Red blood cell alloimmunization and sickle cell disease: a narrative review on antibody induction

Abstract

The high prevalence of red blood cell (RBC) alloantibodies in people with sickle cell disease (SCD) cannot be debated. Why people with SCD are so likely to form RBC alloantibodies, however, remains poorly understood. Over the past decade, a better understanding of non-ABO blood group antigen variants has emerged; RH genetic diversity and the role this diversity plays in RBC alloimmunization is discussed elsewhere. Outside of antigen variants, the immune systems of people with SCD are known to be different than those of people without SCD. Some of these differences are due to effects of free heme, whereas others are impacted by hyposplenism. Descriptive studies of differences in white blood cell (WBC) subsets, platelet counts and function, and complement activation between people with SCD and race-matched controls exist. Studies comparing the immune systems of alloimmunized people with SCD to non-alloimmunized people with SCD to race-matched controls without SCD have uncovered differences in T-cell subsets, monocytes, Fcγ receptor polymorphisms, and responses to free heme. Studies in murine models have documented the role that recipient inflammation plays in RBC alloantibody formation, with human studies reporting a similar association. Murine studies have also reported the importance of type 1 interferon (IFNα/β), known to play a pivotal role in autoimmunity, in RBC alloantibody formation. The goal of this manuscript is to review existing data on factors influencing RBC alloantibody induction in people with SCD with a focus on inflammation and other immune system considerations, from the bench to the bedside.

HLA-identical sibling hematopoietic stem cell transplantation following reduced-toxicity myeloablative conditioning regimen in sickle cell disease

“…Alloimmunization is a common complication of SCD that is attributed to the combination of the in ammatory component of the disease and the antigenic differences between blood donors and SCD recipients 39 . Data from a Brazilian SCD cohort of 2,794 individuals revealed that 88% of children and 95.9% of adults have received transfusion of blood products 40 .…”

Transfusional Approach in Multi-Ethnic Sickle Cell Patients: Real-World Practice Data From a Multicenter Survey in Italy

“…Although the alloimmunization rate was not available due to the study's retrospective design, the low alloimmunization events in both African and Caucasian patients, might reflect the satisfactory level of donor-recipient exact matching for ABO Rhesus and Kell antigen for RBC compatibility, consistent with the Italian guidelines for children and adults released on 2014 ( 11 , 15 ). Antigen mismatch between donor and recipient is the basis for antibody formation, as the recipient recognizes those antigens as non-self and, thereby, an immune response might be elicited ( 53 , 54 ). Transfused SCD patients have the highest rates of RBC alloimmunization over their lifetimes (up to 40–50%), compared to fewer than 5% of other transfused individuals with either thalassemia major or myelodysplasia ( 55 , 56 ).…”

“…Transfused SCD patients have the highest rates of RBC alloimmunization over their lifetimes (up to 40–50%), compared to fewer than 5% of other transfused individuals with either thalassemia major or myelodysplasia ( 55 , 56 ). Detection of alloantibodies may make locating compatible RBC units for future transfusion difficult, delayed, and sometimes impossible ( 54 ). Potential reasons for alloimmunization include (i) number of donor exposures; (ii) antigenic mismatches between donor RBCs and recipient RBCs related to ethnicity (mainly between Caucasian donors and African descent recipients); (iii) the inflammatory state of recipients ( 57 ).…”

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

“…Among all transfused recipients, alloimmunization to RBC antigens usually occurs in about 2%–5% [ 3 ]. However, approximately 40%–50% of the transfused SCD patients develop RBC alloantibodies in the absence of RBC antigen phenotype matching beyond ABO and RhD matching [ 4 , 5 ]. Alloimmunization to RBC antigens in SCD patients has a significantly higher rate than other chronically transfused patient populations, potentially due to the differences in RBC antigen expression frequencies between people of different ethnic backgrounds (antigen disparity), high transfusion burden, genetic diversity and immune system considerations etc.…”

“…Alloimmunization to RBC antigens in SCD patients has a significantly higher rate than other chronically transfused patient populations, potentially due to the differences in RBC antigen expression frequencies between people of different ethnic backgrounds (antigen disparity), high transfusion burden, genetic diversity and immune system considerations etc. [ 3 , 4 ]. As a result, RBC alloimmunization can complicate the selection of future compatible transfusion units and furthermore, increase the risk of haemolytic transfusion reactions (HTRs), and the development of additional RBC alloantibodies and autoantibodies in subsequent transfusions [ 6 , 7 , 8 ].…”