The humoral factors of nonspecific defense of the body include. Non-specific protective factors
humoral factors - the complement system. Complement is a complex of 26 proteins in the blood serum. Each protein is designated as a fraction in Latin letters: C4, C2, C3, etc. Under normal conditions, the complement system is in an inactive state. When antigens enter, it is activated, the stimulating factor is the antigen-antibody complex. Complement activation is the beginning of any infectious inflammation. The complex of complement proteins is built into the cell membrane of the microbe, which leads to cell lysis. Complement is also involved in anaphylaxis and phagocytosis, as it has chemotactic activity. Thus, complement is a component of many immunolytic reactions aimed at freeing the body from microbes and other foreign agents;
AIDS
The discovery of HIV was preceded by the work of R. Gallo and his collaborators, who isolated two human T-lymphotropic retroviruses on the T-lymphocyte cell culture they obtained. One of them, HTLV-I (English, humen T-lymphotropic virus type I), discovered in the late 70s, is the causative agent of a rare but malignant human T-leukemia. A second virus, designated HTLV-II, also causes T-cell leukemias and lymphomas.
After registration in the United States in the early 80s of the first patients with acquired immunodeficiency syndrome (AIDS), then an unknown disease, R. Gallo suggested that its causative agent is a retrovirus close to HTLV-I. Although this assumption was refuted a few years later, it played a large role in the discovery of the true causative agent of AIDS. In 1983, from a piece of tissue from an enlarged lymph node of a homosexual, Luc Montenier and a group of employees of the Pasteur Institute in Paris isolated a retrovirus in a culture of T-helpers. Further studies showed that this virus was different from HTLV-I and HTLV-II - it reproduced only in T-helper and effector cells, designated T4, and did not reproduce in T-suppressor and killer cells, designated T8.
Thus, the introduction of cultures of T4 and T8 lymphocytes into virological practice made it possible to isolate three obligate lymphotropic viruses, two of which caused the proliferation of T-lymphocytes, which is expressed in various forms of human leukemia, and one, the causative agent of AIDS, caused their destruction. The latter is called the human immunodeficiency virus - HIV.
Structure and chemical composition. HIV virions have a spherical shape 100-120 nm in diameter and are similar in structure to other lentiviruses. The outer shell of the virions is formed by a double lipid layer with glycoprotein "spikes" located on it (Fig. 21.4). Each spike consists of two subunits (gp41 and gp!20). The first penetrates the lipid layer, the second is outside. The lipid layer originates from the outer membrane of the host cell. The formation of both proteins (gp41 and gp!20) with a non-covalent bond between them occurs when the HIV outer envelope protein (gp!60) is cut. Under the outer shell is the core of the virion, cylindrical or cone-shaped, formed by proteins (p!8 and p24). The core contains RNA, reverse transcriptase, and internal proteins (p7 and p9).
Unlike other retroviruses, HIV has a complex genome due to the presence of a system of regulatory genes. Without knowing the basic mechanisms of their functioning, it is impossible to understand the unique properties of this virus, which are manifested in a variety of pathological changes that it causes in the human body.
The HIV genome contains 9 genes. Three structural genes gag, pol and env encode components of viral particles: gene gag- internal proteins of the virion, which are part of the core and capsid; gene pol- reverse transcriptase; gene env- type-specific proteins that are part of the outer shell (glycoproteins gp41 and gp!20). The large molecular weight of gp!20 is due to their high degree of glycosylation, which is one of the reasons for the antigenic variability of this virus.
Unlike all known retroviruses, HIV has a complex system of regulation of structural genes (Fig. 21.5). Among them, genes attract the most attention. tat and rev. Gene product tat increases the rate of transcription of both structural and regulatory viral proteins by dozens of times. Gene product rev is also a transcriptional regulator. However, it controls the transcription of either regulatory or structural genes. As a result of this transcription switch, capsid proteins are synthesized instead of regulatory proteins, which increases the rate of virus reproduction. Thus, with the participation of the gene rev the transition from a latent infection to its active clinical manifestation can be determined. Gene nef controls the cessation of HIV reproduction and its transition to a latent state, and the gene vif encodes a small protein that enhances the ability of the virion to bud from one cell and infect another. However, this situation will become even more complicated when the mechanism of regulation of proviral DNA replication by gene products is finally elucidated. vpr and vpu. At the same time, at both ends of the DNA of the provirus integrated into the cellular genome, there are specific markers - long terminal repeats (LTR), consisting of identical nucleotides, which are involved in the regulation of the expression of the considered genes. At the same time, there is a certain algorithm for turning on genes in the process of viral reproduction in different phases of the disease.
