The role of complement regulatory proteins in prevention of cell injury

Complement is a form of innate immunity that protects the host from infection. If not properly regulated, activated complement on the other hand has the potential to cause significant damage to host cells. Several soluble and cell surface-bound proteins exist to protect host cells from complement injury in vivo. Decay Accelerating Factor (DAF, CD55) and Complement Receptor 1-Related Gene Y (Crry) are two cell surface-anchored complement regulators that are similar in their mechanism of action and their expression pattern. Over the years, these proteins have been evaluated for their roles in several models of complement-mediated pathological disorders and have been found to be highly protective against complement-mediated injuries. Their respective in vivo functions, however, have not yet been clearly characterized. The objective of the thesis is to delineate differential as well as overlapping in vivo roles of DAF and Crry in prevention of complement-mediated inflammatory injury. Here, we described that due to the differential expression level on a given cell type, only the Crry expression was required for the survival of erythrocytes, whereas either the DAF or Crry expression was sufficient to protect the platelets against complement-mediated phagocytosis. We further characterized that the phagocytosis of the complement-susceptible platelets was mediated by CRIg, a newly identified complement receptor. Interestingly, the phagocytosis of the complement-susceptible erythrocytes was independent of CRIg and any other known complement receptors. During the investigation, we serendipitously discovered that the endogenously expressed Crry molecules or the retrovirally over-expressed DAF molecules on blood cells could regulate the spontaneous and systemic complement activation, thereby preventing complement depression and defect in vivo. The subsequent study also revealed that the deficiency of DAF and Crry on endothelial cells could cause spontaneous complement activation and depression. Collectively, these results established the dynamic relationship between the expression of membrane complement regulators and the regulation of complement activation/homeostasis