Regulatory mechanisms of complement. Protective functions of complement

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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

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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.

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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 – the first to be discovered – proteins of the complement system denoted by the letter C(from the English word complement) with the corresponding number.

2. The remaining fractions of the complement system are designated other Latin letters or combinations thereof.

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Complement activation pathways

There are three pathways of complement activation: classical, lectin and alternative.

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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 am producing large quantities of the 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).

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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).

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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 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 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 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.

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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.

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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).

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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.

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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 proteins intercellular matrix (for example, collagens, elastins, fibronectin) and even proteins of the complement system.

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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.

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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 finished form, and the degranulation process occurs quickly, histamine appears very early at the site 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.

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Lipid mediators.

Humoral factors of lipid nature play an important 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 various types cells especially 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.

The common property of these groups of factors is their 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).

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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 blood 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.

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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 (hydroxy-, hydroxy-), are designated by 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.

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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.

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Cytokines

Related information.

Complement– a system of blood serum proteins that takes part in the regulation of inflammatory processes, activation of phagocytosis and destructive (lytic) effect on cell membranes.

The complement system includes about two dozen proteins, their content is ~ 5% of all blood plasma proteins, i.e. the concentration in the blood is 3 – 4 g/l. Complement proteins are designated by the symbol ʼʼCʼʼ and a number corresponding to the chronology of their discovery; the products of the breakdown of complement components are designated by a small Latin letter (C3b, C5a, etc.). IN the greatest number the blood contains component C3, which plays a central role in the activation of complement.

This system is characterized by a rapid, multiply enhanced response to an antigenic signal due to a cascade process. In this case, the product of one reaction is a catalyst for the next one.

In the absence of antigen, complement components are inactive. There are two ways of activating complement without the participation of antibodies - alternative, and with the participation of antibodies - classical. Activation of complement via the alternative pathway is caused by components of microbial cells; according to the classical pathway, it is caused by antigen-antibody complexes. Common to both pathways is the formation of the enzyme C3 convertase, which cleaves the C3 component into fragments C3a and C3b. A smaller fragment of C3a is involved in development inflammatory process and chemotaxis. The larger C3b fragment, binding to C3 convertase, forms C5 covertase, an enzyme that catalyzes the cleavage of C5 into fragments C5a and C5b. The released C5b fragment remains fixed on the membrane and sequentially attaches C6, C7, C8 and C9, resulting in the formation of the membrane attack complex (MAC), which lyses the target cell due to the formation of a transmembrane channel. Through this channel, Na + ions and water enter the cell, the cell swells and bursts, i.e., lyses. Among other effects of the complement system, the following should be noted:

- development of the inflammatory response and chemotaxis. Complement components C3a and C5a can attract immunocompetent cells, such as phagocytes, to the site of inflammation, which attack and devour bacteria.

- Opsonization (facilitation of recognition) of microorganisms. C3b fragments bind to the surface of bacteria, thereby creating a mark for recognition by phagocytes that have receptors for this complement component.

Rice. 13. Activation of proteins of the complement system

The activity of the complement system is controlled by plasma inhibitors that block the excessive reaction.

Phagocytosis("eating" by cells) - the first reaction immune system to the introduction of a foreign antigen. The mechanism of phagocytosis includes 8 successive stages (Fig. 14)˸

1. Chemotaxis– directed movement of phagocytic cells towards an object along a concentration gradient of chemotactic compounds.

Rice. 14. Stages of phagocytosis

2. Adhesion - recognition and attachment of a foreign object to the surface of the phagocyte. The adhesion process is enhanced by opsonins (complement C3b, antibodies) that envelop the objects of phagocytosis. In this case, binding occurs with the participation of phagocytic receptors for complement C3b and/or Fc antibodies.

Organism. It is an important component of both innate and acquired immunity.

