Compound heterozygosity of HLA-DRB3*01:01 and HLA-DRB4*01:01 as a potential predictor of fetal neonatal alloimmune thrombocytopenia.
BACKGROUND
Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder in the fetus or neonate caused by maternal alloantibodies directed against fetal platelet (PLT) antigens inherited from the father. The immune-dominant antigen leading to severe FNAIT is the human PLT antigen (HPA)-1, whose polymorphism constitutes an epitope for human leukocyte antigens (HLAs), usually DRB3*0101 leading to an immune response.


METHODS
In this study our aims were to find whether other allele variants of the β subunit of the HLA-DR family specifically focused on the HLA residues that bind Position 33 of the HPA-1 integrin contribute to FNAIT development and affect response to treatment and whether coexistence of both anti-HPA-1a and anti-HLA class I specific against the father's antigens leads to a more severe thrombocytopenia in the newborn. We examine the genotype of 23 mothers to newborns with FNAIT compared to a control group.


RESULTS
Our results suggested that, when HPA-1 incompatibility with the husband is found, the presence of two HLA alleles (DRB3*01:01 and DRB4*01:01) in the mother increases the risk and severity of FNAIT and reduces the success of a preventive immunoglobulin G treatment. We provide a structural model for the molecular basis of the rational effects of the different HLA alleles. In addition, we found that the presence of both anti-HPA-1 and anti-HLAs did not aggravate FNAIT in comparison to mothers harboring only anti-HPA-1.


CONCLUSIONS
Overall, we suggest that a specific genotyping of the mother in relation to HLA-DRB as well as HPA-1 can serve as an antenatal diagnostic tool, particularly in siblings of women who gave birth to neonates with FNAIT.
Tissue Typing Laboratory, the Fetal Medicine Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Israel.
Ron
R
Loewenthal
Nurit
N
Rosenberg
Rivka
R
Kalt
Rima
R
Dardik
Meytal
M
Landau
Vered
V
Yahalom
Ofelia
O
Avishai
Orit
O
Frenkel
Ephraim
E
Gazit
David M
DM
Steinberg
Shlomo
S
Lipitz
Ophira
O
Salomon
D016022:Case-Control Studies; D005260:Female; D005315:Fetal Diseases / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D059826:HLA-DRB3 Chains / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008958:Models, Molecular; D010375:Pedigree; D011247:Pregnancy; D011379:Prognosis; D020836:Protein Structure, Quaternary; D054098:Thrombocytopenia, Neonatal Alloimmune / Q000175:diagnosis* / Q000235:genetics*
D059811:HLA-DRB1 Chains; D059826:HLA-DRB3 Chains; C487016:HLA-DRB4*01:01 antigen