HLA Class II regulation of immune response in sickle cell disease patients: Susceptibility to red blood cell alloimmunization (systematic review and meta‐analysis)

Abstract

Background and Objectives Sickle cell disease (SCD) patients are commonly treated with red blood cell (RBC) transfusion. Pretransfusion tests commonly involve limited serological antibody testing. RBC alloimmunization to RBC antigens is a frequently encountered complication seen in chronically transfused patients. Genetic factors such as the human leukocyte antigen (HLA) are known to influence and regulate immune responses. HLAs are highly polymorphic and play an essential role in regulating immune responses, including RBC alloimmunization. The aim of this study was to conduct a systematic review and meta‐analysis to evaluate the association between HLA Class II allelic polymorphisms with the possible risk of developing RBC alloantibodies. Materials and Methods Four databases were systematically searched for relevant studies between the years 2000 and 2021 following the PRISMA guidelines. Four articles met the eligibility and quality criterion, and three alleles, HLA‐DRB1*04, HLA‐DRB1*15 and HLA‐DQB1*03, that were found to be potentially associated with an increased risk in alloantibody formation were included. Results The primary outcome measure was alloimmunization by RBC antigen exposure in multiply transfused SCD patients. The total estimate of alloimmunization of the SCD patients was 2.33 (95% CI, 1.58–3.44), demonstrating susceptibility to RBC alloantibody formation. Heterogeneity between the studies was insignificant, suggesting the differences associated with random sampling errors. The results showed that SCD patients carry an increased risk of producing RBC alloantibodies. Conclusion A strategy to prevent RBC alloimmunization is genotyping for genetically susceptible SCD patients receiving multiple transfusions. Early identification of genetic variants that can potentially increase the risk of RBC alloimmunization could aid in the screening process and selection of phenotypically matched RBC units.

Investigation of variables affecting the immunogenicity of blood group antigens using a calculation formula

“…Moreover, different populations have a different genetic background that affects immunologic reaction, which can ultimately influence immunogenicity. Immunogenicity may be influenced by human leukocyte antigen (HLA) molecules that are highly polymorphic and vary significantly among ethnic groups 12 The peptide-binding affinity differs with the HLA type, resulting in variable immune responses by alloantigen exposure 13 , 14 .…”

Red Blood Cell Alloimmunization: Life-Threatening Response

“…Alloimmunization is the formation of antibodies against non-self-antigens from a different member of the same species due to exposure to them via transfusion, pregnancy, or transplantation [1,2]. The likelihood of alloimmunization can differ from population to population according to blood group antigens expression frequencies [3]. Despite many researches in this field, alloimmunization still remains a common and serious issue in blood transfusion and medical sciences [4].…”

Asian‐type DEL (RHD*DEL1) with an allo‐anti‐D: A paradoxical observation in a healthy multiparous woman

“…Various HLA alleles have been reported to increase or decrease red cell alloimmunization 18–27 . A few HLA class I and class II alleles have been suggested by several investigators to increase anti‐D immunization rates in RhD‐negative pregnancies 19–24 .…”

“…23 Contradictory results showing no association between specific HLA loci and anti-D have also been reported. [31][32][33][34] A recent meta-analysis could not confirm a statistically significant association between any specific HLA allele and anti-D, 18 but this was based on a limited number of studies (n = 4). Similarly, in another study, no HLA-DR/HLA-DQ allele combination could be associated with any red cell immunization.…”

“…6,8 Various HLA alleles have been reported to increase or decrease red cell alloimmunization. [18][19][20][21][22][23][24][25][26][27] A few HLA class I and class II alleles have been suggested by several investigators to increase anti-D immunization rates in RhDnegative pregnancies. [19][20][21][22][23][24] The HLA-DRB1*15:01 allele has been associated with anti-D immunization in multiple studies [28][29][30] and the HLA-DQB1*02:01 allele with anti-D of high titers.…”