Complement system
The complement system is one of the fundamental components of the well-known defensive immune response against a hostile agent (for example, microorganisms). It consists of a set of plasma molecules involved in different biochemical cascades, whose functions are to enhance the inflammatory response, facilitate phagocytosis, paralyze pathogens and direct cell lysis, including apoptosis. They constitute 15% of the immunoglobulin fraction of the serum.
History
It was discovered more than a century ago, when the bactericidal capacity of fresh serum was verified, an action mediated by two factors: one thermo-stable (specific antibodies against microorganisms) and another thermolabile, which was called the plugin. The components themselves are named with the letter C and a number: C1, C2, C3, C4, C5, C6, C7, C8, and C9.
Waterfalls
It is made up of approximately 30 glycoproteins and fragments found in serum and other organic fluids in an inactive form, and which, when activated sequentially, produce a series of reactions with the aim of destroying the target cell. The system is activated in three different ways.
Classic way
So named because it was first discovered. Its activation is initiated by immune complexes made up of IgG (immunoglobulin G) and IgM (immunoglobulin M). This pathway begins with the union of two (in the case of IgG involvement) or more (in the case of IgM) immunoglobulin molecules bound to the respective antigens by producing allosteric changes at the Fc terminus.
C1q
The Fc fragments of the antibodies thus bound to their antigens bind to the radiating arms of the C1q molecule which will recruit C1r and C1s. Binding to C1q of more than one Fc portion of the Ig is required to stabilize the C1qrs pool. This poly-Fc:C1qrs complex in turn causes proteolysis (by C1s) of C4 into C4a and C4b and C2 into C2a and C2b. At this point C4b and C2b will form a complex that will be located on the surface of the target cell, the C3 convertase, as detailed later. C1 would continue with its enzymatic activity degrading many C4 molecules until it was inactivated by its inhibitor.
C1q molecules are not associated with the opsonization process, since their function is to be the enzyme that initiates the classical complement cascade. C1q can also be activated by C-reactive protein (acute phase protein that binds phosphocholine to dying cells and pathogens).
C3 convertase
C3a, C4a and C5a have functions of anaphylotoxins, favoring the degranulation of mast cells, thus releasing histamine, a substance that promotes inflammation. C4b binds covalently to the invading cell membrane or to an immune complex and to C2b in the presence of Mg++, forming the classical pathway C3 convertase, called C4bC2b. C3 convertase has a potent proteolytic action on factor C3, cleaving it into C3a and C3b (C3a is also anaphylotoxin). The binding of C3b on the membrane in question is a critical element for the process of opsonization by phagocytes.
(In many old books it says that the fragment that binds with C4b is C2a. This has to be discarded, the WHO said that the fragment that binds to C4b is C2b and therefore the convertase is formed by C4bC2b)..
C5 convertase
C3b binds to the C4bC2b complex, forming the C5 convertase of the classical pathway made up of C4bC2bC3b. This will cause cleavage of C5 into components a and b. As with the previous ones, C5a is an anaphylatoxin that degranulates mast cells and releases their intracellular mediators and is also a chemotactic factor. The C5b component will bind to the membrane stabilized by C6, particularly due to the hydrophobic nature of C5b. C7 inserts into the lipid bilayer of the membrane bound to the C5bC6b complex further stabilizing the lytic sequence against the invader. The other factors C8 and Poly-C9 will be fixed (the latter contributing from 12 to 15 units). When the components have joined, a cylindrical pore is formed in the cell that allows the passage of ions and water, causing cell lysis due to osmotic imbalance. This set of proteins that make up the pore is known as MAC: Membrane Attack Complex.
Alternative route
Phylogenetically more primitive, its activation is initiated by immunoglobulins, by polysaccharides and similar polymeric structures (bacterial lipopolysaccharides, for example those produced by gram negative bacilli). This pathway constitutes a state of permanent activation of the C3 component that generates C3b. In the absence of foreign microorganisms or antigens, the amount of C3b produced is inactivated by Factor H. When C3 binds to an invading surface (evades the action of Factor H), it forms a complex with Factor B, which is cleaved by action of factor D in the presence of Mg++. The C3bBb complex is highly unstable and the alternative pathway does not continue without the stabilizing role of a circulating protein called properdin or P. The alternative pathway C3 convertase (composed of C3bBbP) is thus formed, which acts enzymatically on additional molecules of C3, initiating the amplification cycle. Even some of this C3b can bind to C3 convertase and form the C5 convertase of the alternative pathway (C3bBbPC3b) that will hydrolyze C5 into C5a and C5b, converging on the same final steps of the classical pathway.
Lectin pathway
It is a kind of variant of the classical route, however it is activated without the need for the presence of antibodies. Activation is carried out by means of an MBL (mannose binding lectin / mannose binding lectin) or also called MBP (mannan-binding protein / mannose binding protein), which detects residues of this sugar on the bacterial surface, and activates the C1qrs complex. Otherwise, a second esterase, the esterase associated with MBP (called MASP, from the acronym for MBL associated serine proteases / MBL associated with serine proteases, and of which there are different types: MASP-1, MASP-2, MASP- 3 and MAP, with MASP-2 being the most common) acts on C4. The rest of the route is similar to the classic one.
These pathways produce an enzyme with the same specificity: C3; and from the activation of this component they follow a common activation terminal sequence. The purpose of this complement system through its three pathways is the destruction of microorganisms, the neutralization of certain viruses, and the promotion of the inflammatory response, which facilitates the access of immune system cells to the site of infection.
The functions of the plugin system
A. Cell lysis
MAC (membrane attack complex) can lyse gram-negative bacteria, parasites, encapsulated viruses, erythrocytes, and nucleated cells. Gram-positive bacteria are quite resistant to complement action.
b. Inflammatory response
The small fragments that result from the fragmentation of complement components, C3a, C4a and C5a, are called anaphylatoxins. These bind to receptors on mast cells or mast cells and basophils. The interaction induces its degranulation, releasing histamine and other pharmacologically active substances. These substances increase permeability and vasodilation. Likewise, C3a, C5a and C5b67 induce monocytes, macrophages and neutrophils to adhere to the endothelium to initiate their extravasation.
C. Opsonization
C3b is the main complement opsonin. C3b-coated antigens bind to specific receptors on phagocytic cells, and thus phagocytosis is facilitated.
D. Virus neutralization
C3b induces the aggregation of viral particles forming a thick layer that blocks the attachment of the virus to the host cell. This aggregate can be phagocytosed through the interaction of complement receptors and C3b on phagocytic cells.
E. Elimination of immune complexes
Immune complexes (circulating antigen-antibody complexes) can be cleared from the circulation if the complex binds to C3b. Red blood cells have type 1 complement receptors that interact with C3b-coated immune complexes and deliver them to the liver and spleen for destruction.
Additional images
Classical
Alternative
Classical
