Abstract and Introduction
Abstract
The introduction of C4d in daily clinical practice in the late nineties aroused an ever-increasing interest in the role of antibody-mediated mechanisms in allograft rejection. As a marker of classical complement activation, C4d made it possible to visualize the direct link between anti-donor antibodies and tissue injury at sites of antibody binding in a graft. With the expanding use of C4d worldwide several limitations of C4d were identified. For instance, in ABO-incompatible transplantations C4d is present in the majority of grafts but this seems to point at 'graft accommodation' rather than antibody-mediated rejection. C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy. In all these fields, C4d holds promise to detect patients at risk for the consequences of antibody-mediated disease. Moreover, the emergence of new therapeutics that block complement activation makes C4d a marker with potential to identify patients who may possibly benefit from these drugs. This review provides an overview of the past, present, and future perspectives of C4d as a biomarker, focusing on its use in solid organ transplantation and discussing its possible new roles in autoimmunity and pregnancy.
Introduction
In the 1950s it was generally accepted that allograft rejection occurred due to T-cell–mediated cellular cytotoxicity. The introduction of C4d staining in daily clinical practice in the late nineties aroused an ever-increasing interest in the role of antibody-mediated mechanisms in allograft rejection. C4d as a marker made it possible to visualize, for the first time, the direct link between anti-donor antibodies and tissue injury at sites of antibody binding. It is illustrative that C4d as a biomarker has been called 'a magic marker', because of its stability, its strong association with antibody-mediated rejection (AMR), and finally, its major impact on graft survival and patient treatment.
However, with the expanding use of C4d by transplant pathologists worldwide, several shortcomings of C4d were identified, and C4d appeared to be a less-sensitive marker than initially thought. For instance, in ABO-incompatible transplantations C4d is present in the majority of grafts, but this does not seem to be alarming, and certainly does not seem to indicate acute AMR or an inferior graft prognosis. In addition, molecular studies provided insight, suggestive of a complement-independent form of AMR or C4d-negative AMR, in which C4d is obviously not helpful as a diagnostic tool.
C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy. In all these fields, C4d holds promise to detect patients at risk for the consequences of antibody-mediated disease. Moreover, the emergence of new therapeutics that inhibit complement activation makes C4d a marker with potential to identify patients who may possibly benefit from these drugs.
This review provides an overview of the past, present, and future perspectives of C4d as a biomarker, focusing on its use in transplantation and discussing its possible new roles in autoimmunity and pregnancy. For this purpose, a group of experts were interviewed about the role of C4d within their fields of expertise and challenged to think about the following issues:
Will we still be using C4d in 10 years time, and if not, what alternatives would you suggest?
What would you like to investigate if you would receive funding to be spent on research in the field of C4d?
What is your take home message for readers and listeners?
The interviews form the backbone of this review, together with a review of the recent literature on C4d. We would like to motivate readers to listen to the audio files that can be found online (Supplementary Material online), which include highlights, quotes and authors' comments on both the state of the art and controversies in the field of C4d. A summary of this reviews most important points is given in Box 1.