a antibodies may affect trophoblast functions crucial for placental development: A laboratory study using an in vitro model
Background:
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder caused by maternal
antibodies against paternal human platelet antigens (HPAs) on fetal platelets. Antibodies against HPA-1a are
accountable for the majority of FNAIT cases. We have previously shown that high levels of maternal anti-HPA-1a
antibodies are associated with clinically significant reduced birth weight in newborn boys. Chronic inflammatory
placental lesions are associated with increased risk of reduced birth weight and have previously been reported in
connection with FNAIT pregnancies. The HPA-1a epitope is located on integrin
β
3 that is associated with integrin
α
IIb (the fibrinogen receptor) on platelets and megakaryocytes. Integrin
β
3 is also associated with integrin
α
V
forming the
α
V
β
3 integrin heterodimer, the vitronectin receptor, which is expressed on various cell types, including
trophoblast cells. It is therefore thinkable that maternal anti-HPA-1a antibodies present during early pregnancy may
affect placenta function through binding to the HPA-1a antigen epitope on invasive throphoblasts. The aim of the
study was to examine whether interaction of a human anti-HPA-1a monoclonal antibody (mAb) with HPA-1a on
trophoblast cells affect adhesion, migration and invasion of extravillous trophoblast cells.
Methods:
An in vitro model with human anti-HPA-1a mAb, clone 26.4, and the first trimester extravillous trophoblast
cell line HTR8/SVneo was employed. The xCELLigence system was utilized to assess the possible effect of anti-HPA-1a
mAb on adhesion and migration of HTR8/SVneo cells. Specially designed chambers precoated with Matrigel were used
to assess the effect on the invasive capacity of cells.
Results:
We found that human anti-HPA-1a mAb 26.4 partia
lly inhibits adhesion and migratory capacity of
HTR8/SVneo cells.
Conclusions:
Our findings suggest that anti-HPA-1a antibodies may affect trophoblast functions crucial for normal placental development. Future studies including
primary throphoblast cells and polyclonal anti-HPA-1a
antibodies are needed to confirm these results