The Complement System and Antibody-Mediated Transplant Rejection

Abstract

Complement activation is an important cause of tissue injury in patients with Ab-mediated rejection (AMR) of transplanted organs. Complement activation triggers a strong inflammatory response, and it also generates tissue-bound and soluble fragments that are clinically useful markers of inflammation. The detection of complement proteins deposited within transplanted tissues has become an indispensible biomarker of AMR, and several assays have recently been developed to measure complement activation by Abs reactive to specific donor HLA expressed within the transplant. Complement inhibitors have entered clinical use and have shown efficacy for the treatment of AMR. New methods of detecting complement activation within transplanted organs will improve our ability to diagnose and monitor AMR, and they will also help guide the use of complement inhibitory drugs.

Figure 1. Complement activation in antibody mediated rejection

A) The classical pathway of complement is activated when C1q binds to IgG clustered on endothelial HLA. Each C1q deposits multiple C4 molecules on target surfaces. Efficient complement regulation stops the reaction before C3 molecules are deposited. In contrast, complete complement activation results in covalent fixation of multiple C3 fragments to the target tissue. This process is augmented by the alternative pathway amplification loop, although several regulatory proteins control the alternative pathway. Complement regulatory proteins metabolize the C3b to iC3b and then to C3dg. B) Complete complement activation generates several biologically active products, including C3a, C3b, C5a, and C5b-9. Abbreviations: C4bp, C4 binding protein; CR1, complement receptor 1; fI, Factor I; fH, Factor H; MCP, membrane cofactor protein; DAF, decay accelerating factor.

Figure 2. C4 and C3 deposition in tissues by the classical pathway of complement

A) Linear staining of capillary endothelium for A) C4d and B) C3d in a cardiac biopsy from a patient with AMR. The staining pattern for C4d and C3d was identical in this biopsy. C) C3 and C4 deposition in glomerulus of a mouse kidney. IgM deposition in the mesangium causes C4 deposition (red). Efficient complement regulation prevents C3 deposition (green) at the same location. Some alternative pathway-mediated C3 deposition is seen on Bowman’s capsule and in the tubulointerstitium. Glomeruli are indicated with arrowheads. Modified with permission from references (34) and (59).