It is not a function of the complement system. Proteins of the complement system: properties and biological activity. Classic pathway of complement system activation
Complement is one of the most important polyfunctional systems of the body. On the one hand, it can be regarded as a principal effector of antibody-dependent reactions. It is involved not only in lytic and bactericidal reactions, but also in other antibody-dependent effects, among which the increase in phagocytosis is one of its most important functions in vivo. On the other hand, complement acts as the main system - an amplifier of inflammatory reactions. It is possible that in the evolutionary aspect this is its main (primary) function, and it is not at all necessary to associate it with antibodies and other immunological mechanisms.
The central event in the process of complement activation is the cleavage of the C3 component along the classical (named only because it was discovered first, and not because of its exceptional significance) and alternative pathways. The second fundamental point is the possible depth of the process: stops
whether it is at the stage of splitting C3, while providing a number of biological effects, or deepens further (from C5 to C9). The last stage of activation is often called the terminal, final (membrane attacking), it is common, identical for the classical and alternative pathways, and the lytic function of the complement is associated with it.
Currently, there are at least 20 plasma proteins that are combined in the complement system. Basically, they are divided into 3 groups. The components involved in the classical activation pathway and in the final (membrane-attacking) stage are designated as Clq, Clr, C1, C4, C2, C3, C5, C6, C7, C8, and C9. The proteins involved in the alternative activation pathway are called factors and are designated as C, D, R. Finally, a group of proteins that regulate the intensity of the reaction, or a group of control proteins, is distinguished: they include the C1 inhibitor (C1INH), C3b inactivator (C3bINa ), pIH factor - C4 - BP, anaphylotoxin inhibitor. The fragments resulting from the enzymatic cleavage of the main components are indicated by small letters (for example, C3, C3b, C3d, C5a, etc.). To designate components or fragments with enzymatic activity, a bar is placed over their symbols, for example, Cl, C42, C3bBb.
The following is the content of individual complement components in blood serum:
Component Concentration, µg/ml
classic way
C1 70
C1 34
C1 31
С4 600
C2 25
SZ 1200
Alternative path
Propertydin 25
Factor B 200
Factor D 1
Membrane attack complex
C5 85
C6 75
C7 55
C8 55
C9 60
Regulatory proteins
C1 inhibitor 180
Factor H 500
Factor I 34
The complement system is one of the "trigger" enzymes.
cal systems, as well as the blood coagulation system, fibrinolysis, and the formation of kinins. It is characterized by a rapid and rapidly increasing response to stimulation. This amplification (amplification) is caused by a cascade phenomenon, which is characterized by the fact that the products of one reaction are catalysts for the next. Such a cascade can be linear, unidirectional (eg, the classical complement pathway), or involve feedback loops (alternative pathway). Thus, both variants take place in the complement system (Scheme 1).
The classical pathway is activated by immune complexes
antigen - an antibody, which includes IgM, IgG as antigens (subclasses 3, 1, 2; they are arranged in descending order of activity). In addition, the classical pathway can be activated by IgG aggregates, CRP, DNA, and plasmin. The process begins with the activation of C1, which consists of 3 components Clq, Clr, Cls. Clq (relative molecular weight 400), has a peculiar structure: 6 subunits with a collagen rod and a non-collagen head, 6 rods are combined at the end of the molecule opposite to the head. On the heads there are sites for attaching to antibody molecules, while sites for attaching C1G and Cls are located on collagen rods. After Clq is attached to AT, C1r becomes C1r, an active protease, by conformative transformations. cleaves Cls, converting the entire complex into C1 serinesterase. The latter splits C4 into 2 fragments - C4a and C4b and C2 into C2a and C2b. The resulting C4b2b(a) complex is an active enzyme that cleaves the C3 component (C3 convertase of the classical pathway); sometimes it is designated C42.
The classical pathway is regulated by the C1 inhibitor (C1INH), which inhibits the activity of C1r and Cls by irreversibly binding to these enzymes. It has been found that C1INH also reduces the activity of kallikrein, plasmin and Hageman factor. Congenital deficiency of this inhibitor leads to uncontrolled activation of C4 and C2, manifested as innate anti-edema.
The alternative (properdine) pathway consists of a series of successive reactions that do not include Cl, C4, and C2 components and, nevertheless, lead to the activation of C3. In addition, these reactions lead to the activation of the final membrane attack mechanism. Activation of this pathway is initiated by endotoxin from Gram-negative bacteria, certain polysaccharides such as inulin and zymosan, immune complexes (ICs) containing IgA or IgG, and certain bacteria and fungi (eg, Staf. epidermis, Candida albicans). Four components are involved in the reaction: factors D and B, C3, and properdin (P). In this case, factor D (enzyme) is similar to Cls of the classical pathway, C3 and factor B, respectively, are similar to C4 and C2 components. As a result, the alternative pathway convertase C3bBb is formed. The resulting complex is extremely unstable, and in order to perform its function, it is stabilized by properdin, forming a more complex C3bBbF complex. The regulatory proteins of the alternative pathway are piH and the C3b inactivator (C3JNA). The former binds to C3b and forms the binding site for the inactivator (C3bINA). Artificial removal of these factors or their genetic deficiency, the existence of which has recently been established in humans, leads to uncontrolled activation of the alternative pathway, which can potentially result in the complete depletion of C3 or factor B.
Terminal membrane attack mechanism. As already mentioned, both pathways converge on the C3-component, which is activated by either of the resulting C42 or C3bBb convertases. For
the formation of C5-convertase requires the cleavage of an additional amount of C3. C3b bound on the cell surface and free B, P, or p1H form a site for C5 binding and render the latter sensitive to proteolysis of any of the C3 convertases. At the same time, a small C5a peptide is cleaved from C5, and the remaining large C5b attaches to the cell membrane and has a site for attaching Cb. Next, components C7, C8, C9 are sequentially attached. As a result, a stable transmembrane channel is formed, which provides two-way movement of ions and water through the bilipid layer of the cell. The membrane is damaged and the cell dies. So, in particular, the killing of alien microorganisms is carried out.
In the course of complement activation, a number of fragments, peptides, are formed that play an important role in the processes of inflammation, phagocytosis, and allergic reactions.
