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 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-b), 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.
SLIDE 1
Lecture No. 4. Humoral factors of innate immunity
1. Complement system
2. Proteins of the acute phase of inflammation
3. Biogenic amymnas
4. Lipid mediators
5. Cytokines
6. Interferons
SLIDE 2
Humoral component of innate immunity is represented by several interconnected systems - the complement system, the cytokine network, bactericidal peptides, as well as humoral systems associated with inflammation.
The operation of most of these systems is subject to one of two principles - cascade and network. The complement system operates according to a cascade principle, when activated, factors are sequentially involved. Moreover, the effects of cascade reactions appear not only at the end of the activation pathway, but also at intermediate stages.
The network principle is characteristic of the cytokine system and implies the possibility of simultaneous functioning of various components of the system. The basis for the functioning of such a system is close interconnection, mutual influence and a significant degree of interchangeability of network components.
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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.
SLIDE 4
Complement activation pathways
There are three pathways of complement activation: classical, lectin and alternative.
SLIDE 5
1. Classic way complement activation is fundamental. Participation in this pathway of complement activation - main function of antibodies.
Complement activation via the classical pathway triggers the immune complex: complex of antigen with immunoglobulin (class G or M). Antibodies can “take” their place C-reactive protein– such a complex also activates complement via the classical pathway.
Classic pathway of complement activation carried out in the following way.
A. At first fraction C1 is activated: it is assembled from three subfractions (C1q, C1r, C1s) and turns into an enzyme C1-esterase(С1qrs).
b. C1-esterase breaks down the C4 fraction.
V. The active fraction C4b covalently binds to the surface of microbial cells - here joins faction C2.
d. Fraction C2, in combination with fraction C4b, is cleaved by C1-esterase with formation of active fraction C2b.
e. Active fractions C4b and C2b into one complex – С4bС2b– possessing enzymatic activity. This is the so-called C3 convertase of the classical pathway.
e. C3 convertase breaks down the C3 fraction, I 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).
SLIDE 6
2. Lectin pathway complement activation is triggered by a complex of normal blood serum protein - mannan-binding lectin (MBL) - with carbohydrates of the surface structures of microbial cells (with mannose residues).
SLIDE 7
3. Alternative path complement activation begins with covalent binding of the active fraction C3b - which is always present in the blood serum as a result of the spontaneous cleavage of the C3 fraction that constantly occurs here - with the surface molecules of not all, but some microorganisms.
1. Further events are developing in the following way.
A. C3b binds factor B, forming the C3bB complex.
b. In the form associated with C3b factor B acts as a substrate for factor D(serum serine protease), which breaks it down to form an active complex С3bВb. This complex has enzymatic activity, is structurally and functionally homologous to the C3 convertase of the classical pathway (C4bC2b) and is called Alternative pathway C3 convertase.
V. Alternative pathway C3 convertase itself is unstable. In order for the alternative pathway of complement activation to continue successfully, this enzyme stabilized by factor P(properdine).
2. Basics functional difference An alternative pathway of complement activation, compared to the classical one, is the speed of response to the pathogen: since it does not require time for the accumulation of specific antibodies and the formation of immune complexes.
It is important to understand that both the classical and alternative pathways of complement activation act in parallel, also amplifying (i.e. strengthening) each other. In other words, complement is activated not “either along the classical or alternative” pathways, but “through both the classical and alternative” activation pathways. This, with the addition of the lectin activation pathway, is a single process, the different components of which may simply manifest themselves to different degrees.
SLIDE 8
Functions of the complement system
The complement system plays a very important role in protecting the macroorganism from pathogens.
1. The complement system is involved in inactivation of microorganisms, incl. mediates the effect of antibodies on microbes.
2. Active fractions of the complement system activate phagocytosis (opsonins - C3b and C5b).
3. Active fractions of the complement system take part in formation of an inflammatory response.
SLIDE 9
The active complement fractions C3a and C5a are called anaphylotoxins, as they are involved, among other things, in an allergic reaction called anaphylaxis. The most powerful anaphylotoxin is C5a. Anaphylotoxins act on different cells and tissues of the macroorganism.
1. Their effect on mast cells causes degranulation of the latter.
2. Anaphylotoxins also act on smooth muscle, causing them to contract.
3. They also act on vessel wall: cause activation of the endothelium and an increase in its permeability, which creates conditions for extravasation (exit) of fluid and blood cells from the vascular bed during the development of the inflammatory reaction.
In addition, anaphylotoxins are immunomodulators, i.e. they act as regulators of the immune response.
1. C3a acts as an immunosuppressor (i.e. suppresses the immune response).
2. C5a is an immunostimulant (i.e. enhances the immune response).
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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.
SLIDE 11
According to their functions, several groups of acute phase proteins are distinguished.
