The term “complement” was first proposed by Borclet as a result of the observation that in order to realize a number of immunological effects (hemolysis, bactericidal activity), along with antibodies, a serum factor is required, which is destroyed when heated to +56°C. Over 70 years of studying complement, it has been established that it is complex system of 11 whey proteins whose activity is regulated by at least as many factors. Complement is a system of cascade-acting highly efficient proteases that are sequentially activated by the cleavage or attachment of peptide fragments and ultimately leads to bacteriolysis or cytolysis. In terms of complexity, the complement system is comparable to the blood coagulation system, with which it is connected, like the kinin system, by functional connections. In phylogenesis, the complement system appeared before the immune system. Ontogenetically, this is manifested in the fact that already a 6-week fetus is able to synthesize individual components of the system, and from the 10th week the hemolytic activity of the synthesized factors can be detected, although normal concentrations of all C-components are determined only during the first year after birth. Of the total amount of whey proteins, the complement system accounts for about 10%. It is the basis of the body's defenses. Functional defects of the complement system can lead to severe recurrent infections and pathological conditions caused by immune complexes. There is a direct functional connection between the complement system and the phagocytic system, since direct or antibody-mediated binding of complement components to bacteria is a necessary condition for phagocytosis (opsonization of microorganisms). Complement is the dominant humoral component of the inflammatory response, since its products are chemotaxins and anaphylactoxins, which have a pronounced effect on phagocytes, metabolism and the blood coagulation system. Thus, complement is considered an important element of the resistance system, as well as an effective part of humoral immunity. In addition, the complement system includes important factors regulating the immune response.
Synthesis and metabolism of C-factors. The formation of C-factors occurs mainly in the liver, bone marrow and spleen. A special position is occupied by C1, which is apparently synthesized in the epithelium of the small intestine. Macrophages play a decisive role in the synthesis of complement components, which reflects the close phylogenetic relationship between these two systems. Continuous use of C-factors in the body and high level their catabolism determines the need for their continuous synthesis, and the rate of synthesis is relatively high. For C3, for example, 0.5-1.0 mg of protein per 1 kg of weight is synthesized hourly. Both activation and inhibition, and consumption and synthesis are in labile equilibrium. At the same time, serum concentrations of individual factors, on the one hand, and the content of fragments and cleavage products, on the other, make it possible to assess the state and level of activation of the entire system.
C-factors usually consist of several polypeptide chains. C3, C4 and C5 are synthesized in the form of a single polypeptide chain, as a result of proteolytic cleavage of which either C3 and C5 or only C4 are formed. Polypeptide chains C1 and C8 are synthesized separately. Glucosylation occurs immediately before secretion and is a necessary prerequisite for this process.
A decrease in the synthesis of complement components is observed when serious illnesses liver, uremia and the use of high concentrations of corticosteroids, affecting mainly C3, C4 and C5. A reduced concentration of C3 in serum is also determined in chronic immune complex pathology due to the activation of an alternative pathway with increased consumption of this component. At the same time, a decrease in the synthesis of this component may occur, which indicates the existence of a negative feedback loop in the regulation of its synthesis through C3d.
Mechanisms of activation of the complement system. Activation after the initial stage can develop in several directions:
The classical pathway of complement activation, starting with C1;
Alternative path activation of complement starting from C3;
Specific activation of complement with the formation various products splitting.
I. The classical pathway of activation of the complement system. The classical pathway of complement activation is an immunologically driven process initiated by antibodies. Immunological specificity is ensured by the interaction of antibodies with antigens of bacteria, viruses and cells. The antigen-antibody reaction is associated with a change in the configuration of the immunoglobulin, which leads to the formation of a binding site for Clq on the Fc fragment near the hinge region. Immunoglobulins can bind to C1. Activation of C1 occurs exclusively between two Fc fragments. Therefore, the activation cascade can be induced by even a single IgM molecule. In the case of IgG antibodies, the proximity of two antibody molecules is necessary, which imposes strict restrictions on the density of antigen epitopes. In this regard, IgM is a much more effective initiator of cytolysis and immune opsonization than IgG. Quantitatively, this estimate corresponds to a value of 800:1. The process of complement activation itself can be divided into certain stages:
1- recognition of immune complexes and formation of C1;
2 - formation of C3-convertase and C5-convertase;
3 - formation of a thermostable complex C5b, 6,7;
4 - membrane perforation.
Membrane perforation. Each C5b, 6,7 complex formed, regardless of membrane binding or S-protein shielding, is associated with 1 C8 molecule and 3 C9 molecules. The free C5b-C9 complex acts hemolytically, while the complex with the S protein does not have this effect. Two membrane-associated C5b-C9 complexes form a ring pair in the membrane, which leads to a sharp change in osmotic pressure in the cell. If erythrocytes are highly sensitive to the formation of such a membrane defect, then nucleated cells are capable of repairing defects of this type and have a certain resistance to complement attack. In this regard, the determining factor in the interaction of complement with the membrane is the total number of Clg molecules bound to the cell, which depends on the number and class of antibodies bound to the cell. Among bacteria, there are species that are resistant to the action of complement. In this case, the effect of opsonization of microorganisms followed by phagocytosis is decisive. Lysozyme plays a certain role in the attack of gram-negative bacteria by complement. Some features of complement activation arise from general patterns and are determined by the initial activation of C1 by soluble or precipitated immune complexes. The reaction proceeds identically until the formation of the C5b, 6,7 complex, which leads to the production of chemotactic factors and anaphylatoxins. Similar processes occur with intravenous administration of aggregated IgG. Clinical manifestations in this case they can vary from serum sickness to anaphylactic shock. The combination of Fc fragments with adhesive components C5b, 6,7 in soluble immune complexes can lead to their deposition on endothelial cells and association with blood cells, causing whole line systemic lesions. Such immune complex mechanisms create the basis for allergic reactions. type III, a cascade of complement activation reactions, an avalanche-like involvement of complement components in the reaction with an increase in the number of pharmacologically active fragments.
Alternative pathway of complement activation. With the alternative pathway of complement activation, factors C1, C4, C2 are not involved in the reactions. Activation begins when C3 is split into fragments C3a and C3b. The further course of the process is identical to the classical path.