At the end of the 19th century, it was discovered that blood serum contains a certain “factor” that has bactericidal properties. In 1896, a young Belgian scientist Jules Bordet, working at the Pasteur Institute in Paris, showed that whey contains two different substances, the joint action of which leads to the lysis of bacteria: a thermostable factor and a thermolabile factor (losing its properties when the whey is heated) factor. The heat-stable factor, as it turned out, could only act against certain microorganisms, while the heat-labile factor had nonspecific antibacterial activity. The thermolabile factor was later named complement. The term “complement” was coined by Paul Ehrlich in the late 1890s. Ehrlich was the author of the humoral theory of immunity and introduced many terms into immunology that later became generally accepted. According to his theory, cells responsible for immune reactions have receptors on their surface that serve to recognize antigens. We now call these receptors “antibodies” (the basis of the variable receptor of lymphocytes is an antibody of the IgD class attached to the membrane, less often IgM. Antibodies of other classes in the absence of the corresponding antigen are not attached to the cells). The receptors bind to a specific antigen, as well as to a thermolabile antibacterial component of the blood serum. Ehrlich called heat-labile factor “complement” because this component of the blood “serves as a complement” to the cells of the immune system.

Ehrlich believed that there are many complements, each of which binds to its own receptor, just as a receptor binds to a specific antigen. In contrast, Bordet argued that there is only one type of “complement.” At the beginning of the 20th century, the dispute was resolved in Borde's favor; It turned out that complement can be activated with the participation of specific antibodies or independently, in a nonspecific way.

Complement is a protein system that includes about 20 interacting components: C1 (a complex of three proteins), C2, C3, ..., C9, factor B, factor D and a number of regulatory proteins. All these components are soluble proteins with a mol. weighing from 24,000 to 400,000, circulating in the blood and tissue fluid. Complement proteins are synthesized mainly in the liver and account for approximately 5% of the total globulin fraction of blood plasma. Most are inactive until activated either by an immune response (involving antibodies) or directly by an invading microorganism (see below). One of the possible results of complement activation is the sequential association of the so-called late components (C5, C6, C7, C8 and C9) into a large protein complex that causes cell lysis (lytic, or membrane attack complex). Aggregation of late components occurs as a result of a series of sequential reactions of proteolytic activation with the participation of early components (C1, C2, C3, C4, factor B and factor D). Most of these early components are proenzymes, sequentially activated by proteolysis. When any one of these proenzymes is cleaved in a specific manner, it becomes an active proteolytic enzyme and cleaves the next proenzyme, etc. Because many of the activated components bind tightly to membranes, most of these events occur on cell surfaces. The central component of this proteolytic cascade is C3. Its activation by cleavage is the main reaction of the entire complement activation chain. C3 can be activated through two main pathways - classical and alternative. In both cases, C3 is broken down by an enzyme complex called C3 convertase. Two different pathways lead to the formation of different C3 convertases, but both of them are formed as a result of the spontaneous combination of two complement components activated earlier in the chain of the proteolytic cascade. C3 convertase cleaves C3 into two fragments, the larger of which (C3b) binds to the target cell membrane next to C3 convertase; As a result, an enzyme complex is formed large sizes with altered specificity - C5 convertase. The C5 convertase then cleaves C5 and thereby initiates the spontaneous assembly of the lytic complex from the late components, C5 to C9. Because each activated enzyme cleaves many molecules of the next proenzyme, the activation cascade of early components acts as an amplifier: each molecule activated at the beginning of the entire chain leads to the formation of many lytic complexes.

The complement system works as a biochemical cascade of reactions. Complement is activated by three biochemical pathways: the classical, alternative and lectin pathways. All three activation pathways produce different variants C3 convertase (protein that cleaves C3). Classic way(it was discovered first, but is evolutionarily new) requires antibodies for activation (specific immune response, acquired immunity), while alternative And lectin pathways can be activated by antigens without the presence of antibodies (nonspecific immune response, innate immunity). The result of complement activation in all three cases is the same: C3 convertase hydrolyzes C3, creating C3a and C3b and causing a cascade of further hydrolysis of elements of the complement system and activation events. In the classical pathway, activation of C3 convertase requires the formation of the C4bC2a complex. This complex is formed by the cleavage of C2 and C4 by the C1 complex. The C1 complex, in turn, must bind to immunoglobulins of class M or G for activation. C3b binds to the surface of pathogenic microorganisms, which leads to a greater “interest” of phagocytes in cells associated with C3b (opsonization). C5a is an important chemoattractant that helps attract new immune cells to the area of ​​complement activation. Both C3a and C5a have anaphylotoxic activity, directly causing mast cell degranulation (and consequently the release of inflammatory mediators). C5b begins the formation of membrane attack complexes (MACs), consisting of C5b, C6, C7, C8 and the polymeric C9. MAC - cytolytic final product activation of the complement system. MAC forms a transmembrane channel that causes osmotic lysis of the target cell. Macrophages engulf complement-tagged pathogens.