Antigens. Core proteins and envelope glycoproteins (gp! 60) have antigenic properties. The latter are characterized by a high level of antigenic variability, which is determined by the high rate of nucleotide substitutions in genes. env and gag, hundreds of times higher than the corresponding figure for other viruses. In the genetic analysis of numerous HIV isolates, there was not one with a complete match of nucleotide sequences. Deeper differences were noted in HIV strains isolated from patients living in different geographical areas (geographic variants).
However, HIV variants share common antigenic epitopes. Intensive antigenic variability of HIV occurs in the body of patients during infection and virus carriers. It allows the virus to “hide” from specific antibodies and cellular immunity factors, which leads to a chronic infection.
The increased antigenic variability of HIV significantly limits the possibilities of creating a vaccine for the prevention of AIDS.
Currently, two types of pathogen are known - HIV-1 and HIV-2, which differ in antigenic, pathogenic and other properties. Initially, HIV-1 was isolated, which is the main causative agent of AIDS in Europe and America, and a few years later in Senegal - HIV-2, which is distributed mainly in West and Central Africa, although individual cases of the disease also occur in Europe.
In the United States, a live adenovirus vaccine is successfully used to immunize military personnel.
Laboratory diagnostics. To detect the viral antigen in the epithelial cells of the mucous membrane of the respiratory tract, immunofluorescent and enzyme immunoassay methods are used, and in feces, immunoelectron microscopy. Isolation of adenoviruses is carried out by infecting sensitive cell cultures, followed by identification of the virus in RNA, and then in the neutralization reaction and RTGA.
Serodiagnostics is carried out in the same reactions with paired sera of sick people.
Ticket 38
Nutrient media
Microbiological research is the isolation of pure cultures of microorganisms, cultivation and study of their properties. Pure cultures are those that contain only one type of microorganism. They are needed in the diagnosis of infectious diseases, to determine the species and type of microbes, in research work, to obtain microbial waste products (toxins, antibiotics, vaccines, etc.).
For the cultivation of microorganisms (cultivation under artificial conditions in vitro) requires special substrates - nutrient media. Microorganisms carry out all life processes on the media (feed, breathe, reproduce, etc.), therefore they are also called “cultivation media”.
Nutrient media
Culture media are the basis of microbiological work, and their quality often determines the results of the entire study. Environments should create optimal (best) conditions for the life of microbes.
Environment Requirements
Environments must meet the following conditions:
1) be nutritious, i.e. contain in an easily digestible form all the substances necessary to meet nutritional and energy needs. They are sources of organogens and mineral (inorganic) substances, including trace elements. Mineral substances not only enter the cell structure and activate enzymes, but also determine the physicochemical properties of media (osmotic pressure, pH, etc.). When cultivating a number of microorganisms, growth factors are introduced into the media - vitamins, some amino acids that the cell cannot synthesize;
Attention! Microorganisms, like all living things, need a lot of water.
2) have an optimal concentration of hydrogen ions - pH, since only with an optimal reaction of the environment that affects the permeability of the shell, microorganisms can absorb nutrients.
For most pathogenic bacteria, a weakly alkaline environment (pH 7.2-7.4) is optimal. The exception is Vibrio cholerae - its optimum is in the alkaline zone
(pH 8.5-9.0) and the causative agent of tuberculosis, which needs a slightly acidic reaction (pH 6.2-6.8).
So that during the growth of microorganisms, acidic or alkaline products of their vital activity do not change pH, the media must have buffering properties, i.e., contain substances that neutralize metabolic products;
3) be isotonic for a microbial cell, i.e., the osmotic pressure in the medium must be the same as inside the cell. For most microorganisms, the optimal environment is 0.5% sodium chloride solution;
4) be sterile, since foreign microbes prevent the growth of the microbe under study, the determination of its properties, and change the properties of the medium (composition, pH, etc.);
5) dense media must be moist and have an optimal consistency for microorganisms;
6) have a certain redox potential, i.e., the ratio of substances that donate and accept electrons, expressed by the RH2 index. This potential indicates the saturation of the medium with oxygen. Some microorganisms need a high potential, others need a low one. For example, anaerobes breed at RH2 not higher than 5, and aerobes - at RH2 not lower than 10. The redox potential of most environments satisfies the requirements for it of aerobes and facultative anaerobes;
7) be as unified as possible, i.e. contain constant amounts of individual ingredients. Thus, the media for the cultivation of most pathogenic bacteria should contain 0.8-1.2 hl of the amino nitrogen NH2, i.e., the total nitrogen of the amino groups of amino acids and lower polypeptides; 2.5-3.0 hl of total nitrogen N; 0.5% chlorides in terms of sodium chloride; 1% peptone.