Thus, the cleavage of C4 and C2 with the help of Cls leads to an increase in vascular permeability and underlies the pathogenesis of congenital anti-edema associated with a deficiency of the C1 inhibitor. Peptides C3a and C5a have the properties of anaphylotoxin. By joining mast cells and basophils, they induce the release of histamine. By binding to platelets, C3 causes the secretion of serotonin. The anaphylotoxic activity of C3a and C5a is easily destroyed by carboxypeptidase B, which cleaves arginine from these peptides. The resulting products acquire the properties of chemoattractants in relation to polymorphonuclear cells, eosinophils and monocytes. The C5i67 complex, which does not have hemolytic properties, and the B-fragment cause chemotaxis only in polymorphonuclear leukocytes. Normal human serum contains the CFi factor, which inhibits the activity of C5a in relation to polymorphonuclear cells, eliminating its ability to stimulate the release of lysosomal enzymes. Patients with sarcoidosis and Hodgkin's disease have an excess of CFi. This may explain the defect in the functioning of these cells. Another C3b peptide is a strong opsonin for polymorphonuclear cells (PMN) and macrophages. Receptors for this peptide have also been found on other cells (monocytes and B-lymphocytes), but their significance for the functioning of these cells is still unclear. The binding of complement by lymphocytes, which is part of the immune complex, may play a role in the formation of the primary immune response.
The study of the complement system in clinical practice can be used to diagnose the disease, determine the activity of the process and evaluate the effectiveness of therapy. The level of serum complement at any given moment depends on the balance of synthesis, catabolism and consumption of its components.
Low values of the hemolytic activity of complement may reflect the insufficiency of individual components or the presence of its cleavage products in the circulation. It should also be borne in mind
that intensive local consumption of complement in such areas as the pleura, joint cavities, may not be combined with a change in the level of complement and serum. For example, in some patients with rheumatoid arthritis, the serum complement level may be normal, while in the synovial fluid it may be sharply reduced due to its active consumption. Complement determination in the synovial fluid is very important for diagnosis.
Congenital complement deficiencies. The inheritance of complement deficiencies is autosomal recessive or codominant, so heterozygotes have about 50% of the normal level of complement components. In most cases, congenital deficiencies of the early initiating components (C1, C4, C2) are associated with systemic lupus erythematosus. Individuals with C component deficiency are susceptible to recurrent pyogenic infections. Terminal component deficiencies are accompanied by increased susceptibility to gonococcal and meningococcal infections. With these complement deficiencies, systemic lupus erythematosus also occurs, but less frequently. The most common is congenital C2 deficiency. Homozygous deficiency for this trait is found in several autoimmune disorders, including lupus-like diseases, Schonlein-Henoch disease, glomerulonephritis, and dermatomyositis. Individuals homozygous for this trait do not show increased susceptibility to infection if the alternative activation pathway is functioning normally. Homozygotes with C2 deficiency were found among practically healthy people.
Heterozygous C2 deficiency may be associated with juvenile rheumatoid arthritis and systemic lupus erythematosus. Family studies have found that C2 and C4 deficiencies are associated with certain HLA haplotypes.
Deficiency of regulatory proteins of the complement system can also have clinical manifestations. Thus, in congenital C3INA deficiency, a clinical picture is observed similar to that in C3 deficiency, because the intake of the latter through an alternative route becomes uncontrolled.
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The complement system, consisting of about 30 proteins, both circulating and expressed on the membrane, is an important effector branch of both innate and antibody-mediated adaptive immune responses. The term "complement" comes from the fact that this temperature-sensitive blood serum material was found to "complement" the ability of antibodies to kill bacteria. Complement is known to play a major role in defense against many infectious microorganisms.
The most important components of its protective function are: 1) the production of opsonins - molecules that increase the ability of macrophages and neutrophils to phagocytosis; 2) the production of anaphylatoxins - peptides that induce local and systemic inflammatory reactions; 3) direct killing of microorganisms.
Other important complement functions are also known, such as enhancing antigen-specific immune responses and maintaining homeostasis (stability within the body) by removing immune complexes and dead or dying cells. We also know that disruption of complement activation can lead to cell and tissue damage in the body.
Complement components are synthesized in the liver, as well as by cells involved in the inflammatory response. The concentration of all complement proteins in the circulating blood is approximately 3 mg/ml. (For comparison: IgG concentration in the blood is about 12 mg/mL) Concentrations of some complement components are high (eg, about 1 mg/mL for C3), while other components (such as factor D and C2) are present in trace amounts. .
Complement activation pathways
The initial stages of complement activation are sequential cascade activation of one after another of its components. At this stage, the activation of one component induces the action of the enzyme, which leads to the activation of the next component in turn. Since one active enzyme molecule is capable of cleaving many substrate molecules, this cascade of reactions amplifies the relatively weak initial signal. These cascade properties of the complement system are similar to those observed in other serum cascades directed towards clot formation and production of kinins, vascular inflammatory mediators.Upon activation, individual components are split into fragments, denoted by lowercase letters. The smaller of the split fragments is usually denoted by the letter "a", the larger - "b". Historically, however, the larger of the cleaved C2 fragments is usually referred to as C2a and the smaller as C2b. (However, in some texts and articles, fragments of C2 complement components are denoted inversely.) Further cleavage fragments are also denoted in small letters, for example, C3d.
There are three pathways for complement activation: classic, lectin and alternative.
The beginning of each of the pathways of activation is characterized by its own components and processes of recognition, however, at later stages in all three cases, the same components are used. The properties of each activation pathway and the substances that activate them are discussed next.
classic way
The classical activation pathway is so called because it was defined first. The protein components of the classical pathway are designated C1, C2, C9. (The numbers are in the order in which the components were discovered, not in which they are activated.) Antigen-antibody complexes are the main activators of the classical pathway. Thus, the latter is the main effector pathway for activating the humoral adaptive immune response.Other activators are certain viruses, dead cells and intracellular membranes (eg, mitochondria), immunoglobulin aggregates, and β-amyloid found in plaques in Alzheimer's disease. C-reactive protein is an acute phase protein - a component of the inflammatory response; it attaches to the polysaccharide phosphorylcholine expressed on the surface of many bacteria (eg Streptococcus pneumoniae) and also activates the classical pathway.
The classical pathway is initiated when C1 attaches to an antibody in an antigen-antibody complex, such as an antibody bound to an antigen expressed on the surface of a bacterium (Figure 13.1). Component C1 is a complex of three different proteins: Clq (containing six identical subcomponents) associated with two molecules (each with two) - Clr and Cls. Upon activation of Cl, its globular regions - subcomponents of Clq - bind to a Clq-specific region on the Fc fragments of either one IgM or two closely spaced IgG molecules associated with the antigen (IgG binding is shown in Fig. 13.1).
Thus, IgM and IgG antibodies are effective complement activators. Human immunoglobulins that have the ability to bind to Cl and activate it, in decreasing order of this ability, are: IgM>> IgG3> IgG 1 » IgG2. Immunoglobulins IgG4, IgD, IgA and IgE do not interact with Clq, do not fix or activate it, i.e. do not activate complement via the classical pathway.
After C1 binds to the Cls antigen-antibody complex, it acquires enzymatic activity. This active form is known as Cls-esterase. It splits the next component of the classical path - C4 - into two parts: C4a and C4b. A smaller part - C4a - remains in a dissolved state, and C4b covalently binds to the surface of the bacterium or other activating substance.
