Complement is an essential element of the immune system of vertebrates and humans, which plays a key role in the humoral mechanism of the body's defense against pathogens. The term was first introduced by Erlich to designate a component of blood serum, without which its bactericidal properties disappeared. Subsequently, it was found that this functional factor is a set of proteins and glycoproteins, which, when interacting with each other and with a foreign cell, cause its lysis.
Complement literally translates as "supplement". Initially, it was considered just another element that provides the bactericidal properties of live serum. Modern ideas about this factor are much broader. It has been established that complement is a highly complex, finely regulated system that interacts with both humoral and cellular factors of the immune response and has a powerful effect on the development of the inflammatory response.
General characteristics
In immunology, the complement system is a group that exhibits bactericidal propertiesinteracting with each other proteins of the blood serum of vertebrates, which is an innate mechanism of the body's humoral defense against pathogens, capable of acting both independently and in combination with immunoglobulins. In the latter case, complement becomes one of the levers of a specific (or acquired) response, since antibodies by themselves cannot destroy foreign cells, but act indirectly.
The effect of lysis is achieved due to the formation of pores in the membrane of a foreign cell. There may be many such holes. The membrane-perforating complex of the complement system is called MAC. As a result of its action, the surface of the foreign cell becomes perforated, which leads to the release of the cytoplasm to the outside.
Complement accounts for about 10% of all serum proteins. Its components are always present in the blood, without any effect until the moment of activation. All effects of complement are the result of successive reactions - either splitting its proteins, or leading to the formation of their functional complexes.
Each stage of such a cascade is subject to strict reverse regulation, which, if necessary, can stop the process. Activated complement components exhibit a wide range of immunological properties. At the same time, the effects can have both positive and negative effects on the body.
Main functions and effects of complement
The action of the activated complement system includes:
- Lysis of foreign cells of bacterial and non-bacterial nature. It is carried out due to the formation of a special complex that is embedded in the membrane and makes a hole in it (perforates).
- Activation of immune complex removal.
- Opsonization. Attaching to the surfaces of targets, complement components make them attractive to phagocytes and macrophages.
- Activation and chemotactic attraction of leukocytes to the focus of inflammation.
- Formation of anaphylotoxins.
- Facilitation of the interaction of antigen-presenting and B-cells with antigens.
Thus, complement has a complex stimulating effect on the entire immune system. However, excessive activity of this mechanism can adversely affect the state of the body. Negative effects of the complement system include:
- Worse course of autoimmune diseases.
- Septic processes (subject to mass activation).
- Negative effect on tissues in the focus of necrosis.
Defects in the complement system can lead to autoimmune reactions, i.e. damage to he althy tissues of the body by its own immune system. That is why there is such a strict multi-stage control of the activation of this mechanism.
Complement proteins
Functionally, the proteins of the complement system are divided into components:
- Classic way (C1-C4).
- Alternative path (factors D, B, C3b and properdin).
- Membrane Attack Complex (C5-C9).
- Regulatory faction.
C-protein numbers correspond to the sequence of their detection, but do not reflect the order of their activation.
Regulatory proteins of the complement system include:
- Factor H.
- C4 binding protein.
- FOOD.
- Membrane cofactor protein.
- Complement receptors type 1 and 2.
C3 is a key functional element, since it is after its breakdown that a fragment (C3b) is formed, which attaches to the membrane of the target cell, starting the process of formation of the lytic complex and triggering the so-called amplification loop (positive feedback mechanism).
Activation of the complement system
Complement activation is a cascade reaction in which each enzyme catalyzes the activation of the next. This process can occur both with the participation of the components of acquired immunity (immunoglobulins), and without them.
There are several ways to activate complement, which differ in the sequence of reactions and the set of proteins involved in it. However, all these cascades lead to one result - the formation of a convertase that cleaves the C3 protein into C3a and C3b.
There are three ways to activate the complement system:
- Classic.
- Alternative.
- Lectin.
Among them, only the first one is associated with the acquired immune response system, while the rest have a non-specific action.
In all activation pathways, 2 stages can be distinguished:
- Starting (or actually activation) - turns on the entire cascade of reactions until the formation of C3/C5-convertase.
- Cytolytic - means the formation of a membrane attack complex (MCF).
The second part of the process is similar in all stages and involves proteins C5, C6, C7, C8, C9. In this case, only C5 undergoes hydrolysis, while the rest simply attach, forming a hydrophobic complex that can integrate and perforate the membrane.
The first stage is based on the sequential launch of the enzymatic activity of proteins C1, C2, C3 and C4 by hydrolytic cleavage into large (heavy) and small (light) fragments. The resulting units are denoted by small letters a and b. Some of them carry out the transition to the cytolytic stage, while others act as humoral factors of the immune response.
Classic way
The classical pathway of complement activation begins with the interaction of the C1 enzyme complex with the antigen-antibody group. C1 is a fraction of 5 molecules:
- C1q (1).
- C1r (2).
- C1s (2).
At the first step of the cascade, C1q binds to immunoglobulin. This causes a conformational rearrangement of the entire C1 complex, which leads to its autocatalytic self-activation and the formation of the active enzyme C1qrs, which cleaves the C4 protein into C4a and C4b. In this case, everything remains attached to the immunoglobulin and, therefore, to the membranepathogen.
After the implementation of the proteolytic effect, the antigen group - C1qrs attaches the C4b fragment to itself. Such a complex becomes suitable for binding to C2, which is immediately cleaved by C1s into C2a and C2b. As a result, the C3-convertase C1qrs4b2a is created, the action of which forms the C5-convertase, which triggers the formation of MAC.
Alternative path
This activation is otherwise called idle, since C3 hydrolysis occurs spontaneously (without the participation of intermediaries), which leads to periodic causeless formation of C3-convertase. An alternative route is carried out when specific immunity to the pathogen has not yet been formed. The cascade consists of the following reactions:
- Blank hydrolysis of C3 to form C3i fragment.
- C3i binds to factor B to form the C3iB complex.
- Bound factor B becomes available for cleavage by the D-protein.
- The Ba fragment is removed and the C3iBb complex remains, which is the C3 convertase.
The essence of blank activation is that in the liquid phase C3-convertase is unstable and rapidly hydrolyzes. However, upon collision with the membrane of the pathogen, it stabilizes and starts the cytolytic stage with the formation of MAC.
Lectin pathway
The lectin pathway is very similar to the classical one. The main difference lies in the firstactivation step, which is carried out not through interaction with immunoglobulin, but through the binding of C1q to the terminal mannan groups present on the surface of bacterial cells. Further activation is completely identical to the classical path.
