C4a: An Anaphylatoxin in Name Only

Abstract

Activation of complement leads to generation of the 3 anaphylatoxins C3a, C4a, and C5a. 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. Combined with the absence of an identified C4a receptor and the inability of C4a to signal through the C3a and C5a receptors, it is clear that C4a should not be included in the family of complement anaphylatoxins.

Increased interleukin-6 correlates with myelin oligodendrocyte glycoprotein antibodies in pediatric monophasic demyelinating diseases and multiple sclerosis

“…C3a may increase inflammation, as it is known to participate in chemoattraction of mast cells and macrophages (Godau et al, 2004), whereas the physiological role of C4a is less clear (Barnum, 2015).…”

Complement-activation fragment C4a mediates effector functions by binding as untethered agonist to protease-activated receptors 1 and 4

“…Although complement activation through the classical and lectin pathways leads to the release of an ∼10-kDa protein from component C4, termed C4a, that shares high homology with the anaphylatoxins, the receptor and biological functions of this activation fragment have thus far remained elusive (4). Previously, C4a had been reported to inhibit C3a-induced O 2…”

Pneumonia: host susceptibility and shared genetics with pulmonary function and other traits

“…The C4A gene encodes the acidic form of complement factor 4, which is part of the classical activation pathway. The C4A is referred to as an anaphylatoxin gene producing an anti‐microbial peptide and a mediator of local inflammation, although some recent work has shown that it should not be considered as a classical anaphylatoxin . The C4A gene product acts as an agonist for two protease‐activated receptors, PAR1 and PAR4.…”