TO transport proteins include prealbumin, albumin, orosomucoid, lipocalins, haptoglobin, transferrin, mannose-binding and retinol-binding proteins, etc. They play the role of carriers of metabolites, metal ions, and physiologically active factors. The role of factors in this group increases significantly and changes qualitatively during inflammation.
Another group is formed proteases(trypsinogen, elastase, cathepsins, granzymes, tryptases, chymases, metalloproteinases), the activation of which is necessary for the formation of many inflammatory mediators, as well as for the implementation of effector functions, in particular the killer one. Activation of proteases (trypsin, chymotrypsin, elastase, metalloproteinases) is balanced by the accumulation of their inhibitors. α2-Macroglobulin is involved in suppressing the activity of proteases of various groups.
In addition to those listed, acute phase proteins include coagulation and fibrinolysis factors, as well as intercellular matrix proteins(for example, collagens, elastins, fibronectin) and even proteins of the complement system.
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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.
SLIDE 13
Biogenic amines
This group of mediators includes histamine and serotonin, contained in mast cell granules. Released during degranulation, these amines cause a variety of effects that play a key role in the development of early manifestations of immediate hypersensitivity.
Histamine (5-β-imidazolylethylamine)- the main mediator of allergies. It is formed from histidine under the influence of the enzyme histidine decarboxylase.
Since histamine is contained in mast cell granules in 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.
SLIDE 14
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 of various types of cells, especially those involved in the development of inflammation, in particular allergic: endothelial and mast cells, basophils, monocytes and macrophages.
The metabolism of arachidonic acid can occur in two ways - catalyzed by cyclooxygenase or 5'-lipoxygenase. The cyclooxygenase pathway leads to the formation of prostaglandins and thromboxanes from unstable intermediates - endoperoxide prostaglandins G2 and H2, and the lipoxygenase pathway leads to the formation of leukotrienes and 5-hydroxyeicosatetraenoate through intermediate products (5-hydroperoxy-6,8,11,14-eicosatetraenoic acid and leukotriene A4 ), as well as lipoxins - products of double lipoxygenation (under the action of two lipoxygenases - see below).
Prostaglandins and leukotrienes exhibit alternative physiological effects in many respects, although significant differences in activity exist within these groups.
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).
SLIDE 15
Leukotrienes (LT)- C 20 fatty acids, the molecule of which contains an OH group at position 5, and sulfur-containing side chains at position 6, for example glutathione.
There are 2 groups of leukotrienes:
One of them includes leukotrienes C4, D4 and E4, called cysteinyl leukotrienes (Cys-LT),
The second includes one factor - leukotriene B4.
Leukotrienes are formed and secreted within 5–10 min after activation of mast cells or basophils.
Leukotriene C4 is present in the liquid phase for 3–5 minutes, during which time it is converted to leukotriene D4. Leukotriene D4 exists for the next 15 minutes, slowly turning into leukotriene E4.
Leukotrienes exert their effect through receptors belonging to the group of purine receptors of the rhodopsin-like receptor family, 7-fold membrane-spanning and associated with protein G.
Leukotriene receptors are expressed on spleen cells, blood leukocytes, in addition, CysLT-R1 is presented on macrophages, intestinal cells, air epithelium, and CysLT-R2 is present on adrenal and brain cells.
Cysteinyl leukotrienes (especially leukotriene D4) cause smooth muscle spasms and regulate local blood flow, reducing 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.
SLIDE 16
Prostaglandins (PG) - C 20 fatty acids, the molecule of which contains a cyclopentane ring.
Variants of prostaglandins, differing in the type and position of substituent groups (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.
SLIDE 17
Thromboxane A2 (TXA2) - C 20 fatty acid; its molecule has a 6-membered oxygen-containing ring.
It is a very unstable molecule (half-life 30 s) and converts to inactive thromboxane B2.
Thromboxane A2 causes constriction of blood vessels and bronchi, platelet aggregation with the release of enzymes and other active factors that promote the mitogenesis of lymphocytes.
Another product of the cycloxygenase pathway is prostaglandin I2(prostacyclin) - also unstable. It exerts its effect through cAMP, greatly dilates blood vessels, increases their permeability, and inhibits platelet aggregation.
Along with the peptide factor bradykinin, prostacyclin causes a sensation of pain during inflammation.
SLIDE 18
Cytokines
Related information.
Complement is one of the most important multifunctional 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 increased 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 (so named only because it was discovered first, and not because of its exceptional importance) and the alternative pathway. The second fundamental point is the possible depth of the process: it stops
whether it is at the stage of C3 cleavage, providing a number of biological effects, or deepens further (from C5 to C9). The last stage of activation is often called terminal, final (membrane attack), it is common, identical for the classical and alternative pathways, and the lytic function of complement is associated with it.