Pillemer first described the Mg+ dependent “properdin system”, in which C3 was activated by zymosan (a polysaccharide) without the participation of antibodies. Other insoluble polysaccharides can also act as activators (inulin, high molecular weight dextran), in addition, bacterial endotoxins aggregated IgG4, IgA and IgE can serve as activators, immune complexes with F fragments, proteases (plasmin, trypsin), cobra venom factor, C3b. In the alternative activation pathway, two C3 convertases act. C3Bb has insignificant activity and appears when C3 interacts with B, D and properdin. C3Bb releases a small amount of C3b, which leads to the formation of a highly active C3b convertase, which results in C3b. Positive feedback occurs, significantly enhancing the response. Suppression of such spontaneous enhancement is carried out by C3b-INA, which inhibits C3b formed in a soluble form. Cobra venom factor is a functional and structural analogue of C3b, but is not inhibited by C3b-INA. Endotoxins and polysaccharides activate properdin and thereby create conditions for the binding and stabilization of C3b, which is inhibited by C3b-INA only in the free state. The defining step in the alternative activation pathway is the formation of C3b, which is transferred to the activated surface. The process begins with the binding of C3b to B, and this stage depends on the presence of Mg2+. C3bB is activated by D into the C3b Bb complex. Properdin binds C3b and thus stabilizes the spontaneously dissociating Bb complex. A specific inhibitor of the alternative pathway is B1H. It competes with factor B for the C3b bond, displacing it from the C3bB complex and making C3b available for the action of C3b-INA. The cytolytic activity of the alternative pathway is completely determined by the properties of the microbial shell and cell membrane. Glycoproteins and glycolipids containing terminal sialic acid residues impart resistance to the membrane to the action of alternatively activated complement, while treatment with neuraminidase abolishes this resistance and makes cells highly sensitive. Sialic acids play an important role in microbial resistance. Most types of bacteria do not contain sialic acids in their shell, but many pathogenic species do. Antibodies can change surface properties and thus increase the sensitivity of targets to complement. An important stage surface activation involves the binding of properdin, resulting in the formation of a high-affinity receptor for C3b and at the same time the formation of a stable C3Bb complex. In this regard, two types of alternative pathway activators are distinguished: 1) properdine-dependent activators (polysaccharides, endotoxins, antibodies); 2) properdin-independent activators (cobra venom factor, proteases).
C5 convertase of the alternative activation pathway arises as a result of the binding of C3b to the C3Bb complex as part of the enhancement mechanism, and the subsequent course of the process corresponds to the classical activation pathway.
Alternative activation of complement is important component systems of nonspecific resistance to bacteria, viruses and single-celled microorganisms. The transition from nonspecific protection to antibody-mediated reactions occurs smoothly, or both processes occur in parallel. As a pathogenetic link alternative activation complement is involved in many diseases. Examples include:
- membranoproliferative nephritis with hypocomplementemia;
- acute glomerulonephritis after streptococcal infection;
- nephritis in SLE;
- pigeon breeders disease;
- fungal infections;
- septicemia with shock caused by endotoxins;
- nocturnal paroxysmal hemoglobinuria;
- partial lipodystrophy.
An alternative pathway is also observed in some cases of complement activation via the classical pathway. In nephritis, the C3NeF factor is detected, which is a complex of autoantibodies with C3bBb, resistant to the action of p1H and functioning as a C3 convertase. Endotoxins, due to lipid A, are effective activators of not only the alternative pathway of complement activation, but also the coagulation system, as well as the kinin system. Activation of factor XII plays a decisive role in this case.
Nonspecific activation of complement. Nonspecific activation of complement can be carried out by proteases (trypsin, plasmin, kallikrein, lysosomal proteases and bacterial enzymes) at each stage from C1 to C5. The initial activated factor is much more effective compared to the inducing protease, and when activated in the liquid phase, activation can begin in several processes at once. Anaphylatoxins appear, which, in addition to the hemolytic effect, give a complete picture of shock in acute pancreatitis and severe infections. Nonspecific activation is one of the components of acute inflammation.
Mechanisms of regulation of the complement activation system
I. Inhibitory mechanisms. Each step of the complement activation cascade is in equilibrium with the non-activated state. The pronounced pharmacological effects of activation products require regulation at various levels.
The limiting factor in the activation system along the classical pathway is C2, which is present in the lowest concentration.
Another limiting group of factors is the need for interaction of Clq with two Fc fragments of antibodies and the possibility of access to the resulting binding sites for activators and reaction substrates (C2a, C4b, C3b, etc. to C9). The instability of C2a, C4b, C5b and Bb in the liquid phase prevents the unlimited development of the reaction and causes the concentration of the process on the activated surface. Specific inhibitors have been described for Clr, Cls, C4b, C2, C3b, C6, C5b-6-7, Bb, C3a and C5a.
II. Stimulating mechanisms. The most important mechanism for enhancing complement activation is positive feedback, as a result of which the appearance of C3b leads to a significant acceleration in the formation of this activation product. Activated properdin stabilizes Bb. The effect of pathological autoantibodies is realized in a similar way.
Biological effects of the complement system
I. Cytolysis and bactericidal activity. Cytolysis and bactericidal activity can be induced in the following way:
- immune cytolysis caused by IgM and IgG antibodies;
- CRP (C-reactive protein) - connection with subsequent activation of complement;
- direct activation of properdin through an alternative pathway of activation by cells and bacteria;
- side effects during the reaction of immune complexes;
- participation of activated phagocytes.
II. Anaphylatoxin formation. The concept of "anaphylatoxin" was first introduced by Friedberger. IN in this case This meant the C3a fragment and the C5a fragment, which bind to the corresponding cell membrane receptors and have similar pharmacological effects:
- release of histamine and other mediators from mast cells and basophils (C5a is more effective compared to C3a);
- contraction of smooth muscles and effects on microcirculation (C3a is more effective compared to C5a);
- activation of phagocytes and secretion of lysosomal enzymes (the effectiveness of C3a and C5a is comparable).
Virus neutralization. The complement system is an important factor in natural resistance against viral infection. Some RNA-containing oncogenic viruses are able to directly bind Clq. Classic activation of complement in this case leads to lysis of the infectious agent. Some other viruses interact with complement through CPB. In addition, complement is able to inactivate the virus located in the soluble immune complex, which leads to its opsonization and phagocytosis.
The antiviral effect of complement is due to the following processes:
- lysis of the virus due to fragments from C1 to C9;
- aggregation of the virus due to immune conglutinins;
- opsonization and phagocytosis;
- blockade of viral ligands for the corresponding cell membrane receptors;
- blockade of virus penetration into the cell.
Complement itself is not capable of inactivating a virus-infected cell.