Factor C3e, formed by the cleavage of factor C3b, has the ability to cause migration of neutrophils from the bone marrow, and in this case cause leukocytosis.

The classical pathway is triggered by activation of the complex C1(it includes one molecule of C1q and two molecules of C1r and C1s). The C1 complex binds via C1q to immunoglobulins of classes M and G associated with antigens. Hexameric C1q is shaped like a bouquet of unopened tulips, the “buds” of which can bind to the -site of antibodies. To initiate this pathway, a single IgM molecule is sufficient; activation by IgG molecules is less efficient and requires more IgG molecules.

С1q binds directly to the surface of the pathogen, this leads to conformational changes in the C1q molecule, and causes the activation of two molecules of serine proteases C1r. They cleave C1s (also a serine protease). The C1 complex then binds to C4 and C2 and then cleaves them to form C2a and C4b. C4b and C2a bind to each other on the surface of the pathogen and form the classical pathway C3 convertase, C4b2a. The appearance of C3 convertase leads to the cleavage of C3 into C3a and C3b. C3b forms, together with C2a and C4b, the C5 convertase of the classical pathway. C5 splits into C5a and C5b. C5b remains on the membrane and binds to the C4b2a3b complex. Then C6, C7, C8 and C9 connect, which polymerizes and a tube appears inside the membrane. This disrupts the osmotic balance and, as a result of turgor, the bacterium bursts. The classical way works more accurately, since it destroys any foreign cell.

An alternative pathway is initiated by hydrolysis of C3 directly on the surface of the pathogen. The alternative pathway involves factors B and D. With their help, the enzyme C3bBb is formed. Protein P stabilizes it and ensures its long-term functioning. Next, PC3bBb activates C3, resulting in the formation of C5 convertase and triggering the formation of the membrane attack complex. Further activation of terminal complement components occurs in the same way as along the classical pathway of complement activation. In the liquid in the C3bBb complex, B is replaced by the H-factor and, under the influence of a deactivating compound (H), is converted into C3bi. When microbes enter the body, the C3bBb complex begins to accumulate on the membrane, catalyzing the cleavage reaction of C3 into C3b and C3a, significantly increasing the concentration of C3b. Another C3b molecule is added to the properdin+C3bBb complex. The resulting complex splits C5 into C5a and C5b. C5b remains on the membrane. Further assembly of the MAC occurs with the alternate addition of factors C6, C7, C8 and C9. After the connection of C9 with C8, polymerization of C9 occurs (up to 18 molecules are cross-linked with each other) and a tube is formed that penetrates the membrane of the bacterium, water is pumped in and the bacterium bursts.

The alternative pathway differs from the classical one in the following way: when the complement system is activated, the formation of immune complexes is not necessary; it occurs without the participation of the first complement components - C1, C2, C4. It is also distinguished by the fact that it is triggered immediately after the appearance of antigens - its activators can be bacterial polysaccharides and lipopolysaccharides (they are mitogens), viral particles, and tumor cells.

The lectin pathway is homologous to the classical pathway of complement activation. It uses mannose-binding lectin (MBL), a C1q-like protein of the classical activation pathway, that binds to mannose residues and other sugars on the membrane, allowing recognition of a variety of pathogens. MBL is a whey protein belonging to the group of collectin proteins, which is synthesized primarily in the liver and can activate the complement cascade by directly binding to the surface of the pathogen.

