ANAPHYLLOTOXINS: TYPES, FUNCTIONS AND RECEPTORS - BIOLOGY - 2024

The anaphylatoxins are peptide fragments of low molecular weight are generated by activation of the complement system. They are highly hydrophilic, with an alpha helix structure linked by 3 disulfide bridges.

They are proteolytically activated by cleavage at a specific site, forming a and b fragments. These peptides bind to specific receptors expressed on the surface of cells and amplify a variety of inflammatory reactions, acting as cell activators.

Anaphyllotoxin C5a protein. By Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute, from Wikimedia Commons.

Its effector functions include chemotaxis, release of inflammatory mediators, and activation of granulocytes, mast cells, and macrophages. Recently, it has also been shown that anaphylatoxins are generated locally within tissues by the presence of pathogens.

Types

Anaphyllotoxins include the C3a, C5a, and C4a peptides. These are low molecular mass cleavage fragments (~ 10 kDa) of the α chain of complement components C3, C4, and C5, respectively, that are released during complement activation.

However, it should be noted that for C4a, it has only been shown that it binds to its receptor with low affinity and no specific receptor for it has been identified.

For its part, C5a is the most potent of these peptides, that is, it promotes inflammation and is a strong chemo attractant for neutrophils, macrophages and monocytes.

Although lower vertebrates possess complement systems that are believed to function similarly to those of mammals, anaphylatoxin receptors have not been previously characterized in any non-mammalian vertebrates.

Features

Anaphyllotoxins are generated from enzymatic cleavage during the course of complement activation through classical, lectin, or alternative pathways.

In the complement activation cascade, cleavage of C3 or C5 by C3 or C5 convertases leads to the generation of a large fragment, C3b or C5b, and a small peptide fragment, C3a or C5a.

C3b and C5b continue the complement activation cascade on microbial or cell surfaces, while C3a and C5a are released in the fluid phase to act as anaphylatoxins, which mediate various biological actions.

They increase vascular permeability, stimulating smooth muscle contractions and inducing the release of histamine from mast cells and secretory granules from granulocytes and macrophages.

Furthermore, C5a, one of the most potent peptides, is a powerful chemoattractant for neutrophils and other leukocytes.

Chemoattractant properties have not yet been attributed to C4a, whereas those of C3a seem to target mainly eosinophils, mast cells, and hemopoietic stem cells, smooth muscle contraction, increased permeability of blood capillaries, and even anaphylactic shock.

Summary of the complement cascade activation pathway. By Perhelion, from Wikimedia Commons.

Association of C5a and C3a with pathogenesis

Although inflammation mediated by C5a and C3a play an important role in infection control, a number of clinical studies have shown that they are also associated with the pathogenesis of various inflammatory and autoimmune diseases such as sepsis, systemic lupus erythematosus (SLE), pregnancy loss, antiphospholipid antibody syndrome (APS), ischemia and asthma.

Thus, it has been suggested that attacking C5a and C3a receptors and / or ligands could reduce unwanted inflammatory responses, as well as tissue damage in certain pathological conditions. C5a and C3a can be efficient therapeutic targets.

Receivers

In general, anaphylatoxins exert the majority of biological activities through the binding of three related receptors, that is; the C3a receptor, the C5a receptor and the C5a-like receptor, C5L2.

In humans, three types of transmembrane receptors have been identified that mediate the actions of anaphylatoxins: C3aR, which specifically binds to C3a; the C5aR, which binds to C5a; and C5L2, for which all three anaphylatoxins can be ligands.

The first two receptors are coupled to regulatory G proteins, whereas the C5L2 receptor has been shown to miscouple to G protein-mediated signaling pathways.

The distribution of these receptors is not limited to leukocytes. They are also expressed in many non-myeloid cell types, including hepatocytes, lung epithelial cells, endothelial cells, brain astrocytes, and microglial cells.

In these cell types, they can mediate the participation of anaphylatoxins in various vascular, pulmonary, regenerative, and degenerative neurological conditions.

If anaphylatoxins do not bind to their receptors, they are rapidly digested by plasma carboxypeptidases, which remove the C-terminal arginine residue from each peptide.

Arginine derivatives are inactive or have activities 10 to 1000 times lower than native peptides.

Complement systems in lower vertebrates

Lower vertebrates, such as reptiles, amphibians, and fish, possess complement systems that, in many ways, are considered functionally similar to those of mammals.

Complement-mediated protective immune responses, such as cytolysis and opsonization, have been demonstrated in some of these animals.

Recently, the C3a of the tunicate Ciona intestinalis has been shown to possess chemotactic activities for tunicate hemocytes, suggesting the presence of a C3aR receptor in these animals.

Protochordates, for their part, may not have C4a and C5a, so it is believed that the classical complement activation pathway, which produces C4a, and the lytic pathway, which generates C5a, are absent in these animals.

However, gnathostomous fish possess all known complement activation pathways, and C3, C4 and C5 molecules have been identified from several species of fish. Interestingly, fish have multiple isoforms of several of the complement components, including C3, C2 / Bf, C4, and C5.

Although different functions have been suggested for the C3 isoforms, it remains to be established whether there are different receptors for these isoforms.

References

1. From Yang. Anaphylatoxins. Handbook of Biologically Active Peptides.pp.625-630
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5. Ogata RT, Rosa PA, Zepf NE. Sequence of the gene for murine complement component C4. The Journal of Biological Chemistry. 1989, 264 (28): 16565-16572.
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