FIGURE 3.

(A) Complement-dependent mechanisms of antibody mediated rejection. Binding of donor specific antibody (DSA) to MHC molecules on the liver allograft causes activation of the classical pathway of complement via binding of the C1 complex. Complement has the potential to damage the graft through three main mechanisms: (1) Opsonization. C4d and C3d covalently bind to target cells marking them for destruction and clearing by cells of the innate immune system. (2) Anaphylatoxin production. C3a and C5a act as potent chemotactic signals recruiting inflammatory cells which cause localized tissue damage. (3) Membrane attack complex (MAC). The C5b-9 MAC has the potential to damage cells by puncturing holes in the membrane, although this action is normally inhibited by endothelial expression of CD59 (protectin). Non-lytic binding of the MAC induces endothelial upregulation of pro-inflammatory, lymphocyte recruitment, and MHC molecules, thus potentiating the rejection response. (B) Complement-independent mechanisms of antibody mediated rejection. DSA binding to MHC molecules promotes the recruitment of cells of the innate immune system such as neutrophils, macrophages and NK cells via interactions with the FC receptor. These inflammatory cells are stimulated to cause graft injury via their various effector mechanisms (see text for details). DSA binding also stimulates intracellular signaling pathways.