Production of complement components by cells of the immune system

Abstract

The complement system is an important part of the innate immune defence. It contributes not only to local inflammation, removal and killing of pathogens, but it also assists in shaping of the adaptive immune response. Besides a role in inflammation, complement is also involved in physiological processes such as waste disposal and developmental programmes. The complement system comprises several soluble and membrane-bound proteins. The bulk of the soluble proteins is produced mainly by the liver. While several complement proteins are produced by a wide variety of cell types, other complement proteins are produced by only a few related cell types. As these data suggest that local production by specific cell types may have specific functions, more detailed studies have been employed recently analysing the local and even intracellular role of these complement proteins. Here we review the current knowledge about extrahepatic production and/or secretion of complement components. More specifically, we address what is known about complement synthesis by cells of the human immune system.

Keywords: cell activation; complement; human.

Figure 1

Schematic representation of the complement system. The complement system can be activated via three different pathways: the classical pathway (CP), the lectin pathway (LP) and the alternative pathway (AP). These pathways have their own sequential manner in forming a C3 convertase: C4b2a or C3bBb. These C3 convertases cleave the central component C3 generating two activation fragments, C3a and C3b. The C3a is able to bind its anaphylatoxin receptor the C3aR, whereas C3b can opsonize a target membrane. C3b and its further degradation products, iC3b, C3c and C3d/C3dg are able to bind various complement receptors (CRs). Additionally, C3b can bind to the former C3 convertase which then results in formation of the C5 convertase: C4bC2aC3b or C3bBbC3b. The C5 convertase cleaves C5 in two activation fragments C5a and C5b. C5a can bind to its anaphylatoxin receptors C5aR1 and C5aR2, whereas C5b marks the start of the formation of the membrane attack complex (MAC). In a sequential manner C5b, C6, C7, C8 and up to 16 molecules of C9 bind together to form a MAC. Various inhibitors of this system are marked in pink boxes. MBL = mannose binding lectin; MASP = MBL‐associated serine protease; FB = factor B; FP = factor P; FD = factor D; FH = factor H; C1INH = C1 inhibitor; FI = factor I (FI), C4BP = C4b‐binding protein; CR = complement receptor.

Figure 2

Production of complement proteins occurs in different tissues and by different cell types. Several sites are depicted in the figure, on the top left by hepatocytes in the liver, on the top right by endothelial and epithelial cells. In this review we focus on the production of complement proteins by immune cells, as illustrated in the bottom panel. Immune cells can secrete complement proteins, respond to complement proteins in the immunological synapse and more recently intracellular functions for complement proteins have been proposed.