Destruction of immune complexes. The appearance of immune complexes containing IgG and IgM antibodies is associated with constant activation of complement. Activated complement components bind to components of immune complexes, including both antibodies and antigens, thereby preventing the formation of large aggregates due to steric effects. Since complement activation is associated with the appearance of protease activity, partial loosening and breakdown of the resulting aggregates occurs. Removal of breakdown products from the bloodstream is carried out due to opsonization using immunophagocytosis and immunoendocytosis, and therefore the availability of C3b complexes associated with binding to cellular receptors plays an important role. Immune complexes deposited in tissues are also removed by phagocytosis, with plasmin and lysosomal enzymes playing a significant role in this process.
Complement, blood coagulation and the kinin system. Complement, the blood coagulation system and the kinin system are closely related functionally. We are talking about a complex set of mechanisms, the activation of each of which leads to the activation of the entire complex. This is clearly seen in the endotoxin-induced Sanarelli-Schwartzmann reaction and in conditions caused by immune complexes. Kallikrein, plasmin and thrombin activate C1 and cleave C3, C5 and factor B. Factor XIIA can also activate C1, and C1 is first cleaved by plasmin, and then the cleavage products are used by kallikrein and factor XIIA. Platelet activation occurs through the interaction of C3, factor B, properdin, fibrinogen and thrombin. Activated macrophages and phagocytes are important sources of tissue proteases and thromboplastin in all types of inflammation. Activation of all three systems occurs through the activation of factor XII (Hageman factor). On the other hand, C1 = 1NH inhibits both kallikrein and factor XIIA. Protease inhibitors - antitrypsin, macroglobulin and antichymotrypsin - have the same effect. As a result, a system with complex dynamics is formed, which can not only perform protective functions, but also participate in pathological processes.
Complement and T cell-mediated immune responses. The complement system has a regulatory effect on both the T-system and B-lymphocytes, with C3 fragments, factor B and B1H acting as the main mediators. Membrane-associated factors and complement components C5, C6, C7, C8, and C9 were detected on cytotoxic lymphocytes (CTLs). On the other hand, the study of CTL target cells using an electron microscope showed that in the area of intercellular contact structures similar to pores formed when complement system factors act on the membrane are determined.
Diagnostic value of the complement system. Complement system assessment aims to address the following: practical issues:
- Are activated components of the complement system involved in the pathogenesis of the disease?
- Are there any defects in the complement system?
To answer these questions, total complement activity is first determined using sheep red blood cells and inactivated antiserum. The test serum in serial dilutions is used as a source of complement and the titer corresponding to 50% hemolysis is determined. The results are expressed in CH50 units. Rabbit erythrocytes can directly activate the alternative pathway of complement activation, in which case the activity of the test serum is measured in AP 50 units. With acute and progressive complement consumption, as well as its defects, a decrease in complement activity is observed. To identify a defect for a specific factor, sera that do not contain the factor being studied are used and added to the test sample. Immunochemical determination of individual components of the complement system (rocket electrophoresis and radial immunodiffusion) is also used, but this approach cannot replace functional tests, since functionally inactive abnormal proteins and inactive cleavage products can lead to erroneous determinations. All test samples should be stored at -70 °C until use. The study of complement consumption can be carried out using radioimmune and enzyme immunoassay methods for determining the cleavage products C3, C4 and B. Special meaning has a quantitative RIA to determine the concentration of C5a, which serves as an indicator of anaphylactic reactions. When identifying primary and secondary complement defects, it is recommended to use the following research program:
- determination of CH50, and possibly AP50 for screening;
- quantitation C4 and C3 to clarify the role of the classical and alternative activation pathways;
- detailed analysis of Clq, C5, P and other factors.
In the acute phase of inflammation, with tumors and during the postoperative period, complement activity is increased.
Complement for diseases of the immune system. The complement system plays an important role in allergic diseases type II (cytotoxic antibodies) and type III (immune complex pathology, Arthus phenomenon). The role of complement is confirmed by the following data:
- pronounced consumption of complement (CH50 is reduced, activity and concentrations of factors are below normal);
- the appearance of breakdown products of components in the serum (C4a, fragments C3, C5a);
- complement deposits in tissues determined using immunohistochemical analysis of specific antibodies (anti-C3, anti-C4, etc.);
- production of cytotoxic antibodies;
- evidence of chronically increased complement consumption.
Typical examples include the following diseases:
- acute viral infections (the effects of immune complexes are especially common in rubella, measles, hepatitis B, and ECHO virus infections);
- acute bacterial infections (activation of complement by immune complexes during streptococcal infections, for example, scarlet fever; activation of the alternative pathway during infection with gram-negative microorganisms or endotoxin);
- glomerulonephritis;
- autoimmune hemolytic anemia;
immune thrombocytopenia;
- systemic lupus erythematosus;
- reaction of transplant rejection caused by antibodies;
- rheumatoid arthritis;
- serum sickness;
- cryoglobulinemia, amyloidosis, plasmacytoma.
In all of these diseases, complement assessment is not entirely informative, as is the case in a wide range of chronic diseases. However, the study of this system allows us to draw a conclusion about the individual dynamics of the disease. Complement testing is mandatory if there is a history of frequent bacterial infections due to the possibility of genetically determined anomalies. This is also true for SLE, which is often associated with birth defects of the complement system.
Complement - essential element immune system of vertebrates and humans, playing key role in the humoral mechanism of the body's defense against pathogens. The term was first introduced by Ehrlich to designate a component of blood serum, without which its bactericidal properties would disappear. Subsequently, it was found that this functional factor is a set of proteins and glycoproteins that, when interacting with each other and with a foreign cell, cause its lysis.
Complement literally translates as “complement.” Initially, it was considered just another element providing the bactericidal properties of living serum. Modern ideas about this factor are much broader. It has been established that complement is a complex, subtle adjustable system, interacting with both humoral and cellular factors immune response and has a powerful influence on the development of the inflammatory response.
general characteristics
In immunology, the complement system is a group of vertebrate blood serum proteins that exhibit bactericidal properties and are 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 themselves cannot destroy foreign cells, but act indirectly.
The lysis 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 MAC. As a result of its action, the surface of the foreign cell becomes holey, which leads to the release of cytoplasm to the outside.
Complement accounts for about 10% of all serum proteins. Its components are always present in the blood, without exerting any effect until activated. All effects of complement are the result of sequential reactions - either breaking down its constituent proteins or leading to the formation of their functional complexes.
Each stage of such a cascade is subject to strict feedback regulation, which, if necessary, can stop the process. Activated complement components exhibit large complex immunological properties. Moreover, the effects can have both positive and negative effects on the body.
Basic functions and effects of complement
The actions of the activated complement system include:
- Lysis of foreign cells of bacterial and non-bacterial nature. It is carried out due to the formation of a special complex, which is built into the membrane and makes a hole in it (perforates).
- Activation of the removal of immune complexes.
