Understanding red blood cell alloimmunization triggers

Abstract

Blood group alloimmunization is "triggered" when a person lacking a particular antigen is exposed to this antigen during transfusion or pregnancy. Although exposure to an antigen is necessary for alloimmunization to occur, it is not alone sufficient. Blood group antigens are diverse in structure, function, and immunogenicity. In addition to red blood cells (RBCs), a recipient of an RBC transfusion is exposed to donor plasma, white blood cells, and platelets; the potential contribution of these elements to RBC alloimmunization remains unclear. Much attention in recent years has been placed on recipient factors that influence RBC alloantibody responses. Danger signals, identified in murine and human studies alike as being risk factors for alloimmunization, may be quite diverse in nature. In addition to exogenous or condition-associated inflammation, autoimmunity is also a risk factor for alloantibody formation. Triggers for alloimmunization in pregnancy are not well-understood beyond the presence of a fetal/maternal bleed. Studies using animal models of pregnancy-induced RBC alloimmunization may provide insight in this regard. A better understanding of alloimmunization triggers and signatures of "responders" and "nonresponders" is needed for prevention strategies to be optimized. A common goal of such strategies is increased transfusion safety and improved pregnancy outcomes.

Red blood cell minor antigen mismatches during chronic transfusion therapy for sickle cell anemia

“…Although the rates of exposure to individual antigen mismatches, as well as the total number of mismatches per transfusion episode, were overall similar for these two groups of patients, the incidence of new RBC alloantibody detection was markedly higher among patients receiving Category 2–matched transfusions. This is in keeping with past observations that alloimmunized patients are a distinct group of immunologic “responders” who have a higher tendency of future alloantibody formation despite increased stringency of antigen matching . Of note, Category 2 patients were older and had a longer duration of CTT than Category 1 patients, which may confound the tendency toward alloimmunization.…”

“…Yet despite observing mismatch rates approaching nearly 50% of transfusions for some antigens, all of the alloimmunization events that occurred during the study frame were to low‐frequency antigens. Therefore, although foreign antigen exposure is the requisite event for alloimmunization to occur, there are other factors that must contribute to this event, which may include donor and unit characteristics, patient's immunologic status, the immunogenicity of individual antigens, the frequency of antigen exposure, or the interaction of all of these factors . This study suggests that alloimmunized patients may benefit from more stringent RBC antigen matching, especially to antigens that are more prevalent in donor populations that are ethnically similar to SCA patients, such as Js a .…”

A unique major histocompatibility complex Class II–binding register correlates with HLA‐DR11–associated immunogenicity of the major K blood group antigen

“…Risk assessments could also be improved by carrying out similar peptide–MHCII‐binding experiments using additional recombinant HLA proteins, for example, including HLA‐DQ and HLA‐DP, and by utilizing HLA tetramers or multimers and immunologic assays such as ELISPOTs to directly query patient T‐cell responses to specific peptides . It is hoped that further elucidation of peptide–MHCII‐binding motifs, together with analysis of clinical samples to map epitopes, determine TCR characteristics and repertoires, and additional immunologic models and studies will eventually lead to novel therapies to tolerize susceptible individuals to K and other blood group antigens …”

Identification of genetic biomarkers for alloimmunization in sickle cell disease

“…It is anticipated that additional variations in genes controlling inflammatory responses will be associated with protection or increased risk of alloimmunization, because the inflammatory status of the recipient can trigger the innate immune system to convert a tolerogenic event into an immunogenic one (Hendrickson et al , ; Zimring & Hendrickson, ; Tatari‐Calderone et al , ). Patients that suffer from acute illness, autoimmune disease or an inflammatory disorder show higher rates of alloimmunization in response to RBC transfusion (Hendrickson & Tormey, ; Evers et al , ). Of interest, SCD patients display a high degree of inflammation and innate immune activation due to chronic haemolysis (Jison et al , ; Hibbert et al , ).…”