Currently, there are at least 20 plasma proteins combined into the complement system. Basically they are divided into 3 groups. The components involved in the classical activation pathway and in the final (membrane attack) stage are designated Clq, Clr, C1„ C4, C2, C3, C5, C6, C7, C8 and C9. Proteins involved in the alternative activation pathway are called factors and are designated as B, D, P. Finally, a group of proteins that regulate the intensity of the reaction, or a group of control proteins, is distinguished: these include C1-inhibitor (C1INH), C3b-inactivator (C3bINa ), pH factor - C4 - BP, anaphylotoxin inhibitor. The fragments resulting from the enzymatic cleavage of the main components are designated in small letters (for example, C3, C3, C3d, C5a, etc.). To designate components or fragments with enzymatic activity, a line is placed above their symbols, for example Cl, C42, C3Bb.
The following is the content of individual complement components in blood serum:
Component Concentration, µg/ml
Classic way
C1 70
C1 34
C1 31
S4 600
C2 25
SZ 1200
Alternative path
Properdin 25
Factor B 200
Factor D 1
Membrane attack complex
C5 85
S6 75
S7 55
S8 55
S9 60
Regulatory proteins
C1-inhibitor 180
Factor H 500
Factor I 34
The complement system is one of the “trigger” enzymes
ical 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 is caused by a cascade phenomenon, in which the products of one reaction act as catalysts for the next. Such a cascade may be linear, unidirectional (eg, the classical complement activation pathway), or involve feedback loops (the alternative pathway). Thus, both options occur in the complement system (Scheme 1).
The classical pathway is activated by immune complexes
antigen - an antibody, which contains 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 aggregates of IgG, 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 united at the end of the molecule opposite the head. On the heads there are sites for attachment to antibody molecules, while sites for attachment of C1G and Cls are located on the collagen rods. After Clq attaches to AT, C1r becomes an active protease through conformational transformations. cleaves Cls, converting the entire complex into serine esterase C1. The latter splits C4 into 2 fragments - C4a and C4b and C2 into C2a and C2b. The resulting complex C4b2b(a) is an active enzyme that cleaves the C3 component (C3 convertase of the classical pathway); sometimes it is designated C42.
The regulator of the classical pathway is the C1 inhibitor (C1INH), which suppresses the activity of C1r and Cls by irreversibly binding to these enzymes. It has been established 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 congenital anti-edema.
The alternative (properdine) pathway consists of a series of sequential reactions that do not include Cl, C4 and C2 components and nevertheless lead to the activation of S3. 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). The reaction involves 4 components: factors D and B, S3 and proper din (P). In this case, factor D (enzyme) is similar to Cls of the classical pathway, C3 and factor B, respectively, are similar to the C4 and C2 components. As a result, convertase of the alternative pathway C3Bb is formed. The resulting complex is extremely unstable, and in order to perform its function, it is stabilized by properdin, forming a more complex S3bR complex. The regulatory proteins of the alternative pathway are piH and C3JNA. The first binds to C3b and forms a binding site for the inactivator (C3bINA). Artificial deletion of these factors or their genetic deficiency, which has recently been established in humans, leads to uncontrolled activation of the alternative pathway, which can potentially result in complete depletion of S3 or factor B.
Terminal membrane attack mechanism. As already mentioned, both pathways converge on the C3 component, which is activated by any of the resulting C42 or C3Bb convertases. For
The formation of C5 convertase requires the cleavage of an additional amount of C3. C3, bound on the cell surface, and free B, P or p1H form a site for binding C5 and make the latter sensitive to proteolysis of any of the C3 convertases. In this case, a small peptide C5a is cleaved from C5, and the remaining large C5b attaches to the cell membrane and has a site for the attachment of Cb. Next, components C7, C8, C9 are connected sequentially. As a result, a stable transmembrane channel is formed, providing two-way movement of ions and water through the bilipid layer of the cell. The membrane is damaged and the cell dies. This is how, in particular, the killing of foreign microorganisms is carried out.
During the activation of complement, a number of fragments and peptides are formed that play an important role in the processes of inflammation, phagocytosis and allergic reactions.
Thus, the cleavage of C4 and C2 by Cls leads to an increase in vascular permeability and underlies the pathogenesis of congenital anti-edema associated with deficiency of the C1 inhibitor. Peptides C3a and C5a have anaphylotoxin properties. By attaching to mast cells and basophils, they induce the release of histamine. By binding to platelets, SZA causes the secretion of serotonin. The anaphylotoxic activity of C3 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 Bb fragment cause chemotaxis only in polymorphonuclear leukocytes. Normal human serum contains the CFi factor, which inhibits the activity of C5a against 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 peptide C3 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 hemolytic activity of complement may reflect a deficiency of individual components or the presence of its breakdown products in the circulation. It should also be kept in mind
that intensive local consumption of complement in areas such as the pleura and joint cavities may not be combined with changes in the level of complement in the blood serum. For example, in some patients with rheumatoid arthritis, the level of serum complement may be normal, while in the synovial fluid it may be sharply reduced due to its active consumption. Determination of complement in synovial fluid is very important for diagnosis.
