Antibodies, isotypes and complement in allograft rejection

Classical complement activation is a key step in the process of antibody-mediated rejection. Emphasizing novel diagnostic strategies, this study will discuss recent studies highlighting the particular relevance of alloantibodies with complement-fixing ability.

Reinforcing the pivotal role of complement, numerous studies have shown tight associations of capillary C4d deposition, a 'footprint' of alloantibody-triggered complement activation, with the occurrence of allograft injury. Distribution patterns of immunoglobulin isotypes or subclasses, which strongly differ in their ability to activate complement, may not adequately reflect the actual pathogenetic relevance of detected allosensitization. This fact may be explained by the finding that other variables, such as antibody-binding density or a synergism of antibodies against different epitopes of the same antigen, may contribute to complement activation. An attractive approach to distinguish between complement-fixing and presumably less harmful noncomplement-fixing alloreactivities could be the detection of C4d deposition in vitro. Applying such techniques, recent studies have shown that human leukocyte antigen reactivity with C4d-fixing ability, in contrast to noncomplement-fixing sensitization, may strongly predict antibody-mediated rejection and inferior graft survival.

Considering the pivotal role of complement, technologies that uncover the complement-fixing ability of alloantibodies may be of particular interest for the selective detection of deleterious sensitization.