Nonspecific and specific factors of body defense. Nonspecific protective factors Humoral nonspecific protective factors are all except
Phagocytosis
The process of phagocytosis is the absorption of a foreign substance by phagocyte cells. Reticular and endothelial cells of lymph nodes, spleen, bone marrow, Kupffer cells of the liver, histiocytes, monocytes, polyblasts, neutrophils, eosinophils, basophils have phagocytic activity. Phagocytes remove dying cells from the body, absorb and inactivate microbes, viruses, fungi; synthesize biologically active substances (lysozyme, complement, interferon); participate in the regulation of the immune system.
The mechanism of phagocytosis includes the following steps:
1) activation of the phagocyte and its approach to the object (chemotaxis);
2) adhesion stage - adherence of the phagocyte to the object;
3) absorption of an object with the formation of a phagosome;
4) formation of a phagolysosome and digestion of the object using enzymes.
The activity of phagocytosis is associated with the presence of opsonins in the blood serum. Opsonins are proteins in normal blood serum that combine with microbes, making them more accessible to phagocytosis.
Phagocytosis, in which the death of the phagocytosed microbe occurs, is called complete. However, in some cases, microbes located inside phagocytes do not die, and sometimes even multiply. This type of phagocytosis is called incomplete. In addition to phagocytosis, macrophages perform regulatory and effector functions, cooperatively interacting with lymphocytes during a specific immune response.
defense organism antimicrobial phagocytosis
Humoral factors of nonspecific protection
The main humoral factors of nonspecific defense of the body include lysozyme, interferon, complement system, properdin, lysines, lactoferrin.
Lysozyme is a lysosomal enzyme and is found in tears, saliva, nasal mucus, secretions of mucous membranes, and blood serum. It has the property of lysing living and dead microorganisms.
Interferons are proteins that have antiviral, antitumor, and immunomodulatory effects. Interferon acts by regulating the synthesis of nucleic acids and proteins, activating the synthesis of enzymes and inhibitors that block the translation of viral and RNA.
Nonspecific humoral factors include the complement system (a complex protein complex that is constantly present in the blood and is an important factor in immunity). The complement system consists of 20 interacting protein components that can be activated without the participation of antibodies, forming a membrane attack complex with subsequent attack on the membrane of a foreign bacterial cell, leading to its destruction. The cytotoxic function of complement in this case is activated directly by the foreign invading microorganism.
Properdin takes part in the destruction of microbial cells, neutralization of viruses and plays a significant role in the nonspecific activation of complement.
Lysines are blood serum proteins that have the ability to lyse certain bacteria.
Lactoferrin is a local immunity factor that protects epithelial surfaces from microbes.
Humoral factors of nonspecific protection
The main humoral factors of nonspecific defense of the body include lysozyme, interferon, complement system, properdin, lysines, lactoferrin.
Lysozyme is a lysosomal enzyme and is found in tears, saliva, nasal mucus, secretions of mucous membranes, and blood serum. It has the property of lysing living and dead microorganisms.
Interferons are proteins that have antiviral, antitumor, and immunomodulatory effects. Interferon acts by regulating the synthesis of nucleic acids and proteins, activating the synthesis of enzymes and inhibitors that block the translation of viral and RNA.
Nonspecific humoral factors include the complement system (a complex protein complex that is constantly present in the blood and is an important factor in immunity). The complement system consists of 20 interacting protein components that can be activated without the participation of antibodies, forming a membrane attack complex with subsequent attack on the membrane of a foreign bacterial cell, leading to its destruction. The cytotoxic function of complement in this case is activated directly by the foreign invading microorganism.
Properdin takes part in the destruction of microbial cells, neutralization of viruses and plays a significant role in the nonspecific activation of complement.
Lysines are blood serum proteins that have the ability to lyse certain bacteria.
Lactoferrin is a local immunity factor that protects epithelial surfaces from microbes.
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Nonspecific protective factors are understood as innate internal mechanisms for maintaining the genetic constancy of the body, which have a wide range of antimicrobial effects. It is nonspecific mechanisms that act as the first protective barrier to the introduction of an infectious agent. Nonspecific mechanisms do not require restructuring, while specific agents (antibodies, sensitized lymphocytes) appear after a few days. It is important to note that nonspecific defense factors act against many pathogenic agents simultaneously.
Leather. Intact skin is a powerful barrier to the penetration of microorganisms. In this case, mechanical factors are important: rejection of the epithelium and secretions of the sebaceous and sweat glands, which have bactericidal properties (chemical factor).
Mucous membranes. In various organs they are one of the barriers to the penetration of microbes. In the respiratory tract, mechanical protection is provided by ciliated epithelium. The movement of the cilia of the epithelium of the upper respiratory tract constantly moves the mucus film along with microorganisms towards the natural openings: the oral cavity and nasal passages. Coughing and sneezing help remove germs. The mucous membranes secrete secretions that have bactericidal properties, in particular due to lysozyme and immunoglobulin type A.
The secretions of the digestive tract, along with their special properties, have the ability to neutralize many pathogenic microbes. Saliva is the first secretion that processes food substances, as well as microflora entering the oral cavity. In addition to lysozyme, saliva contains enzymes (amylase, phosphatase, etc.). Gastric juice also has a detrimental effect on many pathogenic microbes (the causative agents of tuberculosis and anthrax bacillus survive). Bile causes the death of pasteurella, but is ineffective against salmonella and E. coli.