It is desirable that the media be transparent - it is more convenient to monitor the growth of cultures, it is easier to notice the contamination of the environment by foreign microorganisms.
Media classification
The need for nutrients and the properties of the environment for different types of microorganisms is not the same. This eliminates the possibility of creating a universal environment. In addition, the choice of a particular environment is influenced by the objectives of the study.
Currently, a huge number of media have been proposed, the classification of which is based on the following features.
1. Initial components. According to the initial components, natural and synthetic media are distinguished. Natural media are prepared from animal products and
vegetable origin. Currently, media have been developed in which valuable food products (meat, etc.) are replaced by non-food products: bone and fish meal, fodder yeast, blood clots, etc. Despite the fact that the composition of nutrient media from natural products is very complex and varies depending on from the feedstock, these media have found wide application.
Synthetic media are prepared from certain chemically pure organic and inorganic compounds, taken in precisely specified concentrations and dissolved in doubly distilled water. An important advantage of these media is that their composition is constant (it is known how much and what substances they contain), so these media are easily reproducible.
2. Consistency (degree of density). Media are liquid, solid and semi-liquid. Dense and semi-liquid media are prepared from liquid substances, to which agar-agar or gelatin is usually added to obtain a medium of the desired consistency.
Agar-agar is a polysaccharide derived from certain
seaweed varieties. It is not a nutrient for microorganisms and serves only to compact the medium. Agar melts in water at 80-100°C and solidifies at 40-45°C.
Gelatin is an animal protein. Gelatin media melt at 25-30°C, so cultures are usually grown on them at room temperature. The density of these media at pH below 6.0 and above 7.0 decreases, and they harden poorly. Some microorganisms use gelatin as a nutrient - as they grow, the medium liquefies.
In addition, clotted blood serum, clotted eggs, potatoes, and silica gel media are used as solid media.
3. Composition. Environments are divided into simple and complex. The former include meat-peptone broth (MPB), meat-peptone agar (MPA), Hottinger broth and agar, nutritious gelatin and peptone water. Complex media are prepared by adding to simple media blood, serum, carbohydrates and other substances necessary for the reproduction of one or another microorganism.
4. Purpose: a) the main (generally used) media are used for the cultivation of most pathogenic microbes. These are the aforementioned MP A, MPB, Hottinger broth and agar, peptone water;
b) special media are used to isolate and grow microorganisms that do not grow on simple media. For example, for the cultivation of streptococcus, sugar is added to the media, for pneumo- and meningococci - blood serum, for the causative agent of whooping cough - blood;
c) elective (selective) media serve to isolate a certain type of microbes, the growth of which they favor, delaying or suppressing the growth of associated microorganisms. So, bile salts, inhibiting the growth of Escherichia coli, make the environment
selective for the causative agent of typhoid fever. The media become elective when certain antibiotics, salts are added to them, and the pH changes.
Liquid elective media are called accumulation media. An example of such a medium is peptone water with a pH of 8.0. At this pH, Vibrio cholerae actively reproduces on it, and other microorganisms do not grow;
d) differential diagnostic media make it possible to distinguish (differentiate) one type of microbe from another by enzymatic activity, for example, Hiss media with carbohydrates and an indicator. With the growth of microorganisms that break down carbohydrates, the color of the medium changes;
e) preservative media are intended for primary inoculation and transportation of the test material; they prevent the death of pathogenic microorganisms and suppress the development of saprophytes. An example of such a medium is the glycerin mixture used to collect feces in studies conducted to detect a number of intestinal bacteria.
Hepatitis (A, E)
The causative agent of hepatitis A (HAV-Hepatitis A virus) belongs to the picornavirus family, the genus Enterovirus. It causes the most common viral hepatitis, which has several historical names (infectious, epidemic hepatitis, Botkin's disease, etc.). In our country, about 70% of cases of viral hepatitis are caused by the hepatitis A virus. The virus was first discovered by S. Feystone in 1979 in the feces of patients using immune electron microscopy.
Structure and chemical composition. The hepatitis A virus is similar in morphology and structure to all enteroviruses (see 21.1.1.1). In the RNA of the hepatitis A virus, nucleotide sequences were found that are common with other enteroviruses.