Congenital complement deficiencies. 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 early initiating components (C1, C4, C2) are associated with systemic lupus erythematosus. Individuals with a deficiency of the C component are susceptible to recurrent pyogenic infections. Deficiencies of terminal components 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 congenital deficiency is C2. Homozygous deficiency for this trait is found in some autoimmune disorders, including lupus-like diseases, Henoch-Schönlein disease, glomerulonephritis and dermatomyositis. Individuals homozygous for this trait do not show increased sensitivity to infection if the alternative activation pathway functions 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 deficiency is associated with certain HLA haplotypes.
Deficiency of regulatory proteins of the complement system can also have clinical manifestations. Thus, with congenital deficiency of C3INA, a clinical picture is observed similar to that with deficiency of S3, because the consumption of the latter through the alternative pathway becomes uncontrollable.
Effector mechanisms of immunity are aimed at binding and eliminating pathogens.
There are 2 types of antigen binding receptors. In this regard, there are 2 types of effector mechanisms.
. Antibody dependent, or humoral immunity. It is carried out due to humoral (soluble) factors - antibodies that bind the antigen and remove it using a number of mechanisms: precipitation, agglutination, neutralization, lysis, blockade and opsonization.
. Cell mediated(antibody independent), or cellular immunity. Cellular immunity is realized by cells of the immune system, primarily T-lymphocytes, as well as activated macrophages and NK cells, which directly destroy genetically foreign cells or those infected with viruses and other intracellular pathogens, and tumor cells.
ANTIBODY-DEPENDENT PROTECTION MECHANISMS
Opsonization and triggering of the complement system
The binding of antibodies to an antigen itself is protective in at least two cases:
. if the antigen is a strong poison, the antibody, upon binding, neutralizes its toxicity;
. if an antigen is presented on the surface of a pathogen (virus, prion, bacterium), the antibody, by binding to it, prevents the spread of the pathogen in the body.
However, in these cases, the protective reaction does not end with the formation of macromolecular antigen-antibody complexes. These complexes must be broken down into small metabolites. It happens
when the resulting immune complexes bind to complement components. The ability to fix complement varies among immunoglobulins of different classes (IgM > IgG3 > IgG1). Antigen-antibody-complement complexes are transported by red blood cells, which have receptors for complement components, into the sinusoids of the spleen and liver, where they are phagocytosed and digested by macrophages.
Fc receptors
Fc receptors (FcR) are a family of membrane receptors of cells of the immune system, the main function of which is the recognition and binding of the Fc fragment of immunoglobulins, which are in a free state and as part of the immune complex. FcR, along with TCR and BCR, can be classified as immunoreceptors, since the FcR carrier cell is able to bind antigen (albeit through antibodies) and respond to it. FcRs have been identified not only on lymphocytes, but also on all known leukocytes.
Types and varieties of FcR. Based on the isotype of the immunoglobulin heavy chains they bind, 4 types of FcR are distinguished: γ, ε, α, μ; and according to the affinity of binding to the ligand - 3 types of FcR: I, II and III. Type I FcRs are capable of binding free antibody molecules (this is especially typical for IgE), type II and III FcRs are capable of binding only antigen-antibody complexes.
Fcγ receptors (FcγR) differ in structure and affinity for the Fc portion of IgG, as well as specificity for various IgG subclasses (Fig. 8-1). FcγRI contains 2 polypeptide chains, of which the α chain is responsible for IgG binding, and the γ chain is responsible for signal transmission (this function is performed by the intracellular γ domain). Receptors of the FcyRII type are formed by a single chain. Depending on the structure of their intracellular part, two types of these receptors are distinguished - FcγRIIA and FcγRIIB. In the first case, the intracellular part contains the γ-domain, in the second - the ITIM sequence (Immunoreceptor-Tyrosine-based Inhibitory Motif- tyrosine-containing inhibitory amino acid sequences in immunoreceptors). These features determine the function of the receptors: FcγRIIA transmits a stimulating signal, and FcγRIIB transmits an inhibitory signal. FcγRIII also exists in two variants. The FcγRIIIA variant, like FcγRI, contains an IgG-binding α- and signaling γ- (or ζ-) chains. FcγRIIIB is not
Rice. 8-1. Structure and properties of the main types of Fcγ receptors. Oval symbols indicate domains belonging to the immunoglobulin superfamily; ITIM is an immunoreceptor inhibitory sequence containing tyrosine. At the bottom of the figure, in the “Ligands” line, IgG subclasses are presented in parentheses, arranged in descending order of their affinity for a given type of FcγR. Cells on which Fcγ receptors are localized: N - neutrophil, aN - activated neutrophil, M - monocyte, MF - macrophage, Eo - eosinophil, NK - NK cell, B - B lymphocyte, FDC - follicular dendritic cell
has a signaling function: its only a-chain is anchored in the phospholipid layer of the membrane and lacks a cytoplasmic part. The extracellular domains of the receptor a-chains and single chains of FcγRII belong to the immunoglobulin superfamily.