There are billions of different microorganisms in the animal's intestines, but its mucous membrane contains powerful antimicrobial factors, as a result of which infection through it is rare. Normal intestinal microflora has pronounced antagonistic properties towards many pathogenic and putrefactive microorganisms.
The lymph nodes. If microorganisms overcome the skin and mucous barriers, the lymph nodes begin to perform a protective function. Inflammation develops in them and in the infected area of tissue - the most important adaptive reaction aimed at limiting the effect of damaging factors. In the area of inflammation, microbes are fixed by the fibrin filaments formed. In addition to the coagulation and fibrinolytic systems, the inflammatory process involves the complement system, as well as endogenous mediators (prostaglandids, vasoactive amines, etc.). Inflammation is accompanied by fever, swelling, redness and pain. Subsequently, phagocytosis (cellular defense factors) takes an active part in freeing the body from microbes and other foreign factors.
Phagocytosis (from the Greek phago - eat, cytos - cell) is the process of active absorption by the cells of the body of pathogenic living or dead microbes and other foreign particles entering it, followed by digestion with the help of intracellular enzymes. In lower unicellular and multicellular organisms, the nutritional process is carried out using phagocytosis. In higher organisms, phagocytosis acquired the property of a protective reaction, liberating the body from foreign substances, both those received from the outside and those formed directly in the body itself. Consequently, phagocytosis is not only a reaction of cells to the introduction of pathogenic microbes - it is a more general biological reaction of cellular elements, which is observed in both pathological and physiological conditions.
Types of phagocytic cells. Phagocytic cells are usually divided into two main categories: microphages (or polymorphonuclear phagocytes - PMN) and macrophages (or mononuclear phagocytes - MN). The vast majority of phagocytic PMNs are neutrophils. Among macrophages, a distinction is made between mobile (circulating) and immobile (sedentary) cells. Mobile macrophages are monocytes of peripheral blood, and immobile macrophages are macrophages of the liver, spleen, lymph nodes, lining the walls of small vessels and other organs and tissues.
One of the main functional elements of macro- and microphages are lysosomes - granules with a diameter of 0.25-0.5 microns, containing a large set of enzymes (acid phosphatase, B-glucuronidase, myeloperoxidase, collagenase, lysozyme, etc.) and a number of other substances (cationic proteins, phagocytin, lactoferrin) capable of participating in the destruction of various antigens.
Phases of the phagocytic process. The process of phagocytosis includes the following stages: 1) chemotaxis and adhesion of particles to the surface of phagocytes; 2) gradual immersion (capture) of particles into the cell, followed by separation of part of the cell membrane and the formation of a phagosome; 3) fusion of the phagosome with lysosomes; 4) enzymatic digestion of captured particles and removal of remaining microbial elements. The activity of phagocytosis is associated with the presence of opsonins in the blood serum. Opsonins are proteins in normal blood serum that combine with microbes, making the latter more accessible to phagocytosis. There are thermostable and thermolabile opsonins. The former mainly belong to immunoglobulin G, although opsonins related to immunoglobulins A and M can promote phagocytosis. Thermolabile opsonins (destroyed at a temperature of 56 ° C for 20 minutes) include components of the complement system - C1, C2, C3 and C4.
Phagocytosis, in which the death of the phagocytosed microbe occurs, is called completed (perfect). However, in some cases, microbes located inside phagocytes do not die, and sometimes even multiply (for example, the causative agent of tuberculosis, anthrax bacillus, some viruses and fungi). Such phagocytosis is called incomplete (imperfect). It should be noted that macrophages, in addition to phagocytosis, perform regulatory and effector functions, cooperatively interacting with lymphocytes during a specific immune response.
Humoral factors. Humoral factors of nonspecific defense of the body include: normal (natural) antibodies, lysozyme, properdin, beta-lysines (lysines), complement, interferon, viral inhibitors in blood serum and a number of other substances that are constantly present in the body.
Normal antibodies. In the blood of animals and humans that have never been sick or been immunized before, substances are found that react with many antigens, but in low titers, not exceeding a dilution of 1:10-1:40. These substances were called normal or natural antibodies. They are believed to arise as a result of natural immunization by various microorganisms.
Lysozyme. Lysozyme belongs to lysosomal enzymes, found in tears, saliva, nasal mucus, secretions of mucous membranes, blood serum and extracts of organs and tissues, milk, and there is a lot of lysozyme in the whites of chicken eggs. Lysozyme is resistant to heat (inactivated by boiling) and has the property of lysing living and dead, mainly gram-positive, microorganisms.
Secretory immunoglobulin A. It has been found that SIgA is constantly present in the contents of the secretions of the mucous membranes, in the secretions of the mammary and salivary glands, in the intestinal tract, and has pronounced antimicrobial and antiviral properties.
Properdin (Latin pro and perdere - prepare for destruction). Described in 1954 by Pillimer as a factor of nonspecific protection and cytolysis. Contained in normal blood serum in amounts up to 25 mcg/ml. This is whey protein with a mol. weighing 220,000. Properdin takes part in the destruction of microbial cells, neutralization of viruses, and lysis of some red blood cells. It is generally accepted that activity is due not to properdin itself, but to the properdin system (complement and divalent magnesium ions). Native properdin plays a significant role in nonspecific activation of complement (alternative pathway of complement activation).