The portion of C4b attached to the cell surface then binds C2, which is cleaved by Cls. When C2 is cleaved, a C2b fragment is obtained, which remains in a dissolved state, and C2a. In turn, C2a attaches to C4b on the cell surface to form the C4b2a complex. This complex is called the classical pathway C3 convertase because, as we will see later, this enzyme cleaves the next component, C3.
lectin pathway
The lectin pathway is activated by terminal mannose residues in proteins and polysaccharides located on the surface of the bacterium. These residues are not found on the surface of mammalian cells; therefore, the lectin pathway can be considered as a means of recognizing self and nonself. Because this activation pathway does not require the presence of antibodies, it is part of the innate immune defense system.On fig. Figure 13.1 shows how bacterial mannose residues bind to the circulating mannose-binding lectin (MBL) complex; similar in structure to the Clq of the classical pathway) and two associated proteases called mannose-associated serine proteases (MASP-1 and -2). This binding activates MAP-1 for subsequent cleavage of the classical complement pathway components C4 and C2 to form C4b2a, the classical pathway C3 convertase on the bacterial surface. And MASP-2 has the ability to directly cleave C3. Thus, the lectin pathway after the C3 activation phase is similar to the classical one.
Alternative path
The alternative pathway for complement activation is triggered by almost any foreign substance. The most studied substances are lipopolysaccharides (LPS, also known as endotoxins cell wall gram-negative bacteria), the cell walls of some yeasts, and a protein found in cobra venom (cobra venom factor). Some agents that activate the classical pathway, viruses, immunoglobulin aggregates, and dead cells, also trigger the alternative pathway.Activation occurs in the absence of specific antibodies. Thus, the alternative complement activation pathway is an effector branch of the innate immune defense system. Some components of the alternative pathway are unique to it (serum factors B and D and properdin, also known as factor P), while others (C3, C3b, C5, C6, C7, C8 and C9) are shared with the classical pathway.
The C3b component appears in the blood in small amounts after spontaneous cleavage of the reactive thiol group in C3. This "pre-existing" C3b is able to bind to the hydroxyl groups of proteins and carbohydrates expressed on cell surfaces (see Figure 13.1). Accumulation of C3b on the cell surface initiates an alternative pathway.
It can occur both on a foreign and on the body's own cell; thus, in terms of the alternate path, it is always running. However, as discussed in more detail below, the body's own cells regulate the course of alternative pathway reactions, while non-self cells do not have such regulatory abilities and cannot prevent the development of subsequent events of the alternative pathway.
Rice. 13.1. Launch of the classical, lectin and alternative pathways. Demonstration of activation of each pathway and formation of C3 convertase
In the next step of the alternative pathway, a whey protein, factor B, binds to C3b on the cell surface to form the C3bB complex. Factor D then cleaves factor B, which is located on the cell surface in the C3bB complex, resulting in a fragment of Ba, which is released into the surrounding fluid, and Bb, which remains associated with C3b. This C3bBb is an alternative pathway C3 convertase that cleaves C3 to C3a and C3b.
Usually C3bBb dissolves quickly, but can be stabilized when combined with properdin (see Fig. 13.1). As a result, properdin-stabilized C3bBb is able to bind and cleave large amounts of C3 in a very short time. Accumulation on the cell surface of these rapidly formed large amounts of C3b leads to an almost "explosive" launch of the alternative pathway. Thus, the binding of properdin to C3bBb creates an alternative pathway amplification loop. The ability of properdin to activate the amplification loop is controlled by the opposite action of regulatory proteins. Therefore, the activation of the alternative path does not occur all the time.
Activation of C3 and C5
C3 cleavage is the main phase for all three activation pathways. On fig. 13.2 shows that C3 convertases in the classical and alternative pathways (C4b2a and C3bBb, respectively) cleave C3 into two fragments. The smaller C3a is a soluble anaphylatoxin protein: it activates cells involved in the inflammatory response. The larger fragment, C3b, continues the activation process of the complement cascade by binding to cell surfaces around the site of activation. As shown below, C3b is also involved in host defense, inflammation, and immune regulation.
Rice. 13.2. Cleavage of component C3 by C3-convertase and component C5 by C5-convertase in the classical and lectin (top) and alternative (bottom) pathways. In all cases, C3 is cleaved into C3b, which is deposited on the cell surface, and C3, which is released into liquid medium. In the same way, C5 is cleaved into C5b, which is deposited on the cell surface, and C5a, which is released into the liquid medium.
The binding of C3b to C3 convertases, both in the classical and alternative pathways, initiates the binding and cleavage of the next component, C5 (see Fig. 13.2). For this reason, C3 convertases associated with C3b are classified as C5 convertases (C4b2a3b in the classical pathway; C3bBb3b in the alternative). When C5 is cleaved, two fragments are formed. Fragment C5a is released in a soluble form and is an active anaphylatoxin. The C5b fragment binds to the cell surface and forms a nucleus for binding to the terminal complement components.
terminal path
The terminal components of the complement cascade - C5b, C6, C7, C8 and C9 - are common to all activation pathways. They bind to each other and form a membrane attack complex (MAC), which causes cell lysis (Fig. 13.3).
Rice. 13.3 Formation of the membrane attack complex. Complement components of the late phase - C5b-C9 - sequentially connect and form a complex on the cell surface. Numerous C9 components attach to this complex and polymerize to form poly-C9, creating a channel that spans the cell membrane.
The first phase of MAC formation is the attachment of C6 to C5b on the cell surface. C7 then binds to C5b and C6 and penetrates the outer membrane of the cell. Subsequent binding of C8 to C5b67 leads to the formation of a complex that penetrates deeper into the cell membrane. On the cell membrane, C5b-C8 acts as a receptor for C9, a perforin-type molecule that binds to C8.
Additional C9 molecules interact in complex with the C9 molecule, forming polymerized C9 (poly-C9). These poly-C9 form a transmembrane channel that disrupts the osmotic balance in the cell: ions penetrate through it and water enters. The cell swells, the membrane becomes permeable to macromolecules, which then leave the cell. The result is cell lysis.
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The effector role of complement. Formation of the membrane attack complex and its role in cell lysis.
a) participates in the lysis of microbial and other cells (cytotoxic effect);
b) has chemotactic activity;
c) takes part in anaphylaxis;
d) participates in phagocytosis.
The main beneficial effects of complement:
assistance in the destruction of microorganisms;
intensive removal of immune complexes;
induction and enhancement of the humoral immune response.
The complement system can cause damage to the cells and tissues of your own body in the following cases:
if its generalized massive activation occurs, for example, with septicemia caused by gram-negative bacteria;
if its activation occurs in the focus of tissue necrosis, in particular in myocardial infarction;
if activation occurs during an autoimmune reaction in tissues.