- Opsonization. By attaching to target surfaces, complement components make them attractive to phagocytes and macrophages.
- Activation and chemotactic attraction of leukocytes to the site of inflammation.
- Formation of anaphylotoxins.
- Facilitating the interaction of antigen-presenting cells and B cells with antigens.
Thus, complement has a complex stimulating effect on the entire immune system. However, excessive activity of this mechanism can negatively affect the condition of the body. Negative complements include:
- Worsening of autoimmune diseases.
- Septic processes (subject to mass activation).
- Bad influence on tissue in the area of necrosis.
Defects in the complement system can lead to autoimmune reactions, i.e. to damage to healthy tissues of the body's own immune system. That is why there is such strict multi-stage control over the activation of this mechanism.
Complement proteins
Functionally, proteins of the complement system are divided into components:
- Classical path (C1-C4).
- Alternative pathway (factors D, B, C3b and properdin).
- Membrane attack complex (C5-C9).
- Regulatory faction.
The numbers of C proteins correspond to the sequence of their discovery, but do not reflect the order of their activation.
Regulatory proteins of the complement system include:
- Factor H.
- C4 binding protein.
- Membrane cofactor protein.
- Complement receptors of the first and second types.
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, beginning 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 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:
- Classical.
- Alternative.
- Lectin.
Among them, only the first is associated with the acquired immune response system, and the rest have a nonspecific nature of action.
In all activation pathways, 2 stages can be distinguished:
- Starting (or actual activation) - includes the entire cascade of reactions until the formation of the C3/C5 convertase.
- Cytolytic - refers to the formation of the membrane attack complex (MAC).
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 join, forming a hydrophobic complex capable of inserting and perforating the membrane.
The first stage is based on the sequential launch of the enzymatic activity of proteins C1, C2, C3 and C4 through hydrolytic cleavage into large (heavy) and small (light) fragments. The resulting units are designated 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 classic 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).
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 enzyme C1qrs, which cleaves the C4 protein into C4a and C4b. In this case, everything remains attached to the immunoglobulin and, therefore, to the membrane of the pathogen.
After the proteolytic effect is achieved, the antigen group - C1qrs attaches the C4b fragment to itself. Such a complex becomes suitable for binding to C2, which, under the influence of C1s, is immediately cleaved 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 hydrolysis of C3 occurs spontaneously (without the participation of intermediaries), which leads to periodic, causeless formation of C3 convertase. An alternative path occurs when the pathogen has not yet formed. In this case, the cascade consists of the following reactions:
- Blank hydrolysis of C3 to form fragment C3i.
- C3i binds to factor B, forming the C3iB complex.
- The bound factor B becomes available for cleavage by 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 quickly hydrolyzes. However, upon collision with the membrane of the pathogen, it stabilizes and triggers 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 first step of activation, which occurs not through interaction with immunoglobulin, but through the binding of C1q to terminal mannan groups present on the surface of bacterial cells. Further activation is carried out completely identical to the classical path.
SLIDE 1
Lecture No. 4. Humoral factors of innate immunity
1. Complement system
2. Proteins of the acute phase of inflammation
3. Biogenic amymnas
4. Lipid mediators
5. Cytokines
6. Interferons
SLIDE 2
Humoral component of innate immunity is represented by several interconnected systems - the complement system, the cytokine network, bactericidal peptides, as well as humoral systems associated with inflammation.
The operation of most of these systems is subject to one of two principles - cascade and network. The complement system operates according to a cascade principle, when activated, factors are sequentially involved. Moreover, the effects of cascade reactions appear not only at the end of the activation pathway, but also at intermediate stages.
The network principle is characteristic of the cytokine system and implies the possibility of simultaneous functioning of various components of the system. The basis for the functioning of such a system is close interconnection, mutual influence and a significant degree of interchangeability of network components.
SLIDE 3
Complement- a complex protein complex of blood serum.
The complement system consists of 30 proteins (components, or factions, complement system).
Activated the complement system due to a cascade process: the product of the previous reaction acts as a catalyst for the subsequent reaction. Moreover, when a fraction of a component is activated, its splitting occurs in the first five components. The products of this cleavage are designated as active fractions of the complement system.
1. Larger of the fragments(denoted by the letter b), formed during the cleavage of the inactive fraction, remains on the cell surface - complement activation always occurs on the surface of the microbial cell, but not on its own eukaryotic cells. This fragment acquires the properties of an enzyme and the ability to influence the subsequent component, activating it
2. Smaller fragment(denoted by the letter a) is soluble and “goes” into the liquid phase, i.e. into blood serum.
Fractions of the complement system are designated differently.
1. Nine – open first– proteins of the complement system denoted by the letter C(from English word complement) with the corresponding number.
2. The remaining fractions of the complement system are designated other Latin letters or combinations thereof.
SLIDE 4
Complement activation pathways
There are three pathways of complement activation: classical, lectin and alternative.
SLIDE 5
1. Classic way complement activation is fundamental. Participation in this pathway of complement activation - main function of antibodies.
Complement activation via the classical pathway triggers the immune complex: complex of antigen with immunoglobulin (class G or M). Antibodies can “take” their place C-reactive protein– such a complex also activates complement via the classical pathway.
Classic pathway of complement activation carried out in the following way.
A. At first fraction C1 is activated: it is assembled from three subfractions (C1q, C1r, C1s) and turns into an enzyme C1-esterase(С1qrs).
b. C1-esterase breaks down the C4 fraction.
V. The active fraction C4b covalently binds to the surface of microbial cells - here joins faction C2.
d. Fraction C2, in combination with fraction C4b, is cleaved by C1-esterase with formation of active fraction C2b.
e. Active fractions C4b and C2b into one complex – С4bС2b– possessing enzymatic activity. This is the so-called C3 convertase of the classical pathway.
e. C3 convertase breaks down the C3 fraction, I'm working on large quantities active fraction C3b.
and. Active fraction C3b attaches to the C4bC2b complex and turns it into C5 convertase(С4bС2bС3b).
h. C5 convertase breaks down the C5 fraction.
And. The resulting active fraction C5b joins faction C6.
j. Complex C5bC6 joins the C7 faction.
l. Complex C5bC6C7 embedded in the phospholipid bilayer of the microbial cell membrane.
m. To this complex protein C8 is attached And C9 protein. This polymer forms a pore with a diameter of about 10 nm in the microbial cell membrane, which leads to lysis of the microbe (since many such pores are formed on its surface - the “activity” of one unit of C3 convertase leads to the appearance of about 1000 pores). Complex С5bС6С7С8С9, formed as a result of complement activation is called memranattack complex(POPPY).
