Regular Article TRANSFUSION MEDICINE A novel role for C3 in antibody-induced red blood cell clearance and antigen modulation

Complement is one of the major effector pathways by which antibodies destroy cellular targets to which they bind. C3 plays a pivotal role in this process both by serving as a direct opsonin after attaching to surfaces in the form of C3b and also by leading to downstream assembly of the membrane attack complex. In addition to fixation of C3, antibodies can opsonize cellular targets through ligation of Fcg receptors (FcgRs). Although straightforward in concept, the destruction of targets by antigen-bound antibodies is a dynamic process, with multiple regulatory components. For example, self-tissues have several pathways that actively inhibit complement activation. Moreover, once deposited, C3b is broken down into iC3b, C3d, and C3dg. In this way, self-tissues have evolved methods to avoid destruction by binding of self-antibodies. In addition to regulating the effector function of bound antibodies, the targets of antibody binding can undergo compensatory changes. Antigen modulation is a process by which target cells alter the antigens being recognized by the antibody in question. Antigen modulation occurs in multiple settings with different target tissues and antigens, including nicotinic cholinergic receptors in myasthenia gravis, desmogleins in pemphigus vulgaris, glycoproteins on platelets, and HLA on transplanted tissues. The phenomenology of antigen modulation in humans has been repeatedly described in the context of antibodies binding red blood cells (RBCs). This outcome has been termed depressed antigen, antigen suppression, weakened antigenicity, and antigen loss and has been observed for multiple blood group antigens, including Kell, RhD, RhC, Rhe, Jka, Jkb, Gerbich, LW, AnWJ, and Cromer. Among these, antigen modulation has been described most frequently for antigens in the Kell system. Nevertheless, despite the multiple settings in which antigen modulation occurs and its frequency in RBC biology, relatively little is known about its mechanistic underpinnings. Although immune-mediated destruction of RBCs is often the result of autoor alloantibody binding, it is not the inevitable outcome. In some cases, transfusion of a unit of RBCs against which a recipient has an alloantibody (ie, an “incompatible” unit) causes no clinical symptoms, with the transfused RBCs remaining in circulation and the hematocrit increasing appropriately. In other cases, all of the incompatible RBCs clear rapidly in a hemolytic transfusion reaction (HTR), potentially resulting in coagulopathy, renal failure, and death. In fact, HTRs are a leading cause of transfusion-associated death. The mechanism(s) by which anti-RBC antibodies have such different effects remain poorly understood; however, antigen modulation has been described in some RBCs that escape destruction from alloor autoantibodies.