First phase: attachment of C6 to C5b on the cell surface. C7 then binds to C5b and C6 and enters outer membrane cells. Subsequent binding of C8 to C5b67 leads to the formation of a complex that penetrates deeper into the cell membrane. On the cell membrane, C5b-C8 acts as a receptor for C9, a perforin-type molecule that binds to C8. Additional C9 molecules interact in complex with the C9 molecule, forming polymerized C9 (poly-C9). They form a transmembrane channel that disrupts the osmotic balance in the cell: ions penetrate through it and water enters. The cell swells, the membrane becomes permeable to macromolecules, which then leave the cell. As a result, cell lysis occurs.
Compliment system - a complex of complex proteins that are constantly present in the blood. It's a cascade system proteolytic enzymes designed for humoral protection of the body from the action of foreign agents, it is involved in the implementation immune response organism. It is an important component of both innate and acquired immunity.
Along the classical path Complement is activated by the antigen-antibody complex. For this, participation in the binding of the antigen of one IgM molecule or two IgG molecules is sufficient. The process begins with the addition of component C1 to the AG + AT complex, which breaks down into subunitsC1q, C1r and C1s. Further, sequentially activated "early" complement components in the sequence participate in the reaction: C4, C2, NW. The "early" component of complement C3 activates component C5, which has the ability to attach to the cell membrane. On the C5 component, by successively attaching the “late” components C6, C7, C8, C9, a lytic or membrane-attacking complex is formed that violates the integrity of the membrane (forms a hole in it), and the cell dies as a result of osmotic lysis.
Alternative path complement activation takes place without the participation of antibodies. This pathway is characteristic of protection against gram-negative microbes. The cascade chain reaction in the alternative pathway begins with the interaction of the antigen with proteins B, D and properdin (P) followed by activation of the C3 component. Further, the reaction proceeds in the same way as in the classical way - a membrane attack complex is formed.
Lectin Put Complement activation also occurs without the participation of antibodies. It is initiated by a specific mannose-binding proteinblood serum, which, after interacting with mannose residues on the surface of microbial cells, catalyzes C4. The further cascade of reactions is similar to the classical way.
In the process of complement activation, proteolysis products of its components are formed - subunits C3a and C3b, C5a and C5b, and others that have high biological activity. For example, C3a and C5a take part in anaphylactic reactions, are chemoattractants, C3b plays a role in opsonization of objects of phagocytosis, etc. A complex complement cascade reaction occurs with the participation of Ca ions 2+ and Mg 2+ .
Biological functions of complement
Odintsov Yu.N., Perelmuter V.M. Biological functions of complement
Odintsov Yu.N., Perelmuter V.M.
Siberian State Medical University, Tomsk
© Odintsov Yu.N., Perelmuter V.M.
Complement is one of the most important resistance factors in the body. The complement system can take part in various effector mechanisms, primarily in lysis (complementary killing) and opsonization of microorganisms. Macrophages can take part in switching the lytic function of the complement to the opsonic one. Complement functions in bacterioses depend on the pathogenesis of the infectious disease.
Key words: complement, bacteriolysis, opsonization, infectious process.
One of the true basic resistance factors is complement. Main functions of it consist in bacterial lysis, bacterial opsonisation for phagocytosis. Alteration of lytic function for opsonic function depends upon macrophages. Complement functions at bacteriosis depend on phathogenesis features in infectious disease.
Key words: complement, bacteriolysis, opsonisation, infectious process.
UDC 576:8.097.37
The human body has two main lines of defense against pathogens of infectious diseases: nonspecific (resistance) and specific (immunity).
Factors of the first line of defense (resistance) are characterized by a number of common features: 1) they are formed long before the encounter with the pathogen (prenatal period); 2) non-specific; 3) are genetically determined; 4) genotypically and phenotypically heterogeneous (heterogeneous) in the population; 5) high resistance to one pathogen can be combined with low resistance to another; 6) resistance primarily depends on the functional state of macrophages, which is controlled by genes not associated with HLA, and the state of the complement system (controlled by HLD).
Complement is a multicomponent plasma enzyme system, the composition and function of which are generally well studied, and is one of the most important factors in the body's resistance. In the 1960s-1970s. it was especially popular to determine the complement titer as one of the indicators of resistance. And at present, a lot of research is devoted to the study of complement function. However, there are
not only certain difficulties and contradictions in explaining the mechanism of complement activation, but still
some mechanisms of complement activation and functioning remain insufficiently studied. These controversial issues include the mechanism of action of inhibitors of complement activation in vivo, the mechanism of switching complement activation from lytic to opsonic function, and understanding the role of complement in sanogenesis in various infections.
There are 14 proteins (components) of blood plasma that make up the complement system. They are synthesized by hepatocytes, macrophages and neutrophils. Most of them belong to p-globulins. According to the nomenclature adopted by WHO, the complement system is denoted by the symbol C, and its individual components by the symbols Cl, C2, C3, C4, C5, C6, C7, C8, C9 or capital letters (D, B, P). Part of the components (Cl, C2, C3, C4, C5, B) is divided into their constituent subcomponents - heavier, with enzymatic activity, and less heavy, without enzymatic activity, but retaining independent biological function. Activated complexes of proteins of the complement system are marked with a bar above the complex (for example, C4b2a3b - C5 convertase).
In addition to complement proteins (C1-C9), in the implementation of its biological activity, they take
participation and other proteins that perform regulatory functions:
a) macroorganism cell membrane receptors for complement subcomponents: CR1(CD35), CR2(CD21), CR3(CD11b/CD18), CR4(CD11c/CD18), C1qR, C3a/C4aR, C5aR;
b) membrane proteins of macroorganism cells: membrane cofactor protein (MCP, or MCP - membrane-associated cofactor of proteolysis, CD46), dissociation accelerating factor (FAD, or DAF - decay accelerating factor, CD55), protectin (CD59);
c) blood plasma proteins that carry out positive or negative regulation: 1) positive regulation - factor B, factor D, properdin (P); 2) negative regulation - factor I, factor H, protein-binding C4b (C4 binding protein, C4bp), C1 inhibitor (C1-inh, serpin), S-protein (vitronectin).
Thus, more than 30 components are involved in the functions of the complement system. Each protein component (subcomponent) of complement has certain properties (Table 1).
Normally, complement components are in the plasma in an inactive state. They become active in the process of multistage activation reactions. The activated complement components act in a specific order in the form of a cascade of enzymatic reactions, and the product of the previous activation serves as a catalyst for the inclusion of a new subcomponent or complement component in the subsequent reaction.
The complement system may be involved in various effector mechanisms:
1) lysis of microorganisms (complementary killing);
2) opsonization of microorganisms;
3) splitting of immune complexes and their clearance;
4) activation and chemotactic attraction of leukocytes to the focus of inflammation;
5) enhancing the induction of specific antibodies by: a) enhancing the localization of the antigen on the surface of B-lymphocytes and antigen-presenting cells (APCs); b) lowering the activation threshold of B-lymphocytes.