In blood serum, MBL forms a complex with MASP-I and MASP-II (Mannan-binding lectin Associated Serine Protease, MBL-binding serine proteases). MASP-I and MASP-II are very similar to C1r and C1s of the classical activation pathway and may have a common evolutionary ancestor. When multiple MBL active sites bind in a specific manner to oriented mannose residues on the pathogen's phospholipid bilayer, MASP-I and MASP-II are activated and cleave the C4 protein into C4a and C4b, and the C2 protein into C2a and C2b. C4b and C2a then combine on the surface of the pathogen to form C3 convertase, and C4a and C2b act as chemoattractants for immune system cells.

The complement system can be very harmful to host tissues, so its activation must be well regulated. Most components are active only as part of the complex, while their active forms capable of existing for a very short time. If during this time they do not meet the next component of the complex, then the active forms lose contact with the complex and become inactive. If the concentration of any of the components is below the threshold (critical), then the operation of the complement system will not lead to physiological consequences. The complement system is regulated by special proteins that are found in the blood plasma in even higher concentrations than the complement system proteins themselves. These same proteins are present on the membranes of the body’s own cells, protecting them from attack by proteins of the complement system.

The complement system plays a large role in many immune-related diseases.

In immune complex diseases, complement provokes inflammation mainly in two ways:

Already in the first hours after infection with Ebola hemorrhagic fever, the complement system is blocked

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 a complex system of 11 serum proteins, the activity of which is regulated by at least the same number of 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 referred to as important elements resistance systems, as well as an effective link in 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 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 in severe liver disease, 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 initial stage can develop in several directions:

The classical pathway of complement activation, starting with C1;

Alternative pathway of complement activation starting at C3;

Specific activation of complement with the formation of various cleavage products.

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 sudden change 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 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 a number of systemic lesions. Such immunocomplex mechanisms create the basis for allergic reactions of 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, immune complexes with F fragments, proteases (plasmin, trypsin), cobra venom factor, C3b can serve as activators . 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 an important component of the system 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 of 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 as follows:
- 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 due to the reaction of immune complexes;
- participation of activated phagocytes.

II. Anaphylatoxin formation. The concept of "anaphylatoxin" was first introduced by Friedberger. In this case, we 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 important factor 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. It's about 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, with C1 being cleaved first 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, studying CTL target cells using electron microscope showed that in the area of ​​intercellular contact there are structures similar to pores formed when the complement system factors act on the membrane.

Diagnostic value of the complement system. The assessment of the complement system 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;
- quantitative determination of 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 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. A complement study 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.

No 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. In the first step, the C1 inhibitor blocks the enzymatic activity of Clr and Cls and, consequently, the cleavage of C4 and C2. Activated C2 persists only for a short time, and its relative instability limits the lifetime of C42 and C423. The C3 alternative pathway activating enzyme, C3bBb, also has a short half-life, although binding of properdin to the enzyme complex prolongs the lifetime of the complex.

IN serum there is an anaphylatoxin inactivator - an enzyme that cleaves N-terminal arginine from C4a, C3a and C5a and thereby sharply reduces them 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 proteins of cell membranes - PK1, membrane cofactor protein and accelerating factor decay (FUR) - destroy the C3- and C5-convertase complexes that form on these membranes.

Other cell membrane components- associated proteins (among which CD59 is the most studied) - can bind C8 or C8 and C9, which prevents the integration of the membrane attack complex (C5b6789). Some blood serum proteins (among which the most studied are protein S and clusterin) 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 integration of this complex.

Protective role of complement

Neutralization viruses antibodies are enhanced by C1 and C4 and increase even more upon fixation of C3b, which is formed along the classical or alternative pathway. Thus, complement becomes especially important in the early stages of a viral infection, when the number of antibodies is still small. Antibodies and complement limit the infectivity of at least some viruses and due to the formation of typical complement “holes” visible under 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 phagocytosing microorganisms opsonized by C3b or its cleavage product iC3b. Further inactivation of cell-bound C3b, leading to the appearance of C3d, deprives it of opsonizing activity, but its ability to bind to B lymphocytes is retained. Fixation of C3b on a 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 transport the complex to the liver or spleen, where it is absorbed by macrophages. This phenomenon partially explains the development of serum sickness (immune complex disease) in individuals with C1, C4, C2 or C3 deficiency.