SLIDE 6
2. Lectin pathway complement activation is triggered by a complex of normal blood serum protein - mannan-binding lectin (MBL) - with carbohydrates of the surface structures of microbial cells (with mannose residues).
SLIDE 7
3. Alternative path complement activation begins with covalent binding of the active fraction C3b - which is always present in the blood serum as a result of the spontaneous cleavage of the C3 fraction that constantly occurs here - with the surface molecules of not all, but some microorganisms.
1. Further events are developing in the following way.
A. C3b binds factor B, forming the C3bB complex.
b. In the form associated with C3b factor B acts as a substrate for factor D(serum serine protease), which breaks it down to form an active complex С3bВb. This complex has enzymatic activity, is structurally and functionally homologous to the C3 convertase of the classical pathway (C4bC2b) and is called Alternative pathway C3 convertase.
V. Alternative pathway C3 convertase itself is unstable. In order for the alternative pathway of complement activation to continue successfully, this enzyme stabilized by factor P(properdine).
2. Basics functional difference An alternative pathway of complement activation, compared to the classical one, is the speed of response to the pathogen: since it does not require time for the accumulation of specific antibodies and the formation of immune complexes.
It is important to understand that both the classical and alternative pathways of complement activation act in parallel, also amplifying (i.e. strengthening) each other. In other words, complement is activated not “either along the classical or alternative” pathways, but “through both the classical and alternative” activation pathways. This, with the addition of the lectin activation pathway, is a single process, the different components of which may simply manifest themselves to different degrees.
SLIDE 8
Functions of the complement system
The complement system plays a very important role in protecting the macroorganism from pathogens.
1. The complement system is involved in inactivation of microorganisms, incl. mediates the effect of antibodies on microbes.
2. Active fractions of the complement system activate phagocytosis (opsonins - C3b and C5b).
3. Active fractions of the complement system take part in formation of an inflammatory response.
SLIDE 9
The active complement fractions C3a and C5a are called anaphylotoxins, as they are involved, among other things, in an allergic reaction called anaphylaxis. The most powerful anaphylotoxin is C5a. Anaphylotoxins act on different cells and tissues of the macroorganism.
1. Their effect on mast cells causes degranulation of the latter.
2. Anaphylotoxins also act on smooth muscle, causing them to contract.
3. They also act on vessel wall: cause activation of the endothelium and an increase in its permeability, which creates conditions for extravasation (exit) of fluid and blood cells from the vascular bed during the development of the inflammatory reaction.
In addition, anaphylotoxins are immunomodulators, i.e. they act as regulators of the immune response.
1. C3a acts as an immunosuppressor (i.e. suppresses the immune response).
2. C5a is an immunostimulant (i.e. enhances the immune response).
SLIDE 10
Acute phase proteins
Some humoral reactions of innate immunity are similar in purpose to reactions of adaptive immunity and can be considered as their evolutionary predecessors. Such innate immune responses have an advantage over adaptive immunity in the speed of development, but their disadvantage is the lack of specificity for antigens. We discussed a couple of reactions of innate and adaptive immunity with similar results in the section on complement (alternative and classical activation of complement). Another example will be discussed in this section: acute phase proteins reproduce some of the effects of antibodies in an accelerated and simplified version.
Acute phase proteins (reactors) are a group of proteins secreted by hepatocytes. During inflammation, the production of acute phase proteins changes. When synthesis increases, proteins are called positive, and when synthesis decreases, they are called negative reactants of the acute phase of inflammation.
The dynamics and severity of changes in the serum concentration of various acute phase proteins during the development of inflammation are not the same: the concentration of C-reactive protein and serum amyloid P increases very strongly (tens of thousands of times) - quickly and briefly (almost normalizes by the end of the 1st week); the levels of haptoglobin and fibrinogen increase less (hundreds of times), respectively, in the 2nd and 3rd weeks of the inflammatory reaction. This presentation will only consider positive reactants involved in immune processes.
SLIDE 11
According to their functions, several groups of acute phase proteins are distinguished.
TO transport proteins include prealbumin, albumin, orosomucoid, lipocalins, haptoglobin, transferrin, mannose-binding and retinol-binding proteins, etc. They play the role of carriers of metabolites, metal ions, and physiologically active factors. The role of factors in this group increases significantly and changes qualitatively during inflammation.
Another group is formed proteases(trypsinogen, elastase, cathepsins, granzymes, tryptases, chymases, metalloproteinases), the activation of which is necessary for the formation of many inflammatory mediators, as well as for the implementation of effector functions, in particular the killer one. Activation of proteases (trypsin, chymotrypsin, elastase, metalloproteinases) is balanced by the accumulation of their inhibitors. α2-Macroglobulin is involved in suppressing the activity of proteases of various groups.
In addition to those listed, acute phase proteins include coagulation and fibrinolysis factors, as well as intercellular matrix proteins(for example, collagens, elastins, fibronectin) and even proteins of the complement system.
SLIDE 12
Pentraxins. Proteins of the pentraxin family exhibit the properties of acute phase reactants most fully: in the first 2-3 days of the development of inflammation, their concentration in the blood increases by 4 orders of magnitude.
C-reactive protein and serum amyloid P are formed and secreted by hepatocytes. The main inducer of their synthesis is IL-6. PTX3 protein is produced by myeloid (macrophages, dendritic cells), epithelial cells and fibroblasts in response to stimulation through TLRs, as well as under the influence of proinflammatory cytokines (eg, IL-1β, TNFα).
The concentration of pentraxins in the serum increases sharply with inflammation: C-reactive protein and serum amyloid P - from 1 μg/ml to 1-2 mg/ml (i.e. 1000 times), PTX3 - from 25 to 200-800 ng/ ml. Peak concentrations are reached 6–8 hours after induction of inflammation. Pentraxins are characterized by the ability to bind to a wide variety of molecules.
C-reactive protein was first identified due to its ability to bind polysaccharide C ( Streptococcus pneumoniae), which determined its name. Pentraxins also interact with many other molecules: C1q, bacterial polysaccharides, phosphorylcholine, histones, DNA, polyelectrolytes, cytokines, extracellular matrix proteins, serum lipoproteins, complement components, with each other, as well as with Ca 2+ and other metal ions.
For all pentraxins under consideration, there are high-affinity receptors on myeloid, lymphoid, epithelial and other cells. In addition, this group of acute phase proteins has a fairly high affinity for receptors such as FcγRI and FcγRII. The large number of molecules with which pentraxins interact determines the wide variety of their functions.
The recognition and binding of PAMPs by pentraxins gives reason to consider them as a variant of soluble pathogen recognition receptors.