Lysines are blood serum proteins that have the ability to lyse certain bacteria or red blood cells. The blood serum of many animals contains beta-lysines, which cause lysis of Bacillus subtilis and are also very active against many pathogenic microbes.
Lactoferrin. Lactoferrin is a non-hymine glycoprotein with iron-binding activity. Binds two ferric iron atoms to compete with microbes, resulting in microbial growth being inhibited. It is synthesized by polymorphonuclear leukocytes and grape-shaped cells of the glandular epithelium. It is a specific component of the secretion of glands - salivary, lacrimal, mammary, respiratory, digestive and genitourinary tracts. It is generally accepted that lactoferrin is a factor of local immunity that protects epithelial integuments from microbes.
Complement. Complement is a multicomponent system of proteins in blood serum and other body fluids that play an important role in maintaining immune homeostasis. It was first described by Buchner in 1889 under the name “alexin” - a thermolabile factor, in the presence of which lysis of microbes is observed. The term “complement” was introduced by Ehrlich in 1895. It has long been noted that specific antibodies in the presence of fresh blood serum can cause hemolysis of red blood cells or lysis of a bacterial cell, but if the serum is heated at 56 ° C for 30 minutes before the reaction, then lysis will not happen. It turned out that hemolysis (lysis) occurs due to the presence of complement in fresh serum. The largest amount of complement is found in the blood serum of guinea pigs.
The complement system consists of at least 11 different serum proteins, designated C1 to C9. C1 has three subunits: Clq, Clr, C Is. The activated form of complement is indicated by a dash above (C).
There are two ways of activation (self-assembly) of the complement system - classical and alternative, differing in trigger mechanisms.
In the classical activation pathway, the first complement component C1 binds to immune complexes (antigen + antibody), which include sequential subcomponents (Clq, Clr, Cls), C4, C2 and C3. The complex of C4, C2 and C3 ensures the fixation of the activated C5 complement component on the cell membrane, and is then activated through a series of reactions of C6 and C7, which contribute to the fixation of C8 and C9. As a result, damage to the cell wall or lysis of the bacterial cell occurs.
In the alternative pathway of complement activation, the activators themselves are the viruses, bacteria or exotoxins themselves. The alternative activation pathway does not involve components C1, C4 and C2. Activation begins at the S3 stage, which includes a group of proteins: P (properdin), B (proactivator), D (S3 proactivator convertase) and inhibitors J and H. In the reaction, Properdin stabilizes convertases S3 and C5, therefore this activation pathway is also called the properdin system . The reaction begins with the addition of factor B to S3; as a result of a series of sequential reactions, P (properdin) is inserted into the complex (S3 convertase), which acts as an enzyme on S3 and C5; a cascade of complement activation begins with C6, C7, C8 and C9, which leads to to cell wall damage or cell lysis.
Thus, for the body, the complement system serves as an effective defense mechanism, which is activated as a result of immune reactions or through direct contact with microbes or toxins. Let us note some biological functions of activated complement components: Clq is involved in regulating the process of switching immunological reactions from cellular to humoral and vice versa; Cell-bound C4 promotes immune attachment; S3 and C4 enhance phagocytosis; C1/C4, by binding to the surface of the virus, block the receptors responsible for the introduction of the virus into the cell; C3 and C5a are identical to anaphylactosins, they act on neutrophil granulocytes, the latter secrete lysosomal enzymes that destroy foreign antigens, provide directed migration of microphages, cause contraction of smooth muscles, and increase inflammation (Fig. 13).
It has been established that macrophages synthesize C1, C2, C4, C3 and C5. Hepatocytes - C3, C6, C8 cells.
Interferon, Isolated in 1957 by English virologists A. Isaac and I. Lindenman. Interferon was initially considered as an antiviral defense factor. Later it turned out that this is a group of protein substances whose function is to ensure the genetic homeostasis of the cell. In addition to viruses, inducers of the formation of interferon are bacteria, bacterial toxins, mitogens, etc. Depending on the cellular origin of interferon and the factors inducing its synthesis, there are interferon, or leukocyte, which is produced by leukocytes treated with viruses and other agents, interferon, or fibroblast, which produced by fibroblasts treated with viruses or other agents. Both of these interferons are classified as type I. Immune interferon, or γ-interferon, is produced by lymphocytes and macrophages activated by non-viral inducers.
Interferon takes part in the regulation of various mechanisms of the immune response: it enhances the cytotoxic effect of sensitized lymphocytes and K-cells, has antiproliferative and antitumor effects, etc. Interferon has tissue specificity, i.e. it is more active in the biological system in which it is produced, protects cells from a viral infection only if it interacts with them before contact with the virus.
The process of interaction of interferon with sensitive cells is divided into several stages: 1) adsorption of interferon on cellular receptors; 2) induction of an antiviral state; 3) development of antiviral resistance (accumulation of interferon-induced RNA and proteins); 4) pronounced resistance to viral infection. Consequently, interferon does not interact directly with the virus, but prevents the penetration of the virus and inhibits the synthesis of viral proteins on cellular ribosomes during the replication of viral nucleic acids. Interferon has also been shown to have radiation protective properties.
Serum inhibitors. Inhibitors are nonspecific antiviral substances of protein nature, contained in normal native blood serum, secretions of the epithelium of the mucous membranes of the respiratory and digestive tracts, and in extracts of organs and tissues. They have the ability to suppress the activity of viruses outside the sensitive cell, when the virus is in the blood and liquids. Inhibitors are divided into thermolabile (lose their activity when blood serum is heated at 60-62 °C for 1 hour) and thermostable (withstand heating up to 100 °C). Inhibitors have universal virus neutralizing and antihemagglutinating activity against many viruses.
