Complement system

The complement system

The complement system is an enzymatic cascade composed of around thirty participants whose purpose is the production of the membrane attack complex (MAC). However, certain intermediate players exert their own function, such as C4d forming tissue deposits or C3a, which is a powerful pro-inflammatory molecule.

It is one of the pillars of the non-specific immune reaction, although one of the activation pathways uses antibodies, which could make it an actor on the border of innate and specific immunity.

The components of the complement cascade are most often produced by the liver, but also by immunity actors, such as macrophages. Complement components represent approximately 15% of the globulin fraction of plasma proteins, or 3 mg/mL!

There are three pathways of complement cascade activation: the classical pathway, the lectin pathway, and the alternate pathway.

Regardless of the activation pathway:

1. The pivot of the complement cascade is represented by C3 convertase

   C3 convertase constitutes an important amplification step in the inflammatory reaction because a single C3 convertase molecule can cleave hundreds of C3 molecules. There are two types of C3 convertase, which have exactly the same effect, namely the cleavage of C3 into:

   • A small C3a fragment which is an anaphylatoxin.
   • A larger C3b fragment, which will attach to the C3 convertase to form the C5 convertase on the one hand, and have an opsonin function on the other hand.
2. The second crucial point in the cascade is C5 convertase

   C5 convertase cleaves C5 into:

   • A small C5a fragment, which is an anaphylatoxin.
   • A larger C5b fragment which initiates the formation of the membrane attack complex.
3. Formation of the membrane attack complex

   The membrane attack complex is a molecular structure capable of embedding itself in the membranes of cells or pathogens to induce their lysis. It is the product of the successive assembly of fragments C5b, C6, C7, C8, and then multiple C9, which form the pore itself.

The classical pathway

The formation of immune complexes allows the binding of the C1 complex, which will successively cleave C4 and C2 to form the C3 convertase C4b2a.

The lectin pathway

The recognition of certain carbohydrate motifs often associated with pathogens by lectins allows the binding of MASP. The lectin/MASP complex then behaves exactly like the C1 complex, and will therefore successively cleave C4 and C2 to form the same C3 convertase as in the classic pathway, namely C4b2a.

The alternative pathway

The C3 fragment, when present in large quantities in serum, is capable of autohydrolysing and recruiting protein B. The association of hydrolyzed C3 and the Bb fragment constitutes the C3 convertase of the alternative pathway, C3bBb. It should be noted that the C5 convertase of the alternative pathway is different from that of the classical pathway and the lectin pathway, but exerts strictly the same activity.

Function	Factors involved	Principle
Opsonization	C3b and C4b	C3b and C4b can attach to the surface of pathogens and cell membranes. They are then recognised by C3b and C4b receptors on the surface of phagocytic cells, which leads to the potentiation of their functions.
Enhanced inflammatory response	C3a, C4a, and C5a = ANAPHYLATOXINS	Anaphylatoxins enhance the inflammatory response via capillary vasodilation, increased vascular permeability, chemotaxis exerted on different leukocyte populations, and the production of free radicals.
Creation of the membrane attack complex	C5b, C6, C7, C8, and multiple C9	The membrane attack complex is responsible for cell lysis and lysis of pathogens thanks to osmotic phenomena
Enhanced antigen presentation	MBL, C1q, C3b, C4b, and C5a	C3b and C4b allow opsonization, which increases the ingestion of pathogens Anaphylatoxin chemotaxis routes antigen-presenting cells to the site of inflammation The C5a receptor, C5aR, induces the synthesis of IL12 by the antigen-presenting cell, which commits the CD4+ T cell to a TH1 profile
Enhanced humoral response	C3d, C3b, and C4b	C3d se lie de façon covalente à l’antigène. L’antigène est reconnu par le BCR tandis que le CD21 reconnait le C3d. Le CD21 est donc un co-récepteur de l’antigène renforçant la stabilité du complexe BCR/CD19/CD21
Endothelial and platelet activation	?	Microvascular thrombosis, itself inducing a pro-inflammatory state, inducing a vicious circle inflammation > thrombosis > necrosis > inflammation
Enhanced cytotoxic response		Little known mechanisms but C3 deficiency reduces CD8 and CD4 responses