Human Leukocyte Antigen-Specific Antibodies and Gamma-Interferon Stimulate Human Microvascular and Glomerular Endothelial Cells to Produce Complement Factor C4

Abstract

We have shown for the first time that human microvascular endothelium can be stimulated to synthesize C4 in vitro. The implications of this for clinical transplantation, especially in the context of antibody-mediated rejection, its histological interpretation and as a potential target for therapy would have to be determined by further studies.

The perfect storm: HLA antibodies, complement, FcγRs, and endothelium in transplant rejection

“…In contrast, intimal thickening during antibody-induced chronic rejection occurred in complement-deficient murine recipients, suggesting there was no requirement for complement in this process [41]. Importantly, local production of complement by donor EC could not be ruled out [42]. These results from animal models are consistent with clinical observations that terminal complement inhibitors could not prevent chronic rejection [43, 44].…”

“…In addition, complement concentration is potentiated in response to local inflammation. Renal epithelium, macrophages, cardiocytes and vascular endothelium [42] are sources of extrahepatic complement production during episodes of rejection. As lowly lytic antibodies have enhanced activity when complement is elevated, and IgG4 activates complement when antigen density and complement levels are increased [28], patients with minimal complement-fixing DSA may have a higher degree of damage during rejection episodes, when complement and antigen are more abundant.…”

Glomerular C4d deposits can mark structural capillary wall remodelling in thrombotic microangiopathy and transplant glomerulopathy: C4d beyond active antibody-mediated injury: a retrospective study

“…Also the complex lectin pathway of complement activation including serine proteases that have activating effects on endothelial cells and the complement cascade via C4 might be of pathophysiologic significance during glomerular capillary wall remodelling and duplication . The capacity of glomerular endothelial cells to synthesize complement factor C4 adds to the role that the complement system might play in this scenario. Recently, complement C4d and C5b‐9 deposits were described in TMA and interpreted as possible diagnostic biomarkers in the clinical work‐up of patients .…”

Not All Antibodies Are Created Equal: Factors That Influence Antibody Mediated Rejection

“…High panel reactive antibodies (PRA) are associated with increased complement activation [92]. Lastly, polymorphisms within the complement genetic locus could potentially affect the degree of complement activation [94, 95], whereas differential expression of complement regulatory proteins by the donor tissue could also affect the response of endothelium to complement components [96]. With respect to the downstream effects of complement activation, Jane-wit et al demonstrated that complement activation and deposition on EC resulted in noncanonical NF κ B activation [97] whereas Cravedi et al highlighted a role for complement activation in promotion of a Th1 response during alloimmune reactions [98].…”