The hepatitis A virus has one virus-specific antigen of a protein nature. HAV differs from enteroviruses in higher resistance to physical and chemical factors. It is partially inactivated when heated to 60°C for 1 hour, at 100°C it is destroyed within 5 minutes, it is sensitive to the action of formalin and UV radiation.
Cultivation and reproduction. The hepatitis virus has a reduced ability to reproduce in cell cultures. However, it has been adapted to continuous human and monkey cell lines. Virus reproduction in cell culture is not accompanied by CPD. HAV is almost not detected in the cultural fluid, since it is associated with cells in whose cytoplasm it is reproduced:
Pathogenesis of human diseases and immunity. HAV, like other enteroviruses, enters the gastrointestinal tract with food, where it reproduces in the epithelial cells of the small intestine mucosa and regional lymph nodes. Then the pathogen penetrates into the blood, in which it is found at the end of the incubation period and in the first days of the disease.
Unlike other enteroviruses, the main target of the damaging effect of HAV is liver cells, in the cytoplasm of which its reproduction occurs. It is not excluded that hepatocytes can be damaged by NK cells (natural killer cells), which in an activated state can interact with them, causing their destruction. Activation of NK cells also occurs as a result of their interaction with interferon induced by the virus. The defeat of hepatocytes is accompanied by the development of jaundice and an increase in the level of transaminases in the blood serum. Further, the pathogen with bile enters the intestinal lumen and is excreted with feces, in which there is a high concentration of the virus at the end of the incubation period and in the first days of the disease (before the development of jaundice). Hepatitis A usually ends in complete recovery, deaths are rare.
After the transfer of a clinically pronounced or asymptomatic infection, lifelong humoral immunity is formed, associated with the synthesis of antiviral antibodies. Immunoglobulins of the IgM class disappear from the serum 3-4 months after the onset of the disease, while IgG persist for many years. The synthesis of secretory immunoglobulins SlgA was also established.
Epidemiology. The source of infection are sick people, including those with a common asymptomatic form of infection. The hepatitis A virus circulates widely in the population. On the European continent, serum antibodies against HAV are present in 80% of the adult population over 40 years of age. In countries with a low socio-economic level, infection occurs already in the first years of life. Hepatitis A often affects children.
The patient is most dangerous to others at the end of the incubation period and in the first days of the peak of the disease (before the onset of jaundice) due to the maximum release of the virus with feces. The main mechanism of transmission - fecal-oral - through food, water, household items, children's toys.
Laboratory diagnostics is carried out by detecting the virus in the patient's feces by immunoelectron microscopy. Viral antigen in faeces can also be detected by enzyme immunoassay and radioimmunoassay. The most widely used serodiagnosis of hepatitis is the detection by the same methods in paired blood sera of antibodies of the IgM class, which reach a high titer during the first 3-6 weeks.
specific prophylaxis. Vaccination for hepatitis A is under development. Inactivated and live culture vaccines are being tested, the production of which is difficult due to the poor reproduction of the virus in cell cultures. The most promising is the development of a genetically engineered vaccine. For passive immunoprophylaxis of hepatitis A, immunoglobulin obtained from a mixture of donor sera is used.
The causative agent of hepatitis E has some similarities with caliciviruses. The size of the viral particle is 32-34 nm. The genetic material is represented by RNA. Transmission of hepatitis E virus, as well as HAV, occurs by the enteral route. Serodiagnostics is carried out by determining antibodies to the E-virus antigen.
Mechanisms of formation of protective reactions
Protection of the body from everything foreign (microorganisms, foreign macromolecules, cells, tissues) is carried out with the help of non-specific protection factors and specific protection factors - immune responses.
Nonspecific defense 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 multiplicity impact.
The non-specific protective factors of the body include:
1. Protective factors of the skin and mucous membranes.
The skin and mucous membranes form the first barrier of the body's defense against infections and other harmful influences.
2. Inflammatory reactions.
3. Humoral substances of serum and tissue fluid (humoral protective factors).
4. Cells with phagocytic and cytotoxic properties (cellular protective 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 impervious to microorganisms;
b) the presence of fatty acids on the surface of the skin, lubricating and disinfecting the surface of the skin;
c) acidic reaction of secrets secreted to the surface of the skin and mucous membranes, the content of lysozyme, properdin and other enzymatic systems in secrets that act bactericidal on microorganisms. Sweat and sebaceous glands open onto the skin, the secrets of which have an acidic pH.
The secrets of the stomach and intestines contain digestive enzymes that inhibit the development of microorganisms. The acid reaction of gastric juice is not suitable for the development of most microorganisms.