To the most important functions of pentraxins They include their participation in innate immune reactions as factors that trigger the activation of complement through C1q and participate in the opsonization of microorganisms.
The complement-activating and opsonizing ability of pentraxins makes them a kind of “protoantibodies” that partially perform the functions of antibodies at the initial stage of the immune response, when true adaptive antibodies have not yet had time to be developed.
The role of pentraxins in innate immunity also includes the activation of neutrophils and monocytes/macrophages, the regulation of cytokine synthesis and the manifestation of chemotactic activity towards neutrophils. In addition to participating in innate immune responses, pentraxins regulate the functions of the extracellular matrix during inflammation, control of apoptosis, and elimination of apoptotic cells.
SLIDE 13
Biogenic amines
This group of mediators includes histamine and serotonin, contained in mast cell granules. Released during degranulation, these amines cause a variety of effects that play a key role in the development of early manifestations of immediate hypersensitivity.
Histamine (5-β-imidazolylethylamine)- the main mediator of allergies. It is formed from histidine under the influence of the enzyme histidine decarboxylase.
Since histamine is contained in mast cell granules in ready-made form, and the degranulation process occurs quickly, histamine appears very early in the focus of an allergic lesion, and immediately in high concentration, which determines the manifestations of immediate hypersensitivity. Histamine is rapidly metabolized (95% in 1 minute) with the participation of 2 enzymes - histamine-N-methyltransferase and diamine oxidase (histaminase); this produces (in a ratio of approximately 2:1) N-methylhistamine and imidazole acetate, respectively.
There are 4 types of receptors for histamine H 1 -H 4. In allergic processes, histamine acts primarily on smooth muscles and vascular endothelium, binding to their H1 receptors. These receptors provide an activation signal mediated by the transformation of phosphoinositides with the formation of diacylglycerol and the mobilization of Ca 2+.
These effects are partly due to the formation of nitric oxide and prostacyclin in cells (the targets of histamine). Acting on nerve endings, histamine causes a sensation of itching, characteristic of allergic manifestations in the skin.
In humans, histamine plays an important role in the development of skin hyperemia and allergic rhinitis. Less obvious is its participation in the development of general allergic reactions and bronchial asthma. At the same time, through H2 receptors, histamine and related substances exert a regulatory effect, sometimes reducing the manifestations of inflammation, weakening the chemotaxis of neutrophils and their release of lysosomal enzymes, as well as the release of histamine itself.
Through H 2 receptors, histamine acts on the heart, secretory cells of the stomach, suppresses the proliferation and cytotoxic activity of lymphocytes, as well as their secretion of cytokines. Most of these effects are mediated by activation of adenylate cyclase and an increase in intracellular cAMP levels.
Data on the relative role of various histamine receptors in the implementation of its action are very important, since many antiallergic drugs are blockers of H1 (but not H2 and other) histamine receptors.
SLIDE 14
Lipid mediators.
Important role Humoral factors of lipid nature play a role in the regulation of immune processes, as well as in the development of allergic reactions. The most numerous and important of them are eicosanoids.
Eicosanoids are metabolic products of arachidonic acid, a polyunsaturated fatty acid whose molecule contains 20 carbon atoms and 4 unsaturated bonds. Arachidonic acid is formed from membrane phospholipids as a direct product of phospholipase A (PLA) or an indirect product of PLC-mediated transformations.
The formation of arachidonic acid or eicosanoids occurs upon activation of various types of cells, especially those involved in the development of inflammation, in particular allergic: endothelial and mast cells, basophils, monocytes and macrophages.
The metabolism of arachidonic acid can occur in two ways - catalyzed by cyclooxygenase or 5'-lipoxygenase. The cyclooxygenase pathway leads to the formation of prostaglandins and thromboxanes from unstable intermediates - endoperoxide prostaglandins G2 and H2, and the lipoxygenase pathway leads to the formation of leukotrienes and 5-hydroxyeicosatetraenoate through intermediate products (5-hydroperoxy-6,8,11,14-eicosatetraenoic acid and leukotriene A4 ), as well as lipoxins - products of double lipoxygenation (under the action of two lipoxygenases - see below).
Prostaglandins and leukotrienes exhibit alternative physiological effects in many respects, although significant differences in activity exist within these groups.
General property These groups of factors have a predominant effect on the vascular wall and smooth muscles, as well as a chemotactic effect. These effects are realized through the interaction of eicosanoids with specific receptors on the cell surface. Some members of the eicosanoid family enhance the effects of other vasoactive and chemotactic factors, for example, anaphylatoxins (C3a, C5a).
SLIDE 15
Leukotrienes (LT)- C 20 fatty acids, the molecule of which contains an OH group at position 5, and sulfur-containing side chains at position 6, for example glutathione.
There are 2 groups of leukotrienes:
One of them includes leukotrienes C4, D4 and E4, called cysteinyl leukotrienes (Cys-LT),
The second includes one factor - leukotriene B4.
Leukotrienes are formed and secreted within 5–10 min after activation of mast cells or basophils.
Leukotriene C4 is present in the liquid phase for 3–5 minutes, during which time it is converted to leukotriene D4. Leukotriene D4 exists for the next 15 minutes, slowly turning into leukotriene E4.
Leukotrienes exert their effect through receptors belonging to the group of purine receptors of the rhodopsin-like receptor family, 7-fold membrane-spanning and associated with protein G.
Leukotriene receptors are expressed on spleen cells, blood leukocytes, in addition, CysLT-R1 is presented on macrophages, intestinal cells, air epithelium, and CysLT-R2 is present on adrenal and brain cells.
Cysteinyl leukotrienes (especially leukotriene D4) cause smooth muscle spasms and regulate local blood flow, reducing arterial pressure. Cysteinyl leukotrienes are mediators of allergic reactions, in particular, the slow phase of bronchospasm in bronchial asthma.
In addition, they suppress the proliferation of lymphocytes and promote their differentiation.
Previously, the complex of these factors (leukotrienes C4, D4 and E4) was called slow-reacting substance A. Leukotriene B4 (dihydroxyeicosatetraenoic acid) exhibits a chemotactic and activating effect primarily on monocytes, macrophages, neutrophils, eosinophils and even T cells.
Another product of the lipoxygenase pathway, 5-hydroxyeicosatetraenoate, is less active than leukotrienes, but can serve as a chemoattractant and activator of neutrophils and mast cells.
SLIDE 16
Prostaglandins (PG) - C 20 fatty acids, the molecule of which contains a cyclopentane ring.
Variants of prostaglandins, differing in the type and position of substituent groups (oxy-, hydroxy-), are designated in different letters; The numbers in the name indicate the number of unsaturated bonds in the molecule.
