IgG2b enhances alloantibodies to stored red blood cells

Elucidating how interactions between antibodies and red blood cells (RBCs) affect alloimmune responses can provide insights into anti-D mechanisms, delayed hemolytic transfusion reactions, and production of additional anti-RBC antibodies in sensitized patients requiring transfusions. Building on our prior studies showing that passive immunization with IgG2c enhances alloantibody production to transfusion of fresh RBCs, herein, we investigate how preexisting anti-RBC antibodies regulate alloimmune responses to stored RBC transfusions.

Recipient animals were passively immunized with anti-RBC monoclonal antibodies of each IgG subclass (IgG1, IgG2b, IgG2c, and IgG3) followed by a stored allogeneic RBC transfusion. Clearance, complement, and induction of immune responses were assayed. Transgenic mice and blocking antibodies were used to identify Fc receptors and specific cell subsets required for antibody-mediated alloimmune responses.

IgG2c and IgG2b enhanced alloantibody production to stored allogeneic RBCs. Because IgG2c similarly enhances responses to fresh allogeneic RBCs, studies focused on IgG2b, which enhanced only in the context of stored, not fresh, RBCs. IgG2b led to increased complement deposition on transfused RBCs but did not accelerate clearance. IgG2b-mediated enhanced alloimmunization was complement-independent but dependent upon FcγRIV expression on dendritic cells and acted through increased T cell proliferation to enhance alloantibody production.

These findings provide insight into how preexisting antibodies in transfusion recipients increase the risk of future alloimmunization events. Considering that FcγRIV on dendritic cells is also required for IgG2c-enhanced alloantibodies, this pathway represents a potential interventional target for the reduction of RBC alloimmunization risk in transfusion recipients.