Complement Regulators and Receptors

Complement System Regulator / Receptor Distribution

The importance of complement restriction is highlighted by the large number of regulators identified to date, which exceeds that of the components of the complement cascade (C1 to C9).

Complement regulators operate at all levels and are categorized in three major classes: fluid phase complement regulators, membrane­bound complement regulators and membrane-integral complement clearance receptors. surprisingly, several regulators have additional activities beyond complement, as they mediate cell adhesion and extracellular matrix interactions or link the complement cascade with other important physiological networks such as the coagulation cascade.

There are many receptors for complement effector molecules, which bind and respond to effector compounds such as C3a and C5a, C3b-opsonized surfaces, modified self surfaces and tagged microorganisms, toxins or antigens. Five major membrane-bound effector receptors, CR1, CR2, CR3 (also known as CD11b-CD18), CR4 (also known as CD11c-CD18) and CRIg, bind C3b or C4b deposited on the surface of the target and drive effector functions corresponding to the specific form of the C3 and C4 activation compounds.

The action of the anaphylactic fragments C3a and C5a is mediated by members of the seven transmembrane spanning receptor family, including C3aR and the two surface receptors C5aR and C5L2. The biological role of the newly described C5L2 is still under discussion. At present it is unclear whether C5L2 mediates effector functions in response to C5a or whether the receptor acts as a decoy and attenuates C5a function. In addition, C1q is recognized on the cell surface by two receptors: C1qR and the dendritic cell-specific ICAM3- grabbing non-integrin (DC-sIGN) homologue sIGN-related 1 (sIGNR1; also known as CD209).

An important aspect of the role of membrane receptors in regulation and the response to effector compounds is their expression and distribution on individual cell lineages or cell types. surface-attached complement and effector receptors are not uniformly expressed by nucleated host cells, erythrocytes or platelets. Consequently, the distribution and number of individual receptors and the complete receptor repertoire on a given cell membrane are important parameters for defining the protective surface coat and the cellular response to complement.

Complement System Component / Protein, Regulator and Receptor References

1. Zipfel P F, et al. (2009). Complement regulators and inhibitory proteins. Nature Reviews Immunology, 9(10), 729-740.
2. Sims P J, et al. (1988). Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. Journal of Biological Chemistry, 263(34), 18205-18212.
3. Hattori R, et al. (1989). Complement proteins C5b-9 induce secretion of high molecular weight multimers of endothelial von Willebrand factor and translocation of granule membrane protein GMP-140 to the cell surface. Journal of Biological Chemistry, 264(15), 9053-9060.