Complement Anaphylatoxins

Complement Receptors of Complement System List

Complement Anaphylatoxin Functions C3a C4a C5a
Defined receptor + - +
Chemotaxis + ? +
Smooth-muscle contraction + ?  
Vascular permeability + ? +
Myeloid cell activation + - +
Platelet activation + - +
CD4/CD8 and γδ T cell modulation + - +
Induction of acute phase response (cytokine production) + - +
Developmental homing + - +
Regeneration + - +
Antimicrobial + + -
Cross-desensitization   ?  

Complement Anaphylatoxin Background

Complement C4a, C3a and C5a (in increasing order of activity) are all anaphylotoxins which cause basophil/mast cell degranulation and smooth muscle contraction. Undesirable effects of these peptides are controlled by carboxypeptidase B (C3a-INA). They cause smooth muscle contraction, histamine release from mast cells, and enhanced vascular permeability. They also mediate chemotaxis, inflammation, and generation of cytotoxic oxygen radicals. The proteins are highly hydrophilic, with a mainly alpha-helical structure held together by 3 disulfide bridges.

Anaphylatoxins are low-molecular-weight reaction products of the complement system that have phlogogenic activity. Two distinct forms have been described, one derived from the third (C3) and the other from the fifth (C5) components of complement. They are referred to as complement C3a and complement C5a, respectively.

The two peptides may readily be obtained from isolated human C3 and C5. Paradoxically, their activities could never be demonstrated in whole human serum under conditions known to result in dissociation of C3a and C5a. Failure to produce the anaphylatoxins in human serum had been interpreted in the past to indicate that they played no significant role in human biology.

The demonstration of a highly efficient inactivator of the anaphylatoxins in normal human serum (NHS) offered an alternate explanation. It was postulated that both peptides are liberated in human serum upon activation of the complement system, but that the expression of their biological activity is controlled by the anaphylatoxin inactivator (AI). Accordingly, it was anticipated that removal or inhibition of the inactivator would permit detection of both activities in whole human serum.

Complement Anaphylatoxin References

1. Barnum S R. (2015). C4a: an anaphylatoxin in name only. Journal of innate immunity, 7(4), 333-339.
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.
3. Vallota E H, et al. (1973). Formation of C3a and C5a anaphylatoxins in whole human serum after inhibition of the anaphylatoxin inactivator. The Journal of experimental medicine, 137(5), 1109-1123.