Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection

Abstract

Complement split products have emerged as useful markers of antibody-mediated rejection in solid organ transplants. One split product, C4d, is now widely accepted as a marker for antibody-mediated rejection in renal and cardiac allografts. This review summarizes the rationale for the use of C4d as a marker of antibody-mediated rejection, along with the clinical evidence supporting its use in the clinical diagnosis of antibody-mediated rejection. Antibody-independent mechanisms by which C4d can be activated by the classical and lectin pathways of complement activation are also identified. Finally, mechanisms by which complement activation stimulates effector cells (neutrophils, monocytes, macrophages, platelets, and B and T lymphocytes) as well as target cells (endothelial cells) are discussed in relation to antibody-mediated allograft rejection.

Fig 1

The complement cascade can be activated through three different initial pathways: the classical (C1, C4 and C2), alternative (factor B), and mannose binding lectin (MBL) pathways. All three pathways converge in the activation of C3. Activation of C3 and C5 occurs by enzymatic cleavage into two biologically active fragments. The small fragments (C3a and C5a) mediate chemotaxis and activation through separate receptors (C3aR and C5aR) on leukocytes. Activation of monocytes through their C5a receptor causes production of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNFα. The large fragment of C3 can bind covalently to proteins or carbohydrates. Deposition of C3b can be increased through an amplification loop with factor B of the alternative pathway. The terminal components of complement (C5b-C9) form a tubular structure, the membrane attack complex (MAC). *Reprinted with permission from Elsevier. Baldwin WM, III, Larsen CP and Fairchild RL: Innate immune responses to transplants: a significant variable with cadaver donors. Immunity 14: 369–376., 2001.

Fig 2

C4 is activated by enzymatic cleavage into C4a and C4b that can bind covalently to proteins or carbohydrates through a thioester bond. C4b is cleaved successively by factor I leaving first iC4b and then C4d bound to the membrane. CR1 or factor H serve as co-factors to Factor I. C4b and iC4b stimulate cells with complement receptors CR1 or CR3, respectively. C4d has no known receptor. *Reprinted with modifications with permission from Elsevier. Baldwin WM, III, Larsen CP and Fairchild RL: Innate immune responses to transplants: a significant variable with cadaver donors. Immunity 14: 369–376., 2001.