Complement even exerts psychopharmacological control on eating and drinking behavior based on studies in rodents. C3a and C5a, 2 polypeptides derived from proteolytic cleavage of C3 and C5, respectively, mediate a significant number of the biological activities listed above. Collectively, complement C3a and C5a, along with C4a, a third polypeptide derived from cleavage of C4, are known as anaphylatoxins because of their ability to induce a variety of inflammatory responses which can be as severe as type I hypersensitivity allergic responses. Although all 3 peptides are structurally similar, only C3a and C5a share a similar functional profile that includes the classic inflammatory activities and, more recently, developmental homing and regenerative properties among others. In contrast, the functional profile of C4a is questionable in most cases owing to contamination of C4a preparations with physiologically relevant levels of C3a and/or C5a.
Despite the structural similarity between the complement anaphylatoxins, the functional profile of these proteins is dramatically different with respect to C4a. C3a and C5a share an amazing array of diverse functional properties that includes modulation of the innate and adaptive immune response, cell homing, and tissue regeneration. In contrast, C4a mediates almost none of these functions and, in those cases where a functional overlap is reported, closer inspection of the data suggests a significant weakness in the studies. The fundamental problem in most cases is the purity of the C4a preparations. For example, the initial studies identifying C4a as an anaphylatoxin were performed using human C4a in a guinea pig ileum contraction assay. C4a could induce ileum smooth muscle contraction but at concentrations ~ 100-fold higher than those used for complement C3a anaphylatoxin.
C4a and C3a both share antimicrobial activity toward Gram-negative and Gram-positive bacteria based on studies using purified proteins and 20-mer peptides derived from the sequence of various regions of both peptides. It should be noted however, that C3a/C4a antimicrobial activity is receptor independent, relying instead on the overall net charge, percentage of hydrophobic amino acids, and degree of amphipathicity of the peptides. Nevertheless, it is striking that the C4a biological activity is so limited relative to that of C3a and C5a. Although it is possible that C4a contributes to C3a/C5a-mediated immune functions, until more rigorous studies are performed, the in vitro and in vivo data to date fails to support its moniker as an anaphylatoxin.
1. Barnum S R. (2015). C4a: an anaphylatoxin in name only. Journal of innate immunity, 7(4), 333-339.