The most important functions of complement are the lysis of pathogen membranes and the opsonization of microorganisms.
Table 1
Complement components and subcomponents involved in the classical and alternative pathways of complement activation
Component (subcomponent) Molecular mass, kD Subcomponent Concentration in blood serum, μg/ml Function
C1 1124 1 C1q 2 C1r 2 C1s - Enzyme complex
Clq 460 - 80 Binding to a long chain ^ or 1dM antigen-antibody complex
Clr 166 - 30-50 Protease activating Cb
Cls 166 - 30-50 Serine protease activating C4 and C2
C2 110 2a, 2b 15-25 Form C3-convertase (C4b2a), and then C5-convertase (C4b2a3b) of the classical pathway
SZ 190 3a, 3b 1200
С4 200 4a, 4b 350-500
C5 191 5a, 5b 75 Formation of a membrane attack complex that forms a pore in the membrane of the target cell
Factor B 95 Ba, Bb 200 Form C3-convertase (C3bbp), and then C5-convertase (Cbbbb) of the alternative pathway
Factor D 25 - 1
Properdin(R) 220 25 Alternative pathway C3-convertase stabilizer (C3bb), blocks dissociation of C3bb under the action of factor H
Complementary lysis of microorganisms
The lysis of microorganisms occurs as a result of the formation of a membrane attack complex (MAC), consisting of
one of the components of the complement. Depending on how the formation of MAC occurred, there are several ways of complement activation.
Classical (immunocomplex) pathway of complement activation
This complement activation pathway is called the classical one because it was the first to be described and for a long time remained the only one known today. In the classical pathway of complement activation, the starting role is played by the antigen-antibody complex (immune complex (IC)). The first link in complement activation is the binding of the C ^-subcomponent of the C1 component to the immunoglobulin of the immune complex. In particular, in the case of complement activation by class G immunoglobulins (Ig31, IgG2, IgG3, Ig4), this is done by amino acid residues at positions 285, 288, 290, 292 of the DO heavy chain. Activation of this site occurs only after the formation of the antigen-antibody complex (AG-AT). The ability to activate complement along the classical pathway is possessed with decreasing intensity by 1dM, Ig3, DO1 and DO2.
Complement component C^ consists of three subunits (Fig. 1), each of which has two centers for binding to 1g in the AG-AT complex. Thus, a complete C^ molecule has six such centers. During the formation of the AG-1gM complex, the C^ molecule binds to at least two second domains (CH2) of the same 1gM molecule, and when class G immunoglobulins participate in the formation of the AG-AT complex, it binds to the second domains (CH2) of at least two different molecules ^ in the AG-^ complexes. Attached to AG-AT, C^ acquires the properties of a serine protease and initiates the activation and incorporation of two C1r molecules into C^. C1r, in turn, initiates the activation and incorporation of two other molecules, C^, into C^. Activated C^ has serine esterase activity.
The C^ of the C1 complex then cleaves C4 into a larger C4b fragment and a smaller C4a fragment. C4b is connected by covalent bonds with amino and hydroxyl groups of cell membrane molecules (Fig. 2). C4b fixed on the surface of the membrane (or of the AG-AT complex) binds C2, which becomes available for enzymatic cleavage by the same serine protease C^. As a result, a small fragment 2b and a larger fragment C2a are formed, which, by combining with C4b attached to the membrane surface, form the enzyme complex C4b2a, on-
called the C3-convertase of the classical pathway of complement activation.
Rice. Fig. 1. Components of the enzyme complex C1 (1d2r2e) and its interaction with the antigen-antibody complex (AG-I or AG-1gM): J - chain that combines pentamer monomers
SZVV -» -SZVVR
I------------------
Reinforcement loop Fig. 2. Complement activation via the classical pathway
The resulting C3 convertase interacts with C3 and cleaves it into a smaller C3 fragment and a larger C3b fragment. Plasma concentration of C3 is the highest of all complement components, and one enzyme complex C4b2a (C3-convertase) is able to cleave up to 1000 C3 molecules. This creates a high concentration of C3b on the membrane surface (amplification of C3b formation). Then C3b covalently binds to C4b, which is part of the C3-convertase. The formed three-molecular complex C4b2a3b is a C5-convertase. C3b in the C5-convertase binds covalently to the surface of microorganisms (Fig. 2).
The substrate for C5 convertase is the C5 component of the complement, the cleavage of which ends with the formation of a smaller C5a and a larger C5b. About-
the formation of C5b initiates the formation of a membrane attack complex. It proceeds without the participation of enzymes by sequentially adding components C6, C7, C8 and C9 of the complement to C5b. C5b6 is a hydrophilic and C5b67 is a hydrophobic complex that is incorporated into the lipid bilayer of the membrane. Attachment to C5b67 C8 further immerses the resulting C5b678 complex into the membrane. And, finally, 14 C9 molecules are fixed to the C5b678 complex. The formed C5b6789 is the membrane attack complex. Polymerization of C9 molecules in the C5b6789 complex leads to the formation of a non-collapsed pore in the membrane. Water and N8+ enter the cell through the pore, which leads to cell lysis (Fig. 3).
Dissolved compounds
The intensity of MAC formation in the classical pathway of complement activation increases due to the amplification loop of the alternative pathway of complement activation. The amplification loop begins from the moment of formation of the C3b covalent bond with the membrane surface. Three additional plasma proteins are involved in loop formation: B, D, and P (proper-din). Under the influence of factor D (serine esterase), C3b-bound protein B is cleaved into a smaller Ba fragment and a larger Bb fragment, which binds to C3b (see Fig. 2). The addition of properdin, which acts as a stabilizer of the C3b Bb complex, to the C3bb complex completes the formation of the alternative pathway C3-convertase, C3bbp. The alternative pathway C3 convertase cleaves C3 molecules, forming additional C3b, which ensures the formation of all more C5 convertase and eventually more MAC. MAC action-
et independently, and possibly induces apoptosis through the caspase pathway.
Alternative (spontaneous) complement activation pathway
The mechanism of complement activation via the alternative pathway is due to spontaneous hydrolysis of the thioether bond in the native C3 molecule. This process occurs constantly in the plasma and is called "idle" activation of C3. As a result of hydrolysis of C3, its activated form, designated C31, is formed. Further, C3i binds factor B. Factor D splits factor B in the C3iB complex into a small Ba fragment and a large Bb fragment. The resulting C3iBb complex is a liquid-phase C3-convertase of the alternative pathway of complement activation. Next, the liquid-phase convertase C3iBb cleaves C3 into C3a and C3b. If C3b remains free, it is destroyed by being hydrolyzed by water. If C3b covalently binds to the surface of a bacterial membrane (the membrane of any microorganism), then it does not undergo proteolysis. Moreover, it initiates the formation of an alternative path amplification loop. Factor B is attached to the fixed C3b (C3b has a greater affinity for factor B than for factor H), a complex C3bB is formed, from which factor D
splits off a small fragment of Ba. After addition of properdin, which is a stabilizer of the C3bb complex, the C3bbp complex is formed, which is an alternative pathway C3-convertase bound to the membrane surface. Bound C3 convertase initiates attachment of additional C3b molecules at the same site (C3b amplification), which leads to rapid local accumulation of C3b. Further, the bound C3 convertase cleaves C3 into C3a and C3b. Attachment of C3b to C3 convertase forms the C3bb3 complex (C3b2bb), which is an alternative pathway C5 convertase. Then, the C5 component is cleaved and MAC is formed, as in the classical pathway of complement activation.