In addition to serum inhibitors, inhibitors of tissues, secretions and animal excreta have been described. Such inhibitors have proven to be active against many viruses; for example, secretory inhibitors of the respiratory tract have antihemagglutinating and virus-neutralizing activity.
Bactericidal activity of blood serum (BAS). Fresh blood serum of humans and animals has pronounced, mainly bacteriostatic, properties against many pathogens of infectious diseases. The main components that suppress the growth and development of microorganisms are normal antibodies, lysozyme, properdin, complement, monokines, leukins and other substances. Therefore, BAS is an integrated expression of the antimicrobial properties that are part of the humoral factors of nonspecific defense. BAS depends on the conditions of keeping and feeding of animals; with poor housing and feeding, the activity of the serum is significantly reduced.
The meaning of stress. Nonspecific protective factors also include protective-adaptive mechanisms, called “stress,” and factors that cause stress are called stressors by G. Silje. According to Silye, stress is a special nonspecific state of the body that occurs in response to the action of various damaging environmental factors (stressors). In addition to pathogenic microorganisms and their toxins, stressors can be cold, heat, hunger, ionizing radiation and other agents that have the ability to cause responses in the body. Adaptation syndrome can be general and local. It is caused by the action of the pituitary-adrenocortical system associated with the hypothalamic center. Under the influence of a stressor, the pituitary gland begins to intensively secrete adrenocorticotropic hormone (ACTH), which stimulates the functions of the adrenal glands, causing them to increase the release of an anti-inflammatory hormone such as cortisone, which reduces the protective-inflammatory response. If the stressor is too strong or prolonged, then a disease occurs during the adaptation process.
With the intensification of livestock farming, the number of stress factors to which animals are exposed increases significantly. Therefore, the prevention of stress effects that reduce the body’s natural resistance and cause diseases is one of the most important tasks of the veterinary and zootechnical service.
Mechanisms of formation of protective reactions
The body’s protection from everything foreign (microorganisms, foreign macromolecules, cells, tissues) is carried out with the help of nonspecific protective factors and specific protective factors - immune reactions.
Nonspecific protective factors arose in phylogenesis earlier than immune mechanisms and are the first to be included in the body’s defense against various antigenic stimuli; the degree of their activity does not depend on the immunogenic properties and the frequency of exposure to the pathogen.
Immune protective factors act strictly specifically (only anti-A antibodies or anti-A cells are produced against antigen-A), and unlike non-specific protective factors, the strength of the immune reaction is regulated by the antigen, its type (protein, polysaccharide), quantity and frequency impact.
Nonspecific body defense factors include:
1. Protective factors of the skin and mucous membranes.
The skin and mucous membranes form the first barrier to protect the body from infections and other harmful influences.
2.Inflammatory reactions.
3. Humoral substances in serum and tissue fluid (humoral protective factors).
4. Cells with phagocytic and cytotoxic properties (cellular protection factors),
Specific protective factors or immune defense mechanisms include:
1. Humoral immunity.
2. Cellular immunity.
1. The protective properties of the skin and mucous membranes are due to:
a) mechanical barrier function of the skin and mucous membranes. Normal, intact skin and mucous membranes are impermeable to microorganisms;
b) the presence of fatty acids on the surface of the skin, lubricating and disinfecting the surface of the skin;
c) the acidic reaction of secretions released onto the surface of the skin and mucous membranes, the content of lysozyme, properdin and other enzymatic systems in the secretions that have a bactericidal effect on microorganisms. Sweat and sebaceous glands open onto the skin, the secretions of which have an acidic pH.
The secretions of the stomach and intestines contain digestive enzymes that inhibit the development of microorganisms. The acidic reaction of gastric juice is not suitable for the development of most microorganisms.
Saliva, tears and other secretions normally have properties that prevent the development of microorganisms.
Inflammatory reactions.
The inflammatory response is a normal reaction of the body. The development of the inflammatory reaction leads to the attraction of phagocytic cells and lymphocytes to the site of inflammation, activation of tissue macrophages and the release of biologically active compounds and substances with bactericidal and bacteriostatic properties from cells involved in inflammation.
The development of inflammation contributes to the localization of the pathological process, the elimination of factors that caused inflammation from the source of inflammation, and the restoration of the structural integrity of the tissue and organ. The process of acute inflammation is shown schematically in Fig. 3-1.
Rice. 3-1. Acute inflammation.
From left to right, the processes occurring in tissues and blood vessels are presented when tissues are damaged and inflammation develops in them. As a rule, tissue damage is accompanied by the development of infection (bacteria are indicated by black rods in the figure). A central role in the acute inflammatory process is played by tissue mast cells, macrophages and polymorphonuclear leukocytes coming from the blood. They are a source of biologically active substances, pro-inflammatory cytokines, lysosomal enzymes, all factors of inflammation: redness, heat, swelling, pain. When acute inflammation transitions to chronic, the main role in maintaining inflammation passes to macrophages and T-lymphocytes.
Humoral protective factors.
Nonspecific humoral protective factors include: lysozyme, complement, properdin, B-lysines, interferon.