Two types of Fcε receptors are known, differing in structure, affinity for the Fc part of IgE and biological role (Fig. 8-2). The FcεI receptor is constructed similarly to FcγRIIIA, but has an additional β-chain that spans the membrane four times. This receptor plays a major role in triggering mast cell (MC) degranulation, a key event in the development of immediate hypersensitivity reactions. The FcεII receptor has no structural affinity for the FcεI receptor. It plays a role in the regulation of IgE synthesis, as well as in the regulation
Rice. 8-2. Structure and properties of Fcε receptors. Oval symbols indicate domains belonging to the immunoglobulin superfamily; ITAM is an immunoreceptor activation sequence containing tyrosine. Cells on which Fcε receptors are localized: MC - mast cell; B - basophil, M - monocyte, Eo - eosinophil, B and T - B and T lymphocytes, respectively, FDC - follicular dendritic cell. The letter "a" stands for activated cells
lation of growth and differentiation of B lymphocytes. The FcεII receptor also exists in a secreted form, playing the role of a cytokine with a broad spectrum of action.
The Fcα receptor is structurally similar to the FcγRIIIA and FcεIR receptors; its α chain belongs to the immunoglobulin superfamily (Fig. 8-3). The function of this receptor is practically unknown.
The Poly-IgR receptor is designed for the transport of polymeric immunoglobulins (IgA, IgM) through the wall of the mucous membranes. Its fragment associated with these molecules is designated as the secretory component (SC).
Neonatal FcγRn receptor (n - neonatal) is responsible for the transport of IgG that enters the child’s intestines with colostrum or milk, and then through the intestinal wall into the child’s bloodstream. It is also responsible for the transplacental transport of IgG. Its structure is similar to MHC-I molecules (see Fig. 5-1) and contains β2-microglobulin,
Rice. 8-3. Fcα receptor and Fc receptors responsible for the transport of immunoglobulins. Cells on which Fcγ receptors are localized: N - neutrophil, M - monocyte, MF - macrophage, Eo - eosinophil. The letter "a" stands for activated cells
non-covalently associated with the α chain. In addition, FcγRn increases the lifespan of IgG in the body by protecting it from degradation in endosomes.
In Fig. Figure 8-4 schematically shows the main signaling pathways with FcR. When FcR cross-links with a ligand (for example, an opsonized microorganism), the ITAM motif of the γ chain or α chain of FcγRIIA is phosphorylated by Src kinases. This leads to the interaction of the SH2 domains of Syk kinase with the ITAM motif of FcR, its activation and phosphorylation by Scr kinases. Activated Syk kinase phosphorylates the adapter protein SLP-76, involving the Vav protein from the GEF family in the signaling process (Guanine nucleotide Exchange Factor). It activates the GTPase Rac and the adapter protein ADAP, which causes actin reorganization necessary for the formation of the phagocytic cup and engulfment of the microorganism. Using the SLP-76 phospho-
Rice. 8-4. Signaling pathways from the Fc receptor. See text for explanations
Phospholipase C (PLCγ) is rylated, cleaving phosphatidylinositol into inositol triphosphate (IP 3 ; Ca 2+ activator) and diacylglycerol (DAG) - an activator of protein kinase C (PKC). These events determine the development of the processes of antigen uptake, degranulation and oxygen burst. Src kinases, through the adapter protein Gab1, phosphorylate phosphoinositide 3-kinase (PI3K), activating the Akt protein, MAP kinase and support cell survival - inhibition of apoptosis. Src kinases can also initiate the inhibitory pathway. In a resting cell, the phosphatases SHP-1 or SHIP-1 are associated with the ITIM motif. Phosphorylation of the ITIM motif leads to the activation of phosphatases. The latter dephosphorylate activated enzymes and adapter proteins and interrupt the development of the signaling pathway.
Antibody-dependent cellular cytotoxicity
The phenomenon of Antibody-Dependent Cellular Cytotoxicity (ADCCT) manifests itself when an antibody binds an antigen on the surface of a target cell and, through the Fc fragment, attracts effector cells (NK cells, macrophages, eosinophils, etc.) to destroy it.