Spontaneous hydrolysis
I_________________________I
Gain Loop
Rice. 4. Alternative (spontaneous) pathway of complement activation
"idle" activation
Microorganism
Lectin Complement Activation Pathway
Lipopolysaccharides (LPS) of gram-negative bacteria, which may contain residues of mannose, fucose, glucosamine, are bound by lectins (whey proteins that strongly bind carbohydrates) and induce the lectin pathway of complement activation. For example, a trigger for the lectin pathway of complement activation can be a mannan-binding lectin (MBL), like C2, which belongs to the family of calcium-dependent lectins.
It combines with mannose, which is part of the bacterial cell wall, and acquires the ability to interact with two mannan-binding lectin-associated serine proteinases, MASP1 and MASP2, which are identical to C1r and C13, respectively.
The interaction [MSL-MASP1-MASP2] is analogous to the formation of the [C^-C1r-C^] complex. Subsequently, complement activation occurs in the same way as in the classical pathway (Fig. 5).
4a 2b C3a C3b C5a
Gain Loop
Rice. 5. Lectin pathway of complement activation (M - mannose as part of the surface structures of the cell, for example, LPS)
Proteins of the pentraxin family, which have the properties of lectins, such as amyloid protein, C-reactive protein, are also able to activate complement through the lectin pathway, interacting with the corresponding substrates of bacterial cell walls. Thus, C-reactive protein activates forsphorylcholine in the cell wall of Gram-positive bacteria. And then the activated forsphorylcholine starts the classic way of assembling complement components.
C3b, which is formed from C3, under the influence of any C3-convertase, binds to the target membrane and becomes a site for additional formation of C3b. This stage of the cascade is called the "amplification loop". Whatever the pathway of complement activation, if it is not blocked by one of the regulatory factors, it ends with the formation of a membrane attack complex that forms a non-collapsing pore in the bacterial membrane, which leads to its death.
The alternative and lectin pathways of complement activation by the timing of triggering in infectious disease are early. They can be activated already in the first hours after the pathogen enters the internal environment of the macroorganism. The classical pathway of complement activation is late: it begins to “work” only when antibodies appear (1 dM,
Complement activation regulatory proteins
The process of complement activation is regulated by membrane (Table 2) and plasma (Table 3) proteins.
Complement activation pathways and MAC formation can be blocked by various factors:
1) classic, lectin:
The action of a C1 inhibitor that binds and inactivates C1g and C^;
Suppression of the formation of C3-convertase of the classical and lectin pathway (C4b2a) under the influence of factors I, H, C4-Lp, FUD, ICD and C^1;
Suppression of the interaction of complement components with the surface of macroorganism cells by the action of FUD ^55), CR1 (CD35), ICD ^46);
2) alternative:
Dissociation of the C3iBb and C3bb complexes by the action of the H factor;
C3b cleavage by factor I with the participation of one of three cofactors: factor H (plasma), CR1, or LAB (bound on the surface of macroorganism cells);
Suppression of the formation of C3-convertase of the alternative pathway on the surface of macroorganism cells by the action of FUD, CR1 or LAB.
table 2
Membrane regulatory proteins
Cellular (located on the membranes of the cells of the macroorganism)
Factor Expression on cells Function Result
CR1 ^35) B-lymphocytes; monocytes (macrophages); granulocytes; follicular dendritic cells; NK cells Suppresses the binding of C2 to C4b; causes and accelerates the dissociation of C4b2a into C4b and 2a; catabolism cofactor C4b under the action of factor I; catabolism cofactor C3b under the action of factor I; accelerates the dissociation of C3bb with the release of c3b Suppresses complement activation via any pathway on the membranes of the body's own cells
ICD ^46) T-lymphocytes; B-lymphocytes; monocytes (macrophages); granulocytes; dendritic cells; NK cells Suppresses the formation of convertases: C4b2a and C3bb; catabolism cofactor C4b under the action of factor I; catabolism cofactor C3b under the action of factor I The same
FUD ^55) T-lymphocytes; B-lymphocytes; monocytes (macrophages); granulocytes; dendritic cells; NK cells; platelets Inhibits the formation of C4b2a convertase of the classical pathway; inhibits the formation of alternative pathway C3bb convertase; inhibits the binding of C2 to C4b; accelerates the dissociation of C4b2a into C4b and 2a; accelerates the dissociation of C3bb with the release of c3b
Protectin (L59) All cells macro- Binds to 5b678 and inhibits its immersion into the membrane Prevents lysis
organism | and deployment of C9 | own cells
Table H
Plasma regulatory proteins
Factor Function Molecular weight and serum concentration Realization of effect on somatic cells and (or) on pathogens
Factor H (easily binds to sialic acids on the surface of cells of the macroorganism) Suppresses the formation of C4b2a convertase of the classical pathway; inhibits the formation of alternative pathway C3bBb convertase; causes dissociation of the liquid-phase C3iBb convertase into C3i and Bb; catabolism cofactor C3i and Bb; causes dissociation of C3bBb convertase into C3b and Bb 150 Kda, 500 µg/ml
Factor I (plasma protease) Inhibits the formation of classical pathway C4b2a convertase 90 Kda, 35 µg/ml
Together with one of the cofactors (ICB, CR1, C4bp) splits 4b into C4c and C4d; together with one of the cofactors (MCB, CR1, H) cleaves C3b; catabolism factor C3b and C3i Suppresses complement activation through any pathway on the membranes of the body's own cells
C4bp (C4 binding protein, protein-binding C4b) Inhibits C2 binding to C4b; inhibits the formation of convertase C4b2a of the classical pathway; causes dissociation of C4b2a into C4b and 2a; catabolism cofactor C4b under the influence of factor I 560 Kda, 250 µg/ml
C1 inhibitor (C 1-inh, serpin) Binds and inhibits C1r and C1 s (serine protease inhibitor); cleaves C1r and C1s from C1q (C1q remains associated with the Fc fragment of Ig); limits the contact time of C1 s with C4 and C2; limits spontaneous activation of C1 in blood plasma 110 Kda, 180 µg/ml
S-protein (vitronectin) Forms the 5b67-S complex, inactivates its ability to infiltrate the lipid layer of the membrane 85 Kda, 500 µg/ml Blocks the formation of MAC
Suppression of MAC formation In contrast, regulatory proteins of plasma origin
ions inhibit complement activation not only on the surface of somatic cells, but also on the membranes of pathogens.