Lysozyme. Lysozyme was discovered by P. L. Lashchenko. In 1909, he first discovered that egg white contains a special substance that can have a bactericidal effect on certain types of bacteria. Later it was found that this action is due to a special enzyme, which in 1922 was named lysozyme by Fleming.
Lysozyme is a muramidase enzyme. By its nature, lysozyme is a protein consisting of 130-150 amino acid residues. The enzyme exhibits optimal activity at pH = 5.0-7.0 and temperature +60C°
Lysozyme is found in many human secretions (tears, saliva, milk, intestinal mucus), skeletal muscles, spinal cord and brain, amniotic membranes and fetal fluids. In blood plasma its concentration is 8.5±1.4 μg/l. The bulk of lysozyme in the body is synthesized by tissue macrophages and neutrophils. A decrease in serum lysozyme titer is observed in severe infectious diseases, pneumonia, etc.
Lysozyme has the following biological effects:
1) increases phagocytosis of neutrophils and macrophages (lysozyme, changing the surface properties of microbes, makes them easily accessible to phagocytosis);
2) stimulates the synthesis of antibodies;
3) removal of lysozyme from the blood leads to a decrease in the serum levels of complement, properdin, and B-lysines;
4) enhances the lytic effect of hydrolytic enzymes on bacteria.
Complement. The complement system was discovered in 1899 by J. Bordet. Complement is a complex of blood serum proteins consisting of more than 20 components. The main components of complement are designated by the letter C and have numbers from 1 to 9: C1, C2, C3, C4, C5, C6, C7.C8.C9. (Table 3-2.).
Table 3-2. Characteristics of proteins of the human complement system.
| Designation | Carbohydrate content, % | Molecular weight, kD | Number of circuits | P.I. | Content in serum, mg/l | |
| Clq | 8,5 | 10-10,6 | 6,80 | |||
| С1r 2 | 9,4 | 11,50 | ||||
| C1s | 7,1 | 16,90 | ||||
| C2 | + | 5,50 | 8,90 | |||
| C4 | 6,9 | 6,40 | 8,30 | |||
| NW | 1,5 | 5,70 | 9,70 | |||
| C5 | 1,6 | 4,10 | 13,70 | |||
| C6 | 10,80 | |||||
| C7 | 5,60 | 19,20 | ||||
| C8 | 6,50 | 16,00 | ||||
| C9 | 7,8 | 4,70 | 9,60 | |||
| Factor D | - | 7,0; 7,4 | ||||
| Factor B | + | 5,7; 6,6 | ||||
| Properdin R | + | >9,5 | ||||
| Factor H | + | |||||
| Factor I | 10,7 | |||||
| S-protein, Vitronectin | + | 1(2) . | 3,90 | |||
| ClInh | 2,70 | |||||
| C4dp | 3,5 | 540, 590 | 6-8 | |||
| DAF | ||||||
| C8bp | ||||||
| CR1 | + | |||||
| CR2 | + | |||||
| CR3 | + | |||||
| C3a | - | 70* | ||||
| C4a | - | 22* | ||||
| C5a | 4,9* | |||||
| Carboxy-peptidase M (in-activator of anaphyl toxins) | ||||||
| Clq-I | ||||||
| M-Clq-I | 1-2 | |||||
| Protectin (CD 59) | + | 1,8-20 |
* - under conditions of full activation
Complement components are produced in the liver, bone marrow, and spleen. The main complement producing cells are macrophages. The C1 component is produced by intestinal epithelial cells.
Complement components are presented in the form of: proenzymes (esterases, proteinases), protein molecules that do not have enzymatic activity, and as inhibitors of the complement system. Under normal conditions, complement components are in an inactive form. Factors that activate the complement system are antigen-antibody complexes, aggregated immunoglobulins, viruses, and bacteria.
Activation of the complement system leads to the activation of lytic enzymes of complement C5-C9, the so-called membrane attack complex (MAC), which, being embedded in the membrane of animal and microbial cells, forms a transmembrane pore, which leads to hyperhydration of the cell and its death. (Fig. 3-2, 3-3).
Rice. 3-2. Graphical model of complement activation.
Rice. 3-3. Structure of activated complement.
There are 3 ways to activate the complement system:
The first way is classical. (Fig. 3-4).
Rice. 3-4. The mechanism of the classical pathway of complement activation.
E – erythrocyte or other cell. A – antibody.
With this method, activation of the lytic enzymes MAC C5-C9 occurs through cascade activation of C1q, C1r, C1s, C4, C2, followed by the involvement of the central components C3-C5 in the process (Fig. 3-2, 3-4). The main activator of complement along the classical pathway is antigen-antibody complexes formed by immunoglobulins of classes G or M.
Second way - bypass, alternative (Fig. 3-6).
Rice. 3-6. The mechanism of the alternative pathway of complement activation.
This mechanism of complement activation is triggered by viruses, bacteria, aggregated immunoglobulins, and proteolytic enzymes.
With this method, the activation of the lytic enzymes MAC C5-C9 begins with the activation of the C3 component. The first three complement components C1, C4, C2 are not involved in this mechanism of complement activation, but factors B and D are additionally involved in the activation of S3.
Third way represents a nonspecific activation of the complement system by proteinases. Such activators can be: trypsin, plasmin, kallikrein, lysosomal proteases and bacterial enzymes. Activation of the complement system with this method can occur at any segment from C 1 to C5.