.Natural killers. NK cells have a receptor (FcγRIII) for
Fc fragments of IgG. The mechanism of the actual killer effect of NK lymphocytes on the target cell is the same as the killer mechanism of CTLs - perforin-granzyme (see Fig. 1-4 and Fig. 6-4).
.Eosinophils. The mechanism of sanitation from helminths is a variant of antibody-dependent cellular cytotoxicity, where eosinophils with low-affinity receptors for IgE - FcεRII and for IgA - FcαRII act as effector cells. The binding of these receptors to ligands in combination with a signal from the cytokine IL-5 stimulates the synthesis and secretion of highly toxic proteins by eosinophils aimed at destroying helminths. In other words, the activated eosinophil secretes a number of biologically active substances, the action of which explains the symptoms of the so-called eosinophilic inflammatory processes (Table 8-1).
Immediate hypersensitivity
Vascular and myoconstrictor reactions mediated by mast cell and basophil mediators lead to the development of immediate hypersensitivity (IHT). Cytokines from mast cells and basophils support an immune shift in the differentiation of CD4 + T-lymphocyte subsets towards Th2 (IL-4, IL-13), and also support the differentiation and activation of eosinophils (IL-5, IL-3, GM-CSF). In the case of pathology, it is these cells (Th2, mast cells, basophils, eosinophils) and IgE that form a self-sustaining ensemble responsible for HNT reactions. Targets for cytokines are smooth muscle and endothelial cells (hence, blood vessels, bronchi, digestive organs). The systemic reaction of GNT is anaphylactic shock.
Basophilic leukocytes and mast cells. In these antibody reactions, basophils and mast cells are involved in the response. The essential functional characteristics of these cells are similar: the presence of a high-affinity receptor for IgE (FcεRI) on the membrane and the same set of biologically active mediators.
. Mast cells localized in the connective tissue of the own layer of mucous membranes (laminapropria mucosae), in the subcutaneous connective tissue and connective tissue located along all blood vessels. There are at least 2 tissue types of mast cells.
- Mucosal mast cells of serine proteases, they express tryptase and chymase, and secrete a minimum of histamine; of the proteoglycans, chondroitin sulfate predominates in them; from metabolites of arachidonic acid - leukotriene C4 (LTC4). Apparently, the differentiation of these cells depends on T lymphocytes, namely on local stimulation of progenitor cells with the cytokine IL-3.
- Connective tissue mast cells localized in the serous membranes of body cavities and lungs. Of serine proteases, they predominantly express tryptase, of proteoglycans - heparin, secrete a lot of histamine, of arachidonic acid metabolites, prostaglandin D2 predominates in them. The differentiation of these mast cells is stimulated by fibroblasts.
.Basophils circulate in the blood and migrate into tissues only to the site of inflammation (like neutrophils). Basophils express adhesion molecules important for homing to the lesion: LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), CD44.
Activation. Signals that activate both mast cells and basophils.
.Homotypic Fc aggregation e R.I. Cells are activated by a complex of IgE with antigen or antibodies to the receptor. FceRI is able to bind free IgE antibodies before they bind their antigen. Cells with the IgE-FceRI complex on the mast cell membrane are in a state of readiness to degranulate in a matter of seconds and minutes in response to recognition of an incoming antigen (Fig. 8-5). Course of events: the antigen interacts with Fab fragments of IgE and the mast cell activated by this signal undergoes degranulation.
.Anaphylatoxins- fragments of complement system components formed during the development of the cascade.
.Mediators from activated neutrophils.
.Neurotransmitters(norepinephrine, substance P).
Mediators of mast cells and basophils differ in biochemical properties, purpose and timing of release from the activated cell. Mediators stored in granules are the first to be released from the cell in response to an activating signal. Other mediators are synthesized de novo and enter the process later.
Rice. 8-5. Mast cell degranulation
. Histamine. Different cells have different receptors for histamine - H 1, H 2 and H 3. Histamine exhibits vasoactive effects: it causes constriction of endothelial cells, contacts between endothelial cells become less dense, and serum leaves the vessel into the tissue; stimulates the synthesis of prostacyclin and nitric oxide radical (NO") in endothelial cells, causing relaxation of the smooth muscles of the vascular wall and, consequently, vasodilation.
- If the process occurs in the skin, it manifests clinically as blisters and redness (urticaria). In the case of allergic pathology, medications - histamine H1 receptor blockers - help relieve symptoms.
- When a sufficiently large amount of histamine is released, it causes clinically significant contractions of intestinal smooth muscle (peristalsis) and bronchi (bronchospasm), but this effect is short-lived because histamine quickly breaks down in the extracellular environment.