Saliva, tears and other secrets normally have properties that do not allow the development of microorganisms.
inflammatory reactions.
The inflammatory response is a normal response of the body. The development of an inflammatory reaction leads to the attraction of phagocytic cells and lymphocytes to the site of inflammation, the activation of tissue macrophages, and the release of biologically active compounds and substances with bactericidal and bacteriostatic properties from the 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 focus of inflammation, and the restoration of the structural integrity of the tissue and organ. Schematically, the process of acute inflammation is shown in Fig. 3-1.
Rice. 3-1. Acute inflammation.
From left to right, the processes occurring in tissues and blood vessels during tissue damage and the development of inflammation in them are presented. As a rule, tissue damage is accompanied by the development of infection (in the figure, bacteria are indicated by black rods). The 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 the factors that cause inflammation: redness, heat, swelling, pain. When acute inflammation passes into chronic inflammation, the main role in maintaining inflammation passes to macrophages and T-lymphocytes.
Humoral protective factors.
Nonspecific humoral protection factors include: lysozyme, complement, properdin, B-lysins, interferon.
Lysozyme. Lysozyme was discovered by P. L. Lashchenko. In 1909, he first discovered that egg white contains a special substance that can act bactericidal 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 the enzyme muramidase. 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 a temperature of +60C°
Lysozyme is found in many human secretions (tears, saliva, milk, intestinal mucus), skeletal muscles, spinal cord and brain, in the amniotic membranes and fetal waters. 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 level of complement, properdin, B-lysines;
4) enhances the lytic effect of hydrolytic enzymes on bacteria.
Complement. The complement system was discovered in 1899 by J. Borde. Complement is a complex of blood serum proteins, consisting of more than 20 components. The main complement components are designated by the letter C and are numbered from 1 to 9: C1, C2, C3, C4, C5, C6, C7.C8.C9. (Table 3-2.).
Table 3-2. Characterization of the proteins of the human complement system.
| Designation | Carbohydrate content, % | Molecular weight, kD | Number of chains | PI | Content in serum, mg/l | |
| Clq | 8,5 | 10-10,6 | 6,80 | |||
| C1r 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 anafil-toxins) | ||||||
| Clq-I | ||||||
| M-Clq-I | 1-2 | |||||
| Protectin (CD 59) | + | 1,8-20 |
* - in 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 epitheliocytes.
Complement components are presented in the form of: proenzymes (esterases, proteinases), protein molecules that do not have enzymatic activity, and in the form of 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 complement enzymes C5-C9, the so-called membrane attack complex (MAC), which, integrating into the membrane of animal and microbial cells, forms a transmembrane pore, which leads to overhydration of the cell and its death. (Fig. 3-2, 3-3).
Rice. 3-2. Graphical model of complement activation.
Rice. 3-3. The structure of the activated complement.
There are 3 ways to activate the complement system:
First way - classical. (Figure 3-4).
Rice. 3-4. Mechanism of the classical pathway of complement activation.
E - erythrocyte or other cell. A is an antibody.
With this method, the activation of lytic enzymes MAA C5-C9 is carried out through the 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 in the classical pathway are antigen-antibody complexes formed by immunoglobulins of classes G or M.
The second way - bypass, alternative (Fig. 3-6).
Rice. 3-6. Mechanism of the alternative pathway of complement activation.
This complement activation mechanism is triggered by viruses, bacteria, aggregated immunoglobulins, and proteolytic enzymes.
With this method, the activation of lytic enzymes MAC C5-C9 begins with the activation of the C3 component. The first three complement components C1, C4, C2 do not participate in this mechanism of complement activation, but factors B and D additionally participate in the activation of C3.
third way is a non-specific activation of the complement system by proteinases. Such activators can be: trypsin, plasmin, kallikrein, lysosomal proteases and bacterial enzymes. Activation of the complement system in this way can occur at any interval 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 transplant 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 the release of hydrolytic enzymes from them;
7) through the release of biologically active substances and an increase in 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 for 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. Activation of properdin occurs after its combination with factor B on the cell surface.
Activated properdin contributes to:
1) complement activation;
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) the formation of an inflammatory response.
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 complement activation via an alternative pathway.
V-lysines. Blood proteins of various molecular weights with bactericidal properties. The bactericidal action of B-lysine is shown both in the presence and in the absence of complement and antibodies.
Interferon. A complex of protein molecules capable of preventing and suppressing 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 (fibroblast), 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 as follows: interferon, binding to specific receptors of uninfected cells, causes biochemical and genetic changes in them, leading to a decrease in mRNA translation in