The complement system is composed of over 30 proteins, activated in response to tissue injury, invading pathogens or other foreign surfaces. C5a was first described as a cleavage product of complement component 5 (C5) with chemotactic and anaphylatoxic properties. Further characterisation revealed that C5a is an essential part of the innate immune response and evidence now suggests that it may also play a role in adaptive immunity. Although not necessarily the initiating factor, the excessive or uncontrolled production of C5a that occurs in a number of inflammatory diseases, suggests that C5a promotes and perpetuates inflammatory reactions.
The precursor for complement C5a anaphylatoxin, C5, is a 1676 amino acid, 188 kDa protein whose gene is located at 9q33-9q34. Human C5a is an ~11 kDa, 74 amino acid glycoprotein released from the alpha-chain of C5 by C5 convertase enzymes. The N-linked glycosylation is not essential for function. Complement C5a has four anti-parallel alpha helices connected by peptide loops, stabilised by three critical disulphide linkages. Mutagenesis and antibody studies have identified several basic residues that are involved in the interaction with receptors. However, all of the agonist activity is located in the C-terminal region of C5a anaphylatoxin, which assumes an elongated 1.5 turn helix (critical for receptor activation) that spans residues 69-74 and is attached to the helical core by a four-residue loop.
Complement C5a anaphylatoxin, elicits a number of biological effects which are essential in the clearance of pathogens and for host defence, including increased vascular permeability, chemotaxis of inflammatory cells, respiratory burst, cytokine and chemokine release and phagocytosis. However, it is now known that the functions of C5a are not limited to the primary innate immune response. For example, the actions of C5a are also linked with the coagulation system and adaptive immunity. The consequence of C5a activation is dependent on the location of C5a receptors. The expression of its receptors, CD88 and C5L2, is widespread hence C5a elicits a broad range of biological functions.
|Cell Type||Action of Complement C5a Anaphylatoxin|
|Neutrophils||Adhesion molecule expression; Superoxide release; Release of granule enzymes; Cytokine release; Neutrophil apoptosis|
|Monocytes||Cytokine release; Chemotaxis|
|Macrophages||Enhanced phagocytosis; Cytokine release|
|Eosinophils||Chemotaxis; Granule enzyme release|
|Mast cells||Chemotaxis; Histamine release; Induce change to prothrombotic phenotype|
|T- lymphocytes||Co-stimulation; suppression of apoptosis|
|Endothelial cells||Vasodilation; Induce tissue factor activity; Adhesion molecule expression|
|Hepatocytes||Stimulate liver regeneration|
|Vascular smooth muscle cells||Contraction (indirectly)|
1. Chang J Y, et al. (2008). Denaturation and unfolding of human anaphylatoxin C3a: an unusually low covalent stability of its native disulfide bonds. Archives of biochemistry and biophysics, 480(2), 104-110.
2. Bajic G, et al. (2013). Human C3a and C3a desArg anaphylatoxins have conserved structures, in contrast to C5a and C5a desArg. Protein Science, 22(2), 204-212.