Prostaglandins accumulate at the site of inflammation later than kinins and histamine, somewhat later than leukotrienes, but simultaneously with monokines (6–24 hours after the start of inflammation).
In addition to the vasoactive and chemotactic effect achieved in cooperation with other factors, prostaglandins (especially prostaglandin E2) have a regulatory effect in inflammatory and immune processes.
Exogenous prostaglandin E2 causes some manifestations of the inflammatory response, but suppresses the immune response and allergic reactions.
Thus, prostaglandin E2 reduces the cytotoxic activity of macrophages, neutrophils and lymphocytes, the proliferation of lymphocytes, and the production of cytokines by these cells.
It promotes the differentiation of immature lymphocytes and cells of other hematopoietic series.
Some effects of prostaglandin E2 are associated with an increase in intracellular cAMP levels.
Prostaglandins E2 and D2 inhibit platelet aggregation; Prostaglandins F2 and D2 cause contraction of bronchial smooth muscle, while prostaglandin E2 relaxes it.
SLIDE 17
Thromboxane A2 (TXA2) - C 20 fatty acid; its molecule has a 6-membered oxygen-containing ring.
It is a very unstable molecule (half-life 30 s) and converts to inactive thromboxane B2.
Thromboxane A2 causes constriction of blood vessels and bronchi, platelet aggregation with the release of enzymes and other active factors that promote the mitogenesis of lymphocytes.
Another product of the cycloxygenase pathway is prostaglandin I2(prostacyclin) - also unstable. It exerts its effect through cAMP, greatly dilates blood vessels, increases their permeability, and inhibits platelet aggregation.
Along with the peptide factor bradykinin, prostacyclin causes a sensation of pain during inflammation.
SLIDE 18
Cytokines
Related information.
The complement system is a group of at least 26 serum proteins (complement components) that mediate inflammatory reactions with the participation of granulocytes and macrophages (Table 16–3). The components of the system participate in blood coagulation reactions, promote intercellular interactions necessary for the processing of Ag, and cause the lysis of bacteria and cells infected with viruses. Normally, system components are in an inactive form. Activation of complement leads to the alternate (cascade) appearance of its active components in a series of proteolytic reactions that stimulate protective processes. The main functions of complement components in defensive reactions - stimulation of phagocytosis, violation of the integrity of the cell walls of microorganisms membrane-damaging complex (especially in species resistant to phagocytosis, such as gonococci) and induction of synthesis of inflammatory response mediators(eg, IL1; Table 16–4). In addition, the complement system stimulates inflammatory reactions (some components are chemoattractants for phagocytes), participates in the development of immune (through activation of macrophages) and anaphylactic reactions. Activation of complement components can occur through the classical and alternative pathways.
Layout Table 16-3
Table 16–3 . Components of the complement system
| Component | Biological activity |
| Classic way | |
| C1q | Interacts with Fc fragments of AT immune complexes; interaction activates C1r |
| C1r | C1r is cleaved to form protease C1s, which hydrolyzes components C4 and C2 |
| C4 | C4 is cleaved to form C4a and C4b, which is adsorbed on membranes and takes part in the conversion of C3 |
| C2 | C2 interacts with C4b and is converted by C1s to C2b (protease component of C3/C5 convertase) |
| C3* | C2b is cleaved into anaphylatoxin C3a and opsonin C3b; also a component of C3/C5 convertase |
| Alternative path | |
| Factor B | C2 analogue of the classical activation pathway |
| Factor D | Serum protease that activates factor B by cleaving it |
| Membrane-damaging complex | |
| C5 | Cleaved by the C3/C5 complex; C5a is an anaphylatoxin, C5b fixes C6 |
| C6 | Interacts with C5b and forms a fixation complex for C7 |
| C7 | Interacts with C5b and C6, then the entire complex is integrated into cell wall and fixes C8 |
| C8 | Interacts with the complex C5b, C6 and C7; forms a stable membrane complex and fixes C9 |
| C9 | After interaction with the C5–C8 complex, it polymerizes, which leads to cell lysis |
| Receptors for complement components | |
| C1 receptor | Enhances the dissociation of C3 convertases, stimulates the phagocytosis of microorganisms opsonized by C3b and C4b |
| C2 receptor | Mediates the sorption of complement-containing immune complexes; receptor for virus Epstein-Barr |
| C3 receptor | Causes adhesion (protein of the integrin family), stimulates phagocytosis of microorganisms opsonized with C3b |
| C4 receptor | Protein of the integrin family, stimulates phagocytosis of microorganisms opsonized with C3b |
* C3 also serves as a component of the alternative activation pathway.
Layout Table 16-4
Table 16–4 . The main effects of complement proteins and their cleavage fragments
| Component | Activity |
| C2a | Esterase activity towards some arginine and lysine esters |
| С2b | Kinin-like activity, increased phagocyte motility |
| C3a, C4a, C5a | Anaphylatoxins, release histamine, serotonin and other vasoactive mediators from mast cells, increase capillary permeability |
| C3b, iC3b, C4b | Immune adhesion and opsonization bind immune complexes to the membranes of macrophages, neutrophils (increased phagocytosis) and erythrocytes (elimination of complexes by macrophages of the spleen and liver) |
| C5a | Chemotaxis and chemokinesis, attraction of phagocytic cells to the site of inflammation and increase in their overall activity |
| C5b6789 (membrane damaging complex) | Damage to the membrane, formation of transmembrane channels, release of cell contents. Mammalian cells swell and burst; bacteria lose important intracellular metabolites but are not usually lysed |
| Ba | Neutrophil chemotaxis |
| Bb | Activation of macrophages (adhesion and spreading on the surface) |
Classic way
Activation of complement via the classical pathway by Ag–AT complexes. Includes the sequential formation of all 9 components (from C1 to C9). The components of the classical pathway are designated by the Latin letter “C” and Arabic numerals (C1, C2...C9); for complement subcomponents and cleavage products, lowercase letters are added to the corresponding designation letters(C1q, C3b, etc.). Activated components are marked with a line above the letter, inactivated components with the letter “i” (for example, iC3b). Initially, C1 interacts with the Ag–AT complex (subcomponents C1q, C1r, C1s), then the “early” components C4, C2 and C3 join them. They activate the C5 component, which attaches to the membrane of the target cell (bacteria, tumor or virus-infected cells) and triggers the formation of the lytic complex (C5b, C6, C7, C8 and C9). Otherwise it is called membrane-damaging (membrane attacker) complex, since its formation on the membrane causes cell destruction. Examples of microbial products that activate the complement system via the classical pathway are DNA and protein A of staphylococci.
