Complement Anaphylatoxin

Anaphylatoxin refers to the active fragments C3a, C4a, C5a that have inflammatory mediator effects during complement activation. Of the three anaphylatoxin, C5a has the strongest effect, followed by C3a, and no clear role for C4a has been found in humans.

Discovery and Introduction of Anaphylatoxin

Friedberger discovered that C5a, a cleavage fragment of complement C5, could be toxic to guinea pigs in 1910, so he called C5a anaphylatoxin. In 1967, researchers also found that C3 cleavage fragment C3a also has similar activity. Since then, in 1979, another weakly active anaphylatoxin C4a was also discovered. Therefore, there are three types of anaphylatoxin that have been found and confirmed, namely C3a, C4a and C5a. C3a, C4a and C5a are produced by cleavage near the N-terminus of the κ chains of complements C3, C4 and C5, respectively. They are all small molecular peptides, conformationally stable, pH resistant (pH 1-12), and heat resistant. The homology of the primary structure of human C3a with C4a and C5a is 31% and 39%, respectively. These anaphylatoxin can bind to corresponding receptors on the surface of mast cells and basophils, stimulate cell degranulation, release active media such as histamine, cause symptoms such as vasodilation, increased permeability, smooth muscle contraction, bronchospasm and other symptoms.

Fig. 1 The anaphylatoxins impact on intrinsic T cell and DC-mediated activation.¹

Activity, Structure And Receptor of Anaphylatoxin

Anaphylatoxin is composed of 76 amino acids and has a molecular weight of about 10 kD. All three anaphylatoxin contain 6 cysteine residues, and the relative positions of these 6 cysteine are conserved, forming three in-chain disulfide bonds. These three intra-chain disulfide bonds can stabilize the conformation of the core region. Studies have found that if the disulfide bonds are broken, the activity of anaphylatoxin will be significantly weakened. In addition, the N-terminus and C-terminus outside the core region of the anaphylatoxin skeleton are folded in a spiral to form a tertiary structure. Circular dichroism tests show that 40-50% of anaphylatoxin have α helices. Only when this helix structure is present can anaphylatoxin exhibit sufficient biological activity. Rat C5a activity is much stronger than human C5a, which may be caused by different secondary structure conformations. The C-terminus of anaphylatoxin is a pentapeptide structure, and the end of this pentapeptide is the site where anaphylatoxin binds to its receptor.

Anaphylatoxin can act on a variety of cells, of which polymorphonuclear leukocytes are an important one. C3a and C5a bind to their specific receptors C3aR and C5aR to induce an inflammatory response. Local tissues of inflammation bind complement C3a to C3aR on the surface of dendritic cells through autocrine or paracrine effects, and then up-regulate the functions of dendritic cell costimulatory molecules (CD80, CD86, CD40) and MHC-II molecules. This reactive T cell proliferates and expands the immune cascade. At the same time, the binding of C3a to C3aR on the surface of dendritic cells can also induce the release of pro-inflammatory factors (such as IL-2, IL-23), activate the IL-23 / Th17 / IL-17, and recruit concentrated granulocyte airways to aggregate. It also acts on airway epithelial cells to produce chemokine 1 and chemokine 8, causing neutrophil inflammation in the airway.

Biological Actions of Anaphylatoxin

1. Anaphylatoxic Effect

Once the anaphylatoxin receptors on mast cells and basophils are activated, these cells undergo degranulation, releasing histamine and other vasoactive or inflammatory mediators, resulting in anaphylatoxic effects such as smooth muscle contraction, increased capillary permeability, vasodilation, and anaphylactic shock.

1. Phagocyte-activating Effect

Anaphylatoxins is a strong activator of neutrophils and monocytes / macrophages. After activating neutrophils, anaphylatoxins can increase the adhesion of neutrophils, cause the accumulation of neutrophils, start the release of anti-microbial substances such as lysozyme, defensins, and stimulate the oxidative metabolism of neutrophils and the production of toxic reactive oxygen species. In addition, anaphylatoxins can activate monocytes or macrophages, enhance their cytotoxic activity, and stimulate them to produce inflammatory mediators such as cytokines and chemokines.

1. Immunoregulatory Effect

C3a and C5a interact with anaphylatoxin receptors on antigen-presenting cells (APC) such as macrophages and DC cells, which can promote APC recruitment, upregulation of MHC and costimulatory molecules, and production of inflammatory cytokines. C3a and C5a can also regulate the activation of APCs, thereby altering the polarization of subsequent T cells. The interaction of C3a and C5a receptors on T cells with C3a and C5a can serve as survival signals. Therefore, anaphylatoxins play a role in the regulation of innate and adaptive immune responses.

Pathophysiological Effects of Anaphylatoxin

The physiological functions of anaphylatoxins are mainly involved in the host's immune defense and inflammatory response. C3 or C5 gene-deficient individuals often develop severe recurrent bacterial infections due to lack of the terminal membrane attack complex and anaphylatoxins. Anaphylatoxins are also associated with almost all types of inflammation, and when their inflammatory effects are excessive, they can be harmful to the host and cause various diseases.

Diseases related to anaphylatoxins include:

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Reference

1. Schanzenbacher, Jovan, Jörg Köhl, and Christian M. Karsten. "Anaphylatoxins spark the flame in early autoimmunity." Frontiers in Immunology 13 (2022): 958392.
2. From Wikipedia: By Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute, https://commons.wikimedia.org/wiki/File:PDB_1c5a_EBI.jpg

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