Association between HLA‐DRB1*01 and HLA‐DRB1*15 with alloimmunisation in transfusion‐dependent patients with thalassaemia

Abstract

BackgroundAlloantibody production is one of the most challenging complications in transfusion‐dependent thalassaemia patients. Haemolytic anaemia, an increase in blood consumption, difficulty in haematopoietic stem cell transplantation and reduced quality of life are consequences of alloimmunisation. The most predisposed antigens (Ags) for alloantibody development are Rh and Kell blood group Ags.ObjectiveThe aim of the present study is to evaluate any correlation between HLA‐DRB1 alleles and Rh and Kell alloantibodies.Materials and MethodsFifty‐two non‐responders (control) and 54 responders (case) were enrolled in this study. Alloantibody detection was performed using the tube method. Genotyping of HLA‐DRB1*01 and HLA‐DRB1*15 was conducted by single‐specific primer‐polymerase chain reaction.ResultsIn the responder group, 77.8% were hyper‐responders (more than one alloantibody), and only 22.2% were mono‐responders. Most detected alloantibodies were Anti‐K (94.4%), followed by Anti‐E (64.8%), Anti‐C (29.6%) and Anti‐D (25.9%). There was a significant difference in HLA‐DRB1*15 between responder and non‐responder groups, 73.7% vs 26.3%, respectively. (P = .029, OR = 3.290; 95%CI). Our results showed that HLA‐DRB1*15 was more frequent in hyper‐responders than mono‐responders (92.9% vs 7.1%) (P = .007). The greatest HLA‐DRB1*15 was seen in Anti‐K (P = .014, odds ratio [OR = 3.784]; 95% confidence interval [CI]) and Anti‐E (P = .011, OR = 3.609; 95%CI) alloantibodies. There is no association between HLA‐DRB1*01 and alloimmunisation.ConclusionOur findings showed that there is a significant correlation between HLA‐DRB1*15 and Anti‐K and Anti‐E alloantibodies. These findings can be useful in detecting susceptible thalassaemic patients and improving transfusion management.

HLA‐DRB1 molecules and the presentation of anchor peptides from RhD, RhCE, and KEL proteins

“…7 To distinguish the immunological response against epitopes of KEL, RhCE, and RhD proteins, we analyzed separately the three groups of patients who presented immune response against these RBC antigens, evaluating if the presence of the HLA-DRB1*15 allele predisposed the individual to an alloimmunization against specific proteins. The findings reinforced the positive relationship that this allele exerts on alloimmunization against antigens of Rh and Kell systems and may explain why it has often been associated with hyperresponders, especially patients with simultaneous anti-D + C. 21,22,31,32 Although related to the most frequent antibodies against RBC, the association with the HLA-DRB1*15 allele cannot be generalized as Jk a and Di a alloimmunizations were associated only with the HLA-DRB1*01 and *07 alleles, respectively. 17,19 Considering that the combined frequency of the haplotypes encompassing D and C antigens (DCcee = 34.4%, DCCee = 15.5%, DCcEe = 12%, DCCEe = 0.3%, and DCcEE = 0.3%) reached 62.5% in the Brazilian population, 33 one may assume that one of the reasons for observing the anti-D + C combination among pregnant women without a previous transfusion history is the high frequency of incompatible mother/fetus phenotypes.…”

“…To distinguish the immunological response against epitopes of KEL, RhCE, and RhD proteins, we analyzed separately the three groups of patients who presented immune response against these RBC antigens, evaluating if the presence of the HLA‐DRB1*15 allele predisposed the individual to an alloimmunization against specific proteins. The findings reinforced the positive relationship that this allele exerts on alloimmunization against antigens of Rh and Kell systems and may explain why it has often been associated with hyperresponders, especially patients with simultaneous anti‐D + C 21,22,31,32 . Although related to the most frequent antibodies against RBC, the association with the HLA‐DRB1*15 allele cannot be generalized as Jk a and Di a alloimmunizations were associated only with the HLA‐DRB1*01 and *07 alleles, respectively 17,19 …”

“…Previous investigations have shown a high frequency of the HLA‐DRB1*15 allele in hyperresponders, 20–22 which may indicate that physicochemical interactions between specific amino acids of the DRB1*15 molecule are related to a greater presentation of the antigenic peptides, increasing the chance of producing additional alloantibodies in chronic transfusion therapy. Female sex and the presence of the HLA‐DRB1*15 allele have been accepted as potentially useful markers for screening healthy blood donors associated with a high‐responder anti‐D donor profile 23 .…”

“…[14][15][16] Other studies found a significant association between Jk a , K, and Di a alloimmunizations and the HLA-DRB1 molecules whose 13, 70, 71, 74, and 78 residues from the P4 pocket appeared to influence the presentation of the antigenic peptides. [17][18][19] Previous investigations have shown a high frequency of the HLA-DRB1*15 allele in hyperresponders, [20][21][22] which may indicate that physicochemical interactions between specific amino acids of the DRB1*15 molecule are related to a greater presentation of the antigenic peptides, increasing the chance of producing additional alloantibodies in chronic transfusion therapy. Female sex and the presence of the HLA-DRB1*15 allele have been accepted as potentially useful markers for screening healthy blood donors associated with a high-responder anti-D donor profile.…”

Association of multispecific red blood cell alloimmunization with HLA-Class II variants is related to Rh phenotypes

“…Several studies demonstrated that HLA-DRB1*15 was frequently present in multiple RBC antibody responders and might defi ne a high-responding phenotype (13)(14)(15). The other recent investigations confi rmed that the frequency of HLA-DRB1*15 was higher in the multi-responder group than in non-responders, which support the idea that HLA typing before transfusion could be helpful in reducing alloimmunization in chronically transfused patients (21,22).…”