Opsonization of microorganisms by complement components
Complementary lysis of microorganisms is an early reaction of a macroorganism to the ingress of pathogens into its internal environment. The subcomponents C2b, C3a, C4a, C5a, and Ba formed during complement activation via the alternative or lectin pathway attract cells to the inflammation site and activate their effector functions.
Of the complement components, 3b and 4b mainly have opsonizing properties. Two conditions are necessary for their formation: the first is complement activation by one of the pathways described above, and the second is blocking of the activation process, which makes it impossible for MAC formation and pathogen lysis. This is what it consists
on the surface of pathogens.
1. The hydrophobic complex C5b67, which begins to be incorporated into the lipid bilayer of the membrane, can be inactivated by the S-protein (vitronectin). The resulting 5b67S complex cannot be introduced into the lipid layer of the membrane.
2. Attachment of component 8 to the C5b67 complex in the liquid phase can be blocked by low density lipoproteins (LDL).
3. Immersion in the membrane of C5b678 and attachment of C9 prevents CD59 (protectin), a macroorganism cell membrane protein.
4. Removal of membrane fragments of macroorganism cells with built-in MAC by endocytosis or exocytosis.
Thus, regulatory proteins of cellular origin independently inhibit complement activation with the formation of MAC only on the surface of somatic cells and are not effective in inhibiting lytic
There are corresponding receptors for membrane C3b and its membrane subcomponent of C3b degradation on macroorganism cells (Table 4). C3b and inactivated C3b (C3b) are ligands for receptors CR1 (C3b, C3b), CR3 (C3b), CR4 (C3b) located on neutrophils, monocytes (macrophages), and umbilical cord endothelium. СЗЬ and СЗЫ act as active opsonins.
Presumably, the combined action of factors I and H can switch the formation of a lytic complex (MAC, complementary killing) to another mechanism of pathogen destruction - phagocytic killing (Fig. 6). Soluble inhibitors of complement activation (I and H), produced by macrophages that later appear in the inflammation site, act in the phagocyte microenvironment, preventing the formation of C3 convertase on the bacterial surface and thus ensuring the presence of “free” C3b. The macrophage receptor for C3b binds the ligand (C3b) and fixes the bacterium on the surface of the macrophage. Its phagocytosis is carried out with the joint participation of two ligand-receptor complexes: the receptor for C3b + C3b and FcyR + ^. The other pair - C3b + C3 receptor - initiates phagocytosis even without participation of antibodies.
The biological meaning of switching complement activation from lytic to opsonic function is probably that all bacteria that are not lysed before encountering a phagocyte should be phagocytosed by C3b-opsonin. Such a mechanism for switching complement activation to opsonic is necessary not only for phagocytosis of viable pathogens in the early stages of infection, but also for the utilization of microorganism fragments by phagocytes.
Table 4
Receptors for complement subcomponents
Receptor (complement receptor, CR) Ligands Expression on cells Binding effect
CR1 (CD35) C3bi > C3b, C4b Neutrophils, monocytes (macrophages), B-lymphocytes, follicular dendritic cells, erythrocytes, renal glomerular epithelium Opsonized phagocytosis, activation of B-lymphocytes, transport of immune complexes on erythrocytes
CR3 (CD11b/CD18) C3bi Neutrophils, monocytes (macrophages), NK cells, follicular dendritic cells Opsonized phagocytosis
CR4 (p 150-95) (CD11c/CD18) C3bi Neutrophils Opsonized phagocytosis
CR2 (CD21), component of the B-lymphocyte core-ceptor complex (BCR + CD19, CR2, CD81) C3bi, C3dg B-cells, follicular dendritic cells Enhances BCR activation reactions, induces non-phagocytosed binding of the AG-AT complex on follicular dendritic cells
switching of the lytic program of complement activation to the opsonic one.
In the real conditions of the infectious process, switching to the opsonic complement activation program, which provides pathogen phagocytosis and clearance of immune complexes, can occur due to the effects of regulatory proteins. The assembly of complement components on the membrane can end with the formation of a membrane attack complex, or it can be interrupted at the level of formation of 4b and even more actively at the level of formation of 3b by factors I and H.
Factor I is the main enzyme that degrades C3b. Factor H in this process acts as a cofactor. Acting together, they have the ability to inactivate both liquid-phase and membrane C3b (free or as part of any convertase), cleaving off the C3f fragment from it (inactivated C3b is designated as C3b). Then they continue splitting the C3 as follows:
φ ^ subcomponent subcomponent
sz z z z z
Blockade of further complement activation
Bacterium
Switching to the process of phagocytosis
Factor H (cofactor)
Macrophage
Absorption of bacteria
Y Receptor to the Pc fragment X,1 C3b complement component
1| |1 V Receptor for the C3b or C33 component of the complement
Rice. 6. Switching complement activation to phagocytosis
It is appropriate to consider the question of the possible role of complement in the pathogenesis of various groups of bacterioses, previously separated depending on the mechanism of sanogenesis.
Toxigenic bacterioses (diphtheria, gas gangrene, botulism, tetanus, etc.). The usual localization of pathogens is the entrance gate of infection. The main effector of pathogenesis is a toxin (T-dependent antigen, antigen of the first type). T-dependent surface antigens of these bacteria play an insignificant part in the induction of the immune response. The main effector of sanogenesis is antitoxin. The type of immune response is T1l2. Recovery occurs due to the formation and subsequent elimination of immune complexes, as well as phagocytic killing of bacteria in the focus of inflammation. The role of complement in these bacterioses is probably limited to participation in the elimination of toxin-antitoxin immune complexes. Complement does not play a significant role in toxin neutralization (i.e., in the sanogenesis of toxigenic infections).