Activation of the complement system can cause the following biological effects:
1) lysis of microbial and somatic cells;
2) promoting graft rejection;
3) release of biologically active substances from cells;
4) increased phagocytosis;
5) aggregation of platelets, eosinophils;
6) increased leukotaxis, migration of neutrophils from the bone marrow and release of hydrolytic enzymes from them;
7) through the release of biologically active substances and increased vascular permeability, promoting the development of an inflammatory reaction;
8) promoting the induction of an immune response;
9) activation of the blood coagulation system.
Rice. 3-7. Diagram of the classical and alternative pathways of complement activation.
Congenital deficiency of complement components reduces the body's resistance to infectious and autoimmune diseases.
Properdin. In 1954 Pillimer was the first to discover a special type of protein in the blood that can activate complement. This protein is called properdin.
Properdin belongs to the class of gamma immunoglobulins, has m.m. 180,000 daltons. In the serum of healthy people it is in an inactive form. Properdin is activated after it combines with factor B on the cell surface.
Activated properdin promotes:
1) activation of complement;
2) release of histamine from cells;
3) production of chemotactic factors that attract phagocytes to the site of inflammation;
4) the process of blood coagulation;
5) formation of an inflammatory reaction.
Factor B. It is a blood protein of globulin nature.
Factor D. Proteinases having m.m. 23 000. In the blood they are represented by the active form.
Factors B and D are involved in the activation of complement via the alternative pathway.
B-lysines. Blood proteins of various molecular weights that have bactericidal properties. B-lysines exhibit a bactericidal effect both in the presence and absence of complement and antibodies.
Interferon. A complex of protein molecules that can prevent and suppress the development of a viral infection.
There are 3 types of interferon:
1) alpha interferon (leukocyte), produced by leukocytes, represented by 25 subtypes;
2) beta interferon (fibroblastic), produced by fibroblasts, represented by 2 subtypes;
3) gamma interferon (immune), produced mainly by lymphocytes. Interferon gamma is known as one type.
The formation of interferon occurs spontaneously, as well as under the influence of viruses.
All types and subtypes of interferons have a single mechanism of antiviral action. It appears to be as follows: interferon, by binding to specific receptors of uninfected cells, causes biochemical and genetic changes in them, leading to a decrease in the translation of m-RNA in cells and activation of latent endonucleases, which, turning into an active form, are capable of causing the degradation of m-RNA as a virus , and the cell itself. This causes the cells to become insensitive to viral infection, creating a barrier around the site of infection.
Throughout the entire path of evolution, man comes into contact with a huge number of pathogenic agents that threaten him. In order to resist them, two types of protective reactions have been formed: 1) natural or nonspecific resistance, 2) specific protective factors or immunity (from lat.
Immunitas - free from anything).
Nonspecific resistance is caused by various factors. The most important of them are: 1) physiological barriers, 2) cellular factors, 3) inflammation, 4) humoral factors.
Physiological barriers. Can be divided into external and internal barriers.
External barriers. Intact skin is impermeable to the vast majority of infectious agents. Constant desquamation of the upper layers of the epithelium, secretions of the sebaceous and sweat glands help remove microorganisms from the surface of the skin. When the integrity of the skin is damaged, for example, with burns, infection becomes the main problem. In addition to the fact that the skin serves as a mechanical barrier to bacteria, it contains a number of bactericidal substances (lactic and fatty acids, lysozyme, enzymes secreted by the sweat and sebaceous glands). Therefore, microorganisms that are not part of the normal microflora of the skin quickly disappear from its surface.
Mucous membranes also provide a mechanical barrier to bacteria, but they are more permeable. Many pathogenic microorganisms can penetrate even intact mucous membranes.
The mucus secreted by the walls of the internal organs acts as a protective barrier that prevents bacteria from “attaching” to the epithelial cells. Microbes and other foreign particles trapped in mucus are removed mechanically - due to the movement of the cilia of the epithelium, with coughing and sneezing.
Other mechanical factors that help protect the epithelial surface include the flushing effect of tears, saliva, and urine. Many fluids secreted by the body contain bactericidal components (hydrochloric acid in gastric juice, lactoperoxidase in breast milk, lysozyme in tear fluid, saliva, nasal mucus, etc.).
The protective functions of the skin and mucous membranes are not limited to nonspecific mechanisms. On the surface of the mucous membranes, in the secretions of the skin, mammary and other glands, secretory immunoglobulins are present, which have bactericidal properties and activate local phagocytic cells. The skin and mucous membranes take an active part in antigen-specific reactions of acquired immunity. They are considered independent components of the immune system.
One of the most important physiological barriers is the normal microflora of the human body, which inhibits the growth and reproduction of many potentially pathogenic microorganisms.
Internal barriers. Internal barriers include the system of lymphatic vessels and lymph nodes. Microorganisms and other foreign particles that penetrate the tissue are phagocytosed locally or delivered by phagocytes to the lymph nodes or other lymphatic formations, where an inflammatory process develops aimed at destroying the pathogen. If the local reaction is insufficient, the process spreads to the following regional lymphoid formations, which represent a new barrier to pathogen penetration.
There are functional histohematic barriers that prevent the penetration of pathogens from the blood into the brain, reproductive system, and eye.
The membrane of each cell also serves as a barrier to the penetration of foreign particles and molecules into it.
