title: High anti-HLA response in women exposed to intrauterine transfusions for severe alloimmune hemolytic disease is associated with mother-child HLA triplet mismatches, high anti-D titer, and new red blood cell antibody formation.
abstract: BACKGROUND
  Women whose fetuses were treated with intrauterine transfusions (IUTs) for alloimmune hemolytic disease are high responders to red blood cell (RBC) antigens. We investigated the risk for HLA alloimmunization.
  
  
  METHODS
  Women and their children treated with IUT between 1987 and 2008 were included. Participants were HLA antigen typed and studied for the prevalence of HLA antibodies compared to age-matched parous nontransfused blood donors. Anti-D titer, the formation of new RBC antibodies after IUT, and the degree of fetomaternal HLA mismatches on HLA antibody formation and/or persistence were analyzed.
  
  
  RESULTS
  A higher prevalence of HLA Class I antibodies was observed in these women compared to controls (41% vs. 23%). Both a higher anti-D titer (>8000) and formation of new RBC antibodies after IUT were associated with increased HLA immunization. HLA antibody formation was associated with the number of fetomaternal triplet epitope mismatches. Antigens within HLA-Bw4, HLA-B35/51/52/53/18/78-complex and A1/A9, were higher and mismatches within HLA-C were less immunogenic than expected. HLA antibodies against the IUT-treated fetus were more persistent than other antibodies.
  
  
  CONCLUSIONS
  Women whose fetuses were treated with IUT had a high risk of developing and maintain fetal-specific HLA Class I antibodies. Factors associated with increased HLA immunization were a higher amount of fetomaternal HLA triplet mismatches, higher anti-D titer, and additional RBC antibody formation. We presume that the induction of HLA Class I antibodies is the result of increased fetomaternal hemorrhage during IUT, eliciting antibodies in women with an increased susceptibility to alloimmunization.
authors.affiliation: Sanquin-LUMC Jon J. van Rood Center for Clinical Transfusion Research and the Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. e.verduin@sanquin.nl
authors.forename: Esther P
authors.initials: EP
authors.lastname: Verduin
authors.forename: Henk
authors.initials: H
authors.lastname: Schonewille
authors.forename: Anneke
authors.initials: A
authors.lastname: Brand
authors.forename: Geert W
authors.initials: GW
authors.lastname: Haasnoot
authors.forename: Frans H J
authors.initials: FH
authors.lastname: Claas
authors.forename: Irene T M
authors.initials: IT
authors.lastname: Lindenburg
authors.forename: Enrico
authors.initials: E
authors.lastname: Lopriore
authors.forename: Dick
authors.initials: D
authors.lastname: Oepkes
authors.forename: Dave L
authors.initials: DL
authors.lastname: Roelen
authors.forename: Ilias I N
authors.initials: II
authors.lastname: Doxiadis
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D001789:Blood Group Antigens / Q000276:immunology*; D001787:Blood Group Incompatibility / Q000209:etiology / Q000276:immunology; D001805:Blood Transfusion, Intrauterine / Q000009:adverse effects*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D004899:Erythroblastosis, Fetal / Q000276:immunology / Q000628:therapy*; D005260:Female; D005500:Follow-Up Studies; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000097:blood*; D016015:Logistic Models; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D011247:Pregnancy; D012204:Rh-Hr Blood-Group System / Q000276:immunology; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001789:Blood Group Antigens; D006680:HLA Antigens; D007518:Isoantibodies; D012204:Rh-Hr Blood-Group System