Nontoxigenic nongranulomatous bacterioses
1. Pathogens contain surface T-independent antigens (T "1 antigens, antigens of the second type):
Bacteria contain classical LPS (Tantigens of enteropathogenic Escherichia coli, Salmonella, Shigella, etc.). The usual localization of pathogens is from the entrance gate in the mucous membranes of the intestinal tract to the regional lymph nodes. The main effector of pathogenesis is endotoxin and live bacteria. The type of immune response is T1l2. Immune
The response to LPS is characterized by the production of IgM-class antibodies. Sanogenesis occurs primarily as a result of the destruction of bacteria in a non-phagocytic way in the pre-immune phase of the infectious process due to the lectin and alternative pathways of complement activation. In the immune phase of the infectious process - due to immune lysis with the participation of 1dM and complement along the classical pathway of activation. Phagocytosis is not essential in sanogenesis in bacterioses of this group. Activation of the complement system in these diseases may contribute to sanogenesis;
Bacteria contain surface (capsular) 7!-antigens (pneumococci, hemophilic bacteria, etc.). The usual localization of pathogens - from the entrance gate in the mucous membranes of the respiratory tract to the regional lymph nodes, often penetrate into the blood. The main effector of pathogenesis is live bacteria. The type of immune response is T1l2. In the immune response to surface antigens, the formation of IgM-class antibodies occurs. Sanogenesis is carried out primarily due to the destruction of bacteria in a non-phagocytic way in the pre-immune phase of the infectious process due to the lectin and alternative pathways of complement activation. In the immune phase of the infectious process - due to immune lysis with the participation of 1dM and complement along the classical pathway of activation. In the case of penetration of bacteria of this group into the blood, the spleen, the main site of phagocytosis of weakly opsonized (or non-opsonized) bacteria, plays the main role in cleansing the macroorganism from pathogens - and the ability to
DM “targets” the bacteria sensitized by it for phagocytosis by Kupffer cells, followed by the transfer of bacterial fragments that have not yet been completely disintegrated into the bile capillaries. Bile salts break down bacterial fragments that are excreted into the intestines. Activation of the complement system in this group of diseases may also contribute to sanogenesis.
2. Pathogens contain surface T-dependent antigens (T-antigens, antigens of the first type).
Localization of pathogens (staphylococci, streptococci, etc.) - entrance gates (skin, mucous membranes), regional lymph nodes, systemic damage (organs). The main effectors of pathogenesis are living bacteria and, to a lesser extent, their toxins. In the immune response, a change in the synthesis of!dM to DO is clearly seen. The type of immune response with an adequate course of an infectious disease (in patients without signs of immunodeficiency) is T1r2. Sanogenesis is driven by immune phagocytosis, immune lysis, and antitoxins. In these infections, in the preimmune phase, sanogenesis is carried out through an alternative pathway of complement activation and opsonization of bacteria by complement activation products, followed by their phagocytosis. In the immune phase of the infectious process, sanogenesis is associated with complementary killing in the classical pathway of complement activation involving!dM and DO, as well as with phagocytosis of bacteria opsonized by complement activation products and DO.
Granulomatous bacterioses
1. Pathogens of acute non-epithelioid cell granulomatous bacterioses (listeria, salmonella typhoid, paratyphoid A, B, etc.).
The pathogens contain surface T-dependent antigens. The effectors of pathogenesis are living bacteria. Phagocytosis incomplete. The type of immune response is T1r2 and TM. The appearance of!dM is accompanied by the formation of granulomas. Changing!dM to DO leads to the reverse development of granulomas. Sanogenesis is carried out through an alternative pathway of complement activation and opsonization of bacteria by complement activation products with their subsequent phagocytosis. In the immune phase of the infectious process, sanogenesis is associated with complementary killing in the classical pathway of complement activation involving!dM and DO, as well as with phagocytosis of bacteria opsonized by complement activation products and DO.
2. The causative agents of chronic epithelioid cell granulomatous bacterioses (mycobacterium tuberculosis, leprosy; brucella, etc.).
The pathogens contain surface T-dependent antigens. The effectors of pathogenesis are living bacteria. Phagocytosis incomplete. Type of immune response - Th2 and Th1. The appearance of IgM, apparently, can also be a leading factor in the formation of granulomas. The action of Thl-set cytokines is not enough for the completion of phagocytosis, which leads to the appearance of epithelioid cells in the granuloma. None of the variants of complement activation in sanogenesis plays a significant role.
Conclusion
Complement (complement system) is one of the first humoral factors that a pathogen encounters when it enters the internal environment of a macroorganism. The mechanisms of activation of complement components make it possible to use it both for the lysis of pathogens and for enhancing phagocytosis. Not all bacterial infectious diseases can be used as a prognostic test for the content and level of complement in the blood.
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Without regulatory mechanisms acting at many stages, the complement system would be ineffective; unlimited consumption of its components could lead to severe, potentially fatal damage to the cells and tissues of the body. At the first stage, the C1 inhibitor blocks the enzymatic activity of Clr and Cls and, consequently, the cleavage of C4 and C2. Activated C2 lasts only a short time, and its relative instability limits the lifetime of C42 and C423. The C3-activating enzyme of the alternative pathway, C3bBb, also has a short half-life, although the binding of properdin to the enzyme complex prolongs the lifetime of the complex.
V serum there is an inactivator of anaphylatoxins - an enzyme that cleaves off the N-terminal arginine from C4a, C3a and C5a and thereby sharply reduces their biological activity. Factor I inactivates C4b and C3b, factor H accelerates the inactivation of C3b by factor I, and a similar factor, C4-binding protein (C4-bp), accelerates the cleavage of C4b by factor I. Three constitutional cell membrane proteins - PK1, a membrane cofactor protein and a factor that accelerates decay (FUR) - destroy C3- and C5-convertase complexes that form on these membranes.
Other components of cell membranes- associated proteins (among which CD59 is the most studied) - can bind C8 or C8 and C9, which prevents the incorporation of the membrane attack complex (C5b6789). Some blood serum proteins (among which protein S and clusterin are the most studied) block the attachment of the C5b67 complex to the cell membrane, its binding of C8 or C9 (i.e., the formation of a full-fledged membrane attack complex) or otherwise prevent the formation and incorporation of this complex.
The protective role of complement
Neutralization viruses C1 and C4 are enhanced by antibodies and increase even more when C3b is fixed, which is formed along the classical or alternative pathway. Thus, complement is of particular importance in the early stages of a viral infection, when the number of antibodies is still low. Antibodies and complement limit the infectivity of at least some viruses by forming the typical complement "holes" visible on electron microscopy. The interaction of Clq with its receptor opsonizes the target, i.e. facilitates its phagocytosis.
C4a, C3a and C5a are fixed by mast cells, which begin to secrete histamine and other mediators, leading to vasodilation and edema and hyperemia characteristic of inflammation. Under the influence of C5a, monocytes secrete TNF and IL-1, which enhance the inflammatory response. C5a is the main chemotactic factor for neutrophils, monocytes and eosinophils capable of phagocytizing microorganisms opsonized by C3b or its cleavage product iC3b. Further inactivation of cell-bound C3b, leading to the appearance of C3d, deprives it of its opsonizing activity, but its ability to bind to B-lymphocytes is retained. C3b fixation on the target cell facilitates its lysis by NK cells or macrophages.
C3b binding with insoluble immune complexes solubilizes them, since C3b, apparently, destroys the lattice structure of the antigen-antibody complex. At the same time, it becomes possible for this complex to interact with the C3b receptor (PK1) on erythrocytes, which transfer the complex to the liver or spleen, where it is absorbed by macrophages. This phenomenon partly explains the development of serum sickness (immune complex disease) in individuals with C1, C4, C2, or C3 deficiency.
