Absence of the spleen and the occurrence of primary red cell alloimmunization in humans

Marginal Zone B Cells Induce Alloantibody Formation Following RBC Transfusion

“…Moreover, the decreased level of detectable anti-KEL alloantibodies in splenectomized B6 recipients correlated with a lack of C3 on transfused KEL-DiI RBCs (Figure 1D ), as well as no detectable KEL RBC clearance above that of KEL RBCs transfused into KEL positive recipients (Figure 1E ). These findings demonstrate that splenic immune constituents are important for the formation of alloantibodies against KEL on transfused RBCs, consistent with previous studies in patients ( 67 , 68 ).…”

“…Consistent with this, the only prospective study examining immune responses to RBC antigens in splenectomized humans demonstrated that the spleen was absolutely required for anti-RBC antibody formation ( 67 ), suggesting that splenic constituents are key players in the development of an alloantibody response to RBC antigens following transfusion. A recent large retrospective study examining RBC alloimmunization in splenectomized patients corroborated these earlier findings ( 68 ), once again suggesting that the spleen plays a central role in mediating RBC alloantibody formation. While the splenic microenvironment is difficult to recapitulate in vitro , given the distinct localization and activity of MZ B cells within the spleen and the location of the spleen with the circulatory system, these results strongly suggest that similar engagement of allogeneic antigens on transfused RBCs by MZ B cells within the spleen of transfused patients likely represents a key early step in this process.…”

“…To define key initiators in alloantibody formation to the KEL antigen following KEL RBC transfusion, we first sought to determine whether a specific immune compartment was required for the development of anti-KEL alloantibodies. Given the potential role of the spleen in antibody formation against RBC alloantigens ( 67 , 68 ), we sought to determine whether the spleen was responsible for anti-KEL antibody formation following transfusion of KEL RBCs. To accomplish this, KEL negative B6 recipients were splenectomized or sham operated 2 weeks prior to transfusion of a mixture of KEL RBCs labeled with a lipophilic dye, DiI, and B6 RBCs that were labeled with a fluorescently distinct dye, DiO, to facilitate direct examination of specific changes to KEL RBC survival, antibody binding and complement deposition post-transfusion (Figure 1A ).…”

Hemoglobin A clearance in children with sickle cell anemia on chronic transfusion therapy

“…[31][32][33] Further, we demonstrated that DHbA does directly impact CTT outcomes, as increased HbA clearance leads to lower pretransfusion Hb, higher HbS, and higher reticulocytes. Although the factors that dictate RBC alloimmunization continue to be an area of active investigation, [34][35][36][37][38][39] as patients with RBC antibodies have increased HbA clearance, it is possible that increased removal of transfused RBCs may reflect increased RBC uptake by immune cells that are uniquely poised to facilitate RBC alloimmunization. 40 Conversely, in a murine model of alloimmunization, donor RBCs that were subjected to pretransfusion oxidant stress to cause rapid posttransfusion clearance by the reticuloendothelial system were significantly more immunogenic than donor RBCs with longer posttransfusion survival, suggesting that clearance rate by the reticuloendothelial system influences alloimmunization respones.…”

A functional spleen contributes to afucosylated IgG in humans

“…For alloimmune responses, that is foreign antigens on cells such as platelets and anti-red blood cell antigens (RBC) in either pregnancy or after transfusion, we previously described a general reduction of antigen-specific IgG-Fc fucosylation, such as for anti-D and anti-Human Platelet Antigen-1a (HPA-1a) antibodies 24 – 26 . Importantly, immunization to these alloantigens, also generally require a functional spleen 27 , suggesting that immune responses occurring in the spleen may be particularly prone to generate afucosylated IgG responses. Similar afucosylated antigen-specific IgG responses have been observed in virus-specific IgG responses, such as for dengue virus, HIV, cytomegalovirus (CMV), hepatitis B virus (HBV), measles virus, mumps virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 11 – 13 , 28 , 29 , and now recently shown by us to be a hallmark of enveloped viral infections, a response that is mimicked by alloimmunizations 11 .…”