. Lipid mediators. When mast cells are stimulated, lipid metabolic enzymes, namely phospholipase A2, are activated in them. This enzyme is involved in the formation of biologically active mediators, using cell membrane phospholipids and lipids (primarily arachidonic acid) as substrates.
- Prostaglandin D 2- acts as a vasodilator and bronchoconstrictor. Cyclooxygenase is involved in the biosynthesis of prostaglandin D2 from arachidonic acid. A pharmacological inhibitor of this enzyme is acetylsalicylic acid.
- Leukotrienes(LTC 4, LTD 4, LTE 4) - alternative products of arachidonic acid metabolism, formed under the influence of
action 5-lipoxygenases. Leukotriene complex is a slow-reacting component of anaphylaxis. It is he who is most responsible for bronchoconstriction in bronchial asthma. This explains the aggravation of asthmatic attacks by acetylsalicylic acid: by blocking the synthesis of prostaglandin D2, acetylsalicylic acid releases the metabolic shunt of arachidonic acid in favor of leukotrienes.
- Platelet activating factor(PAF) causes bronchoconstriction, as well as relaxation of vascular smooth muscle and endothelial retraction. PAF is produced not only (and perhaps not so much) by mast cells, but also by endothelial cells stimulated by histamine and leukotrienes.
- Enzymes mast cells and basophils [serine proteases (tryptase and chymase), cathepsin G, carboxypeptidase] promote the restructuring of the connective tissue matrix.
- Cytokines mast cells and basophils. These include interleukins, GM-CSF, etc.
CELL-MEDIATED EFFECTIVE MECHANISMS
Antibody-independent effector mechanisms of immunity are primarily implemented by CTLs. These include CD8 + Tαβ lymphocytes and NKT cells - lymphocytes that simultaneously express NK and T cell receptors. There are T-killers among Tγδ-lymphocytes.
The main purpose of CTL is the sanitation of the body from intracellular pathogens, tumor and other altered cells, realized by the killer function of CTL and cytokines.
. Killer function. CTLs carry out the killer function (see Fig. 1-5 and Fig. 6-7) with the help of special proteins - cytotoxins, which include perforin, granzymes and the insufficiently studied cytolysin.
- Synthesis of cytotoxins is happening de novo after the involvement of CTLs in the immune response and their recognition of a specific antigen.
- Accumulation of cytotoxins. As functionally inactive precursor molecules, cytotoxins accumulate in granules concentrated in the cell near the TCR.
- CTL degranulation occurs in the area of intercellular contact formed when the TCR binds to the antigen on the
surface of the target cell. This process obligately depends on
Ca2+.
- Perforin accumulates in granules in the form of a soluble precursor. When released from granules and in the presence of Ca 2+ , perforin rapidly polymerizes in the target cell membrane, forming a cylindrical structure. In this case, the lipophilic regions of perforin molecules are oriented towards the cell membrane, and the hydrophilic ones - towards the channel into the cell. As a result, a pore with a diameter of about 16 nm is formed.
- Granzymes and apoptosis. Through the pore formed by perforin, released CTL granzymes enter the target cell. Three CTL granzymes have been characterized - A, B and C. These are specialized serine proteases, the substrates of which are enzymes that initiate the apoptosis program in the target cell. In this case, the DNA and proteins of the cell are destroyed, and if it is infected with a virus, then the pathogen that infected it.
- Target lysis. If the apoptotic mechanisms of the target cell are disrupted for any reason, the CTL still destroys the cell by osmotic lysis through the pores formed by perforin. However, in this case, intact viral particles and nucleic acids can infect other cells, as happens in the case of some infectious diseases.
. Cytokines. CD8 + CTLs produce cytokines - IFNγ, TNFα and TNFβ (lymphotoxin). Effects IFN γ are listed below:
- directly inhibits viral replication;
- induces increased expression of MHC-I and MHC-II molecules in target cells, promoting more effective presentation of viral antigens to T lymphocytes: both for recognition and killing;
- activates macrophages and NK cells;
- serves as a cofactor in inducing the differentiation of naïve CD4+ T lymphocytes into Th1 cells. This means that CD8 + CTLs contribute to the development of other effector mechanisms of the immune response - with the participation of Th1 lymphocytes.
DELAYED TYPE HYPERSENSITIVITY
Delayed-type hypersensitivity (DTH) is tissue inflammation “organized” by CD4 + T-lymphocytes of the Th1 subpopulation - IFN producers. Activated macrophages serve as executor cells. If a macrophage is activated by a CD4 + Th1 lymphocyte at the site of infection, the microbicidal capabilities of the macrophage increase significantly, and it more effectively destroys engulfed pathogens. Unfortunately, not all pathogens die in a macrophage; viruses, such as HIV, as well as mycobacteria, are especially viable.
