Complement is the most important element of the immune system of vertebrates and humans, playing a key role in the humoral mechanism of protecting the body from pathogens. The term was first coined by Ehrlich to refer to a component of the 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 to “complement." Initially, it was considered only one more element providing bactericidal properties of living serum. Modern ideas about this factor are much wider. It was found that complement is a 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, a complement system is a group of vertebral blood serum proteins that exhibit bactericidal properties, which is an innate mechanism of the humoral defense of the body from pathogens, which can act 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 alone cannot destroy foreign cells, but act indirectly.
The lysing effect is achieved due to the formation of pores in the membrane of a foreign cell. There can be many such holes. The membrane perforating complex of the complement system is called MAK. As a result of its action, the surface of a foreign cell becomes perforated, which leads to the exit of the cytoplasm to the outside.
About 10% of all whey proteins are in complement. Its components are always present in the blood, having no effect until activation. All the effects of complement are the result of successive reactions - either splitting the constituent 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. In this case, the effects can have both positive and negative effects on the body.
The main functions and effects of complement
The action of the activated complement system includes:
- Lysis of foreign cells of a bacterial and non-bacterial nature. It is carried out due to the formation of a special complex, which is embedded in the membrane and makes a hole in it (perforates).
- Activation of the removal of immune complexes.
- Opsonization. By joining the surfaces of the targets, the components of the complement make them attractive to phagocytes and macrophages.
- Activation and chemotactic involvement of leukocytes in the focus of inflammation.
- The 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, the excessive activity of this mechanism can negatively affect the state of the body. The negative effects of the complement system include:
- Deterioration of autoimmune diseases.
- Septic processes (subject to mass activation).
- Negative effect on tissue in the focus of necrosis.
Defects in the complement system can lead to autoimmune reactions, i.e. damage to healthy 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:
- The classic way (C1-C4).
- An alternative route (factors D, B, C3b and properdine).
- Membrane-attacking complex (C5-C9).
- Regulatory fraction.
The numbers of C-proteins 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 of the first and second type.
C3 is a key functional element, because it is after its decay that a fragment (C3b) is formed, which joins the membrane of the target cell, starting the process of formation of the lytic complex and starting the so-called amplification loop (positive feedback mechanism).
Complement system activation
Activation of complement is a cascade reaction in which each enzyme catalyzes the activation of the subsequent one. This process can occur both with the participation of 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 convertase, which cleaves the C3 protein into C3a and C3b.
There are three ways to activate the complement system:
- Classical.
- Alternative.
- Lectin.
Among them, only the first is associated with the acquired immune response system, while the rest are of a non-specific nature.
In all activation paths, 2 stages can be distinguished:
- Start-up (or activation itself) - includes the entire cascade of reactions until the formation of the C3 / C5 convertase.
- Cytolytic - refers to the formation of a membrane-attacking complex (MKF).
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, and the rest simply attach, forming a hydrophobic complex that can integrate and perforate the membrane.
The first stage is based on the sequential start of the enzymatic activity of the C1, C2, C3 and C4 proteins by hydrolytic cleavage into large (heavy) and small (light) fragments. The resulting units are indicated by the lowercase letters a and b. Some of them make the transition to the cytolytic stage, while others play the role of humoral factors in the immune response.
Classic way
The classical complement activation pathway begins with the interaction of the C1 enzyme complex with the antigen-antibody group. C1 is a fraction of 5 molecules:
In 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 C1qrs enzyme, which breaks down the C4 protein into C4a and C4b. In this case, everything remains attached to the immunoglobulin and, therefore, to the pathogen membrane.
After the implementation of the proteolytic effect, the antigen group C1qrs attaches a C4b fragment to itself. Such a complex becomes suitable for binding to C2, which, under the action of C1s, immediately splits into C2a and C2b. As a result, a C3 convertase C1qrs4b2a is created, the action of which forms a C5 convertase, which triggers the formation of MAA.
Alternative way
Such activation is otherwise called idle, since C3 hydrolysis occurs spontaneously (without intermediaries), which leads to periodic unreasonable formation of C3 convertase. An alternative route is when specific immunity to the pathogen has not yet formed. In this case, the cascade consists of the following reactions:
- Idle hydrolysis of C3 to form a C3i fragment.
- C3i binds to factor B to form the C3iB complex.
- Bound factor B becomes available for D-protein cleavage.
- The Ba fragment is removed and the C3iBb complex remains, which is the C3 convertase.
The essence of idle activation is that in the liquid phase, C3-convertase is unstable and quickly hydrolyzes. However, upon collision with the membrane of the pathogen, it stabilizes and starts the cytolytic stage with the formation of MAA.
Lectin path
The lectin path is very similar to the classic one. The main difference lies in the first stage of activation, which is carried out not through interaction with immunoglobulin, but through C1q binding to terminal mannan groups present on the surface of bacterial cells. Further activation is carried out completely identical to the classical path.