Complement - a system of whey proteins and several proteins cell membranes, performing 3 important functions: opsonization of microorganisms for their further phagocytosis, initiation of vascular inflammatory reactions and perforation of membranes of bacterial and other cells. Complement components denoted by letters Latin alphabet C, B and D with the addition of an Arabic numeral (part number) and additional lowercase letters. The components of the classical pathway are designated by the Latin letter “C” and Arabic numerals (C1, C2 ... C9); for complement subcomponents and cleavage products, lowercase Latin letters are added to the corresponding designation (C1q, C3b, etc.). Activated components are marked with a line above the letter, inactivated components with the letter “i” (for example, iC3b).
Complement activation Normally, when the internal environment of the body is “sterile” and pathological decay of its own tissues does not occur, the level of activity of the complement system is low. When microbial products appear in the internal environment, the complement system is activated. It can occur through three pathways: alternative, classical and lectin.
- Alternative activation path. It is initiated directly by the surface molecules of microbial cells [factors of the alternative pathway are designated by letters: P (properdin), B and D].
Of all the proteins of the complement system, C3 is the most abundant in blood serum - its normal concentration is 1.2 mg/ml. In this case, there is always a small but significant level of spontaneous cleavage of C3 with the formation of C3a and C3b. Component C3b is opsonin, i.e. it is capable of covalently binding both to the surface molecules of microorganisms and to receptors on phagocytes. In addition, “settled” on the cell surface, C3b binds factor B. This, in turn, becomes a substrate for serum serine protease - factor D, which splits it into fragments Ba and Bb. C3b and Bb form an active complex on the surface of the microorganism, stabilized by properdin (factor P).
◊ The C3b/Bb complex serves as a C3 convertase and significantly increases the level of C3 cleavage compared to spontaneous ones. In addition, after binding to C3, it cleaves C5 into fragments C5a and C5b. Small fragments C5a (the strongest) and C3a are complement anaphylatoxins, i.e. mediators of the inflammatory response. They create conditions for the migration of phagocytes to the site of inflammation, cause degranulation of mast cells, and contraction of smooth muscles. C5a also causes increased expression on CR1 and CR3 phagocytes.
◊ With C5b, the formation of a “membrane attack complex” begins, causing perforation of the membrane of microorganism cells and their lysis. First, the C5b/C6/C7 complex is formed and inserted into the cell membrane. One of the subunits of the C8 component, C8b, joins the complex and catalyzes the polymerization of 10-16 C9 molecules. This polymer forms a non-collapsing pore in the membrane with a diameter of about 10 nm. As a result, the cells become unable to maintain osmotic balance and lyse.
- Classical and lectin pathways similar to each other and different from alternative way activation of C3. The main C3 convertase of the classical and lectin pathways is the C4b/C2a complex, in which C2a has protease activity, and C4b covalently binds to the surface of microbial cells. It is noteworthy that the C2 protein is homologous to factor B, even their genes are located nearby in the MHC-III locus.
◊ When activated via the lectin pathway, one of the acute phase proteins - MBL - interacts with mannose on the surface of microbial cells, and MBL-associated serine protease (MASP - Mannose-binding protein-Associated Serine Protease) catalyzes the activation cleavage of C4 and C2.
◊ The serine protease of the classical pathway is C1s, one of the subunits of the C1qr 2 s 2 complex. It is activated when at least 2 C1q subunits bind to the antigen-antibody complex. Thus, the classical pathway of complement activation links innate and adaptive immunity.
Complement component receptors. There are 5 types of receptors for complement components (CR - Complement Receptor) on different cells body.
CR1 is expressed on macrophages, neutrophils and erythrocytes. It binds C3b and C4b and, in the presence of other stimuli for phagocytosis (binding of antigen-antibody complexes through FcyR or when exposed to IFNu, a product of activated T-lymphocytes), has a permissive effect on phagocytes. CR1 of erythrocytes, through C4b and C3b, binds soluble immune complexes and delivers them to macrophages of the spleen and liver, thereby ensuring blood clearance of immune complexes. When this mechanism is disrupted, immune complexes precipitate - primarily in the basement membranes of the vessels of the glomeruli of the kidneys (CR1 is also present on the podocytes of the glomeruli of the kidneys), leading to the development of glomerulonephritis.
CR2 of B lymphocytes binds the degradation products of C3 - C3d and iC3b. This increases the susceptibility of the B lymphocyte to its antigen by 10,000-100,000 times. The same membrane molecule - CR2 - is used as its receptor by the Epstein-Barr virus, the causative agent of infectious mononucleosis.
CR3 and CR4 also bind iC3b, which, like the active form of C3b, serves as an opsonin. If CR3 is already bound to soluble polysaccharides such as beta-glucans, binding of iC3b to CR3 alone is sufficient to stimulate phagocytosis.
C5aR consists of seven domains that penetrate the cell membrane. This structure is characteristic of receptors coupled to G proteins (proteins capable of binding guanine nucleotides, including GTP).
Protecting your own cells. The body's own cells are protected from the destructive effects of active complement thanks to the so-called regulatory proteins of the complement system.
C1 -inhibitor(C1inh) disrupts the bond of C1q to C1r2s2, thereby limiting the time during which C1s catalyzes the activation cleavage of C4 and C2. In addition, C1inh limits the spontaneous activation of C1 in the blood plasma. With a genetic defect dinh, hereditary angioedema develops. Its pathogenesis consists of chronically increased spontaneous activation of the complement system and excessive accumulation of anaphylactics (C3a and C5a), causing edema. The disease is treated replacement therapy drug dinh.
- C4 -binding protein- C4BP (C4-Binding Protein) binds C4b, preventing the interaction of C4b and C2a.
- DAF(Decay-Accelerating Factor- degradation accelerating factor, CD55) inhibits convertases of the classical and alternative pathways of complement activation, blocking the formation of the membrane attack complex.
- Factor H(soluble) displaces factor B from the complex with C3b.
- Factor I(serum protease) cleaves C3b into C3dg and iC3b, and C4b into C4c and C4d.
- Membrane cofactor protein MCP(Membrane Cofactor Protein, CD46) binds C3b and C4b, making them available to factor I.
- Protectin(CD59). Binds to C5b678 and prevents subsequent binding and polymerization of C9, thereby blocking the formation of the membrane attack complex. With a hereditary defect in protectin or DAF, paroxysmal nocturnal hemoglobinuria develops. In such patients, episodic attacks of intravascular lysis of their own red blood cells by activated complement occur and hemoglobin is excreted by the kidneys.