Macrophage activation. To activate a macrophage, 2 types of influence from lymphocytes are necessary:
.contact- the CD40L molecule on the Thl lymphocyte binds to the CD40 molecule on the macrophage;
.cytokine - IFNγ, produced by a Th1 cell, CD8+ CTL, or NK cell, binds to a receptor on a macrophage;
.infected macrophage has a greater chance of interacting with a Th1 cell, which is due to the T cell recognizing the antigen on the surface of the macrophage. As a result, it is this macrophage that will receive activating signals from the T cell through interferon and CD40L.
Activation inhibitor macrophages - IL-10.
Characteristics of activated macrophage. A macrophage activated by interaction with a Th1 cell acquires the following characteristics and functional abilities.
.The number of FcγR receptors increases, with the help of which the macrophage binds antigen-antibody complexes and phagocytoses them.
.IFN in macrophages induces the biosynthesis of enzymes that form radicals of reactive oxygen species that oxidize the phagocytosed antigen.
.In macrophages under the influence of IFNγ, TNFα and, possibly, IL-1 induces the expression of NO synthase, which produces the NO* radical, which also oxidizes the phagocytosed material.
.In macrophages, the synthesis of lipid inflammatory mediators - PAF, prostaglandins and leukotrienes (LTE4) - is induced.
.The macrophage synthesizes tissue coagulation factor. As the coagulation process begins, serum thrombin is activated, a protease that stimulates vascular endothelial cells, as well as
neutrophils to the synthesis of PAF, which further contributes to the progression of the inflammatory process.
.IFNγ serves as the most powerful known inducer of the synthesis and expression of MHC-II molecules. In addition, on activated macrophages, in contrast to non-activated ones, the expression of the costimulatory molecule B7 is induced, which makes activated macrophages more effective APCs. The expression of adhesion molecules ICAM-1 and LFA-3 also increases on activated macrophages.
.Activated macrophages produce IL-12, which promotes the differentiation of Th1 lymphocytes.
Site of inflammation. Cytokines of activated macrophages - TNFa, IL-1 and chemokines - create a focus of inflammation in the form of dense nodules of different sizes (symptom of induration). The density of the lesion is due to the effusion of fibrinogen from the vessels and its polymerization into fibrin. Among the cells present in the lesion, neutrophils predominate in the first 6-8 hours, then macrophages and Th1 lymphocytes. The cell density in a fresh focus of HCT is low.
Time frame for reaction development. HRT received this name because at least 24-48 hours pass between the moment of penetration of the antigen into the tissue and the development of a characteristic focus of dense inflammation. After binding of the antigen, the Th1 cell requires approximately 1 hour to induce the biosynthesis of cytokines, as well as for the synthesis and expression of the molecule on the membrane CD40L.
Effects of growth factors. Among the cytokines produced by activated macrophages, there are growth factors, which can significantly change the condition of the tissues adjacent to the lesion. The standard protective reaction is the development of a focus of inflammation similar to HRT, however, in pathological cases, cytokines secreted by activated macrophages cause fibrous tissue degeneration: platelet-derived growth factor PDGF (Platelet-Derived Growth Factor) stimulates the proliferation of fibroblasts, and TGF-β produced by CD4 + T lymphocytes and macrophages stimulates collagen synthesis. In addition, growth factors produced by macrophages cause the formation of additional blood vessels - angiogenesis.
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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 body's own cells and tissues 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 during 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 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 to form 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 and 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. This is a cascade system proteolytic enzymes , intended for humoral protecting the body from the action of foreign agents, it is involved in the implementation immune response body. It is an important component of both innate and acquired immunity.
Along the classical path complement is activated by the antigen-antibody complex. To do this, it is sufficient for one IgM molecule or two IgG molecules to participate in antigen binding. The process begins with the addition of component C1 to the AG+AT complex, which breaks down into subunitsC1q, C1r and C1s. Next, the reaction involves sequentially activated “early” complement components in the sequence: C4, C2, NW. The “early” complement component C3 activates the C5 component, which has the property of attaching to the cell membrane. On the C5 component, through the sequential addition of the “late” components C6, C7, C8, C9, a lytic or membrane-attack 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 occurs 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 B proteins, D and properdin (P) with subsequent activation of the S3 component. Further, the reaction proceeds in the same way as in the classical way - a membrane attack complex is formed.
Lectin put b complement activation also occurs without the participation of antibodies. It is initiated by a special 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 path.
During the activation of complement, proteolysis products of its components are formed - subunits C3 and C3b, C5a and C5b and others, which have high biological activity. For example, C3 and C5a take part in anaphylactic reactions, are chemoattractants, C3b plays a role in the opsonization of objects of phagocytosis, etc. A complex cascade reaction of complement occurs with the participation of Ca ions 2+ and Mg 2+.