Cellular factors. Among the cellular factors of nonspecific protection, the most important is phagocytosis - the absorption and digestion of foreign particles, incl. and microorganisms. Phagocytosis is carried out by two populations of cells:
I. microphages (polymorphonuclear neutrophils, basophils, eosinophils), 2. macrophages (blood monocytes, free and fixed macrophages of the spleen, lymph nodes, serous cavities, Kupffer cells of the liver, histiocytes).
In relation to microorganisms, phagocytosis can be complete, when bacterial cells are completely digested by the phagocyte, or incomplete, which is characteristic of diseases such as meningitis, gonorrhea, tuberculosis, candidiasis, etc. In this case, pathogens remain viable inside phagocytes for a long time, and sometimes they reproduce in them.
In the body, there is a population of lymphocyte-like cells that have natural cytotoxicity towards “target” cells. They are called natural killer cells (NK).
Morphologically, NK are large granule-containing lymphocytes; they do not have phagocytic activity. Among human blood lymphocytes, the EC content is 2–12%.
Inflammation. When a microorganism invades tissue, an inflammatory process occurs. The resulting damage to tissue cells leads to the release of histamine, which increases the permeability of the vascular wall. The migration of macrophages increases, and edema occurs. In the inflammatory focus, the temperature rises and acidosis develops. All this creates unfavorable conditions for bacteria and viruses.
Humoral protective factors. As the name itself indicates, humoral protective factors are found in body fluids (blood serum, breast milk, tears, saliva). These include: complement, lysozyme, beta-lysines, acute phase proteins, interferons, etc.
Complement is a complex complex of blood serum proteins (9 fractions), which, like the proteins of the blood coagulation system, form cascade interaction systems.
The complement system has several biological functions: enhances phagocytosis, causes lysis of bacteria, etc.
Lysozyme (muramidase) is an enzyme that cleaves glycosidic bonds in the peptidoglycan molecule, which is part of the bacterial cell wall. The peptidoglycan content of gram-positive bacteria is higher than that of gram-negative bacteria, therefore lysozyme is more effective against gram-positive bacteria. Lysozyme is found in humans in tear fluid, saliva, sputum, nasal mucus, etc.
Beta-lysines are found in the blood serum of humans and many animal species, and their origin is associated with platelets. They have a detrimental effect primarily on gram-positive bacteria, in particular anthracoid.
Acute phase proteins are the general name for some blood plasma proteins. Their content increases sharply in response to infection or tissue damage. These proteins include: C-reactive protein, serum amyloid A, serum amyloid P, alpha1-antitrypsin, alpha2-macroglobulin, fibrinogen, etc.
Another group of acute phase proteins consists of proteins that bind iron - haptoglobin, hemopexin, transferrin - and thereby prevent the proliferation of microorganisms that require this element.
During infection, microbial waste products (such as endotoxins) stimulate the production of interleukin-1, which is an endogenous pyrogen. In addition, interleukin-1 acts on the liver, increasing the secretion of C-reactive protein to such an extent that its concentration in the blood plasma can increase 1000 times. An important property of C-reactive protein is the ability to bind with the participation of calcium to certain microorganisms, which activates the complement system and promotes phagocytosis.
Interferons (IF) are low molecular weight proteins produced by cells in response to the penetration of viruses. Then their immunoregulatory properties were identified. There are three types of IF: alpha, beta, belonging to the first class, and gamma interferon, belonging to the second class.
Alpha interferon, produced by leukocytes, has antiviral, antitumor and antiproliferative effects. Beta-IF, secreted by fibroblasts, has predominantly antitumor and also antiviral effects. Gamma-IF, a product of T helper cells and CD8+ T lymphocytes, is called lymphocytic or immune. It has an immunomodulatory and weak antiviral effect.
The antiviral effect of IF is due to the ability to activate in cells the synthesis of inhibitors and enzymes that block the replication of viral DNA and RNA, which leads to the suppression of viral reproduction. The mechanism of antiproliferative and antitumor action is similar. Gamma-IF is a multifunctional immunomodulatory lymphokine that affects the growth, differentiation and activity of different types of cells. Interferons inhibit viral reproduction. It has now been established that interferons also have antibacterial activity.
Thus, humoral factors of nonspecific protection are quite diverse. They act in combination in the body, exerting a bactericidal and inhibitory effect on various microbes and viruses.
All of these protective factors are nonspecific, since there is no specific response to the penetration of pathogenic microorganisms.
Specific or immune defense factors are a complex set of reactions that maintain the constancy of the internal environment of the body.
According to modern concepts, immunity can be defined “as a way of protecting the body from living bodies and substances that carry signs of genetically foreign information” (R.V. Petrov).
The concept of “living bodies and substances bearing signs of genetically foreign information” or antigens can include proteins, polysaccharides, their complexes with lipids, and high-polymer nucleic acid preparations. All living things consist of these substances, therefore animal cells, elements of tissues and organs, biological fluids (blood, blood serum), microorganisms (bacteria, protozoa, fungi, viruses), exo- and endotoxins of bacteria, helminths, cancer cells and etc.
The immunological function is performed by a specialized system of tissue and organ cells. This is the same independent system as, for example, the digestive or cardiovascular system. The immune system is a collection of all the lymphoid organs and cells of the body.
The immune system consists of central and peripheral organs. Central organs include the thymus (thymus or thymus gland), bursa of Fabricius in birds, bone marrow, and possibly Peyer's patches.
