Mechanisms involved in antibody- and complement-mediated allograft rejection

Abstract

Antibody-mediated rejection has become critical clinically because this form of rejection is usually unresponsive to conventional anti-rejection therapy, and therefore, it has been recognized as a major cause of allograft loss. Our group developed experimental animal models of vascularized organ transplantation to study pathogenesis of antibody- and complement-mediated endothelial cell injury leading to graft rejection. In this review, we discuss mechanisms of antibody-mediated graft rejection resulting from activation of complement by C1q- and MBL (mannose-binding lectin)-dependent pathways and interactions with a variety of effector cells, including macrophages and monocytes through Fcgamma receptors and complement receptors.

Fig. 1. C4 as a merge point of classical and MBL pathways of complement activation by antibodies

The complement cascade can be activated through three different pathways: the classical (involving C1, C4 and C2) leading to formation of enzymatic molecule C4b2a, the C3 convertase, MBL lectin-dependent pathway and alternative, which is initiated by hydrolyzed C3 and factor B producing alternative pathway C3 convertase, C3bBb. Generation of C3 convertase allows the formation of C5 convertase which is followed by formation a tubular structure of the C5b-9 terminal complement complex, membrane attack complex (MAC). Antibodies activate the complement system primarily through the classical pathway involving C1, which is composed of C1q that binds to antibody, and two C1r and C1s proteases. MBL is associated with MASP-1, 2, 3 serine proteases and initiates the lectin pathway of complement activation through binding to carbohydrates on microorganisms, IgM and some classes of IgG. Both, C1r₂s₂ and MASP proteases enzymatically cleave C4 into two fragments—C4a and C4b. The larger C4b generates C4d fragment, which is the end product of C4 activation. Both, C4b and C4d have the unusual capacity to form a covalent bond with a hydroxyl or amino group on the closest protein or carbohydrate, e.g., endothelial cell membrane or antibody

Fig. 2. A model linking antibody and complement to endothelial cells, macrophages, T and B cells

In this model, alloantibody bound to endothelial cells initiates complement activation through classical- and MBL-dependent pathways and activates macrophages via complement, CRs and FcγRs to produce IL-1-α, IL-1-β, IL-6 and TNF-α. Oligosaccharides attached to the asparagine 297 residue on the Fc fragment of antibody modulate the function of IgG subclasses, especially activation of complement and interaction with FcγRs expressed on mononuclear cells