Dynamic control of the complement system by modulated expression of regulatory proteins

Abstract

The complement system serves many biological functions, including the eradication of invasive pathogens and the removal of damaged cells and immune-complexes. Uncontrolled complement activation causes injury to host cells, however, so adequate regulation of the system is essential. Control of the complement system is maintained by a group of cell surface and circulating proteins referred to as complement regulatory proteins. The expression of the cell surface complement regulatory proteins varies from tissue to tissue. Furthermore, specific cell types can upregulate or downregulate the expression of these proteins in response to a variety of signals or insults. Altered regulation of the complement regulatory proteins can have important effects on local complement activation. In some circumstances this can be beneficial, such as in the setting of certain infections. In other circumstances, however, this can be a cause of complement-mediated injury of the tissue. A full understanding of the mechanisms by which the complement system is modulated at the local level can have important implications for how we diagnose and treat a wide range of inflammatory diseases.

Figure 1. Regulation of complement activation

Three complement activation pathways - the classical, mannose binding lectin and alternative pathways - can form C3 convertases. Cleavage of C3 then enables formation of C5 convertases, which ultimately generate the membrane attack complex. The complement regulatory proteins (in boxes) block this cascade at several steps.

Figure 2. Expression of complement regulatory proteins in the kidney

Even within a single organ, different cell types will express a different repertoire of complement regulatory proteins. Within the kidney, the expression of different complement regulatory proteins is increased or decreased in various diseases. The localization to different structures within the kidney is also altered (see text for greater detail). Crry expression in the kidneys of rodents is similar to that of MCP in humans. We have categorized them as having the same pattern of expression, although this has not be rigorously examined.