The peripheral lymphoid organs include the lymph nodes, spleen, appendix, tonsils, and blood.
The central figure of the immune system is the lymphocyte, also called an immunocompetent cell.
In humans, the immune system consists of two parts that cooperate with each other: the T system and the B system. The T-system carries out a cellular immune response with the accumulation of sensitized lymphocytes. The B system is responsible for the production of antibodies, i.e. for a humoral response. In mammals and humans, no organ has been found that would be a functional analogue of the bursa of Fabricius in birds.
It is believed that this role is played by a set of Peyer's patches of the small intestine. If the assumption that Peyer's patches are an analogue of the bursa of Fabricius is not confirmed, then these lymphoid formations will have to be classified as peripheral lymphoid organs.
It is possible that in mammals there is no analogue of the bursa of Fabricius at all, and this role is played by the bone marrow, which supplies stem cells for all hematopoietic germs. Stem cells leave the bone marrow into the bloodstream, enter the thymus and other lymphoid organs, where they differentiate.
Cells of the immune system (immunocytes) can be divided into three groups:
1) Immunocompetent cells capable of a specific response to the action of foreign antigens. This property is possessed exclusively by lymphocytes, which initially possess receptors for any antigen.
2) Antigen-presenting cells (APCs) – capable of differentiating self and foreign antigens and presenting the latter to immunocompetent cells.
3) Cells of antigen-nonspecific defense, which have the ability to distinguish their own antigens from foreign ones (primarily from microorganisms) and destroy foreign antigens using phagocytosis or cytotoxic effects.
1.Immunocompetent cells
Lymphocytes. The precursor of lymphocytes, like other cells of the immune system, is a pluripotent stem cell of the bone marrow. During the differentiation of stem cells, two main groups of lymphocytes are formed: T- and B-lymphocytes.
Morphologically, a lymphocyte is a spherical cell with a large nucleus and a narrow layer of basophilic cytoplasm. During the process of differentiation, large, medium and small lymphocytes are formed. In the lymph and peripheral blood, the most mature small lymphocytes, capable of amoeboid movements, predominate. They constantly recirculate in the bloodstream and accumulate in lymphoid tissues, where they participate in immunological reactions.
T and B lymphocytes are not differentiated by light microscopy, but are clearly distinguished from each other by their surface structures and functional activity. B lymphocytes carry out the humoral immune response, T lymphocytes carry out the cellular immune response, and also participate in the regulation of both forms of the immune response.
T lymphocytes mature and differentiate in the thymus. They make up about 80% of all blood lymphocytes, lymph nodes, and are found in all tissues of the body.
All T lymphocytes have surface antigens CD2 and CD3. CD2 adhesion molecules mediate contact between T lymphocytes and other cells. CD3 molecules are part of lymphocyte receptors for antigens. There are several hundred of these molecules on the surface of each T lymphocyte.
T-lymphocytes maturing in the thymus differentiate into two populations, the markers of which are the surface antigens CD4 and CD8.
CD4 make up more than half of all blood lymphocytes, they have the ability to stimulate other cells of the immune system (hence their name - T-helpers - from the English Help - help).
The immunological functions of CD4+ lymphocytes begin with the presentation of antigen to them by antigen presenting cells (APCs). Receptors of CD4+ cells perceive antigen only if the cell’s own antigen (major histocompatibility complex class 2 antigen) is simultaneously on the surface of the APC. This “double recognition” serves as an additional guarantee against the occurrence of an autoimmune process.
Thx after exposure to antigen proliferate into two subpopulations: Th1 and Th2.
Th1s are primarily involved in cellular immune responses and inflammation. Th2 contributes to the formation of humoral immunity. During the proliferation of Th1 and Th2, some of them turn into immunological memory cells.
CD8+ lymphocytes are the main type of cells that have a cytotoxic effect. They make up 22–24% of all blood lymphocytes; their ratio with CD4+ cells is 1:1.9 – 1:2.4. Antigen recognition receptors of CD8+ lymphocytes perceive the antigen from the presenting cell in combination with the MHC class 1 antigen. MHC class 2 antigens are found only on APCs, while class 1 antigens are found on almost all cells; CD8+ lymphocytes can interact with any cells in the body. Since the main function of CD8+ cells is cytotoxicity, they play a leading role in antiviral, antitumor and transplantation immunity.
CD8+ lymphocytes can play the role of suppressor cells, but recently it has been found that many types of cells can suppress the activity of immune system cells, so CD8+ cells are no longer called suppressors.
The cytotoxic effect of a CD8+ lymphocyte begins with the establishment of contact with the “target” cell and the entry of cytolysin proteins (perforins) into the cell membrane. As a result, holes with a diameter of 5–16 nm appear in the membrane of the “target” cell, through which enzymes (granzymes) penetrate. Granzymes and other enzymes of the lymphocyte deal a lethal blow to the “target” cell, which leads to cell death due to a sharp rise in the intracellular Ca2+ level, activation of endonucleases and destruction of the cell’s DNA. The lymphocyte then retains the ability to attack other “target” cells.
Natural killer cells (NK) are close to cytotoxic lymphocytes in their origin and functional activity, but they do not enter the thymus and are not subject to differentiation and selection, and do not participate in specific reactions of acquired immunity.
B lymphocytes make up 10–15% of blood lymphocytes, 20–25% of lymph node cells. They provide the formation of antibodies and are involved in the presentation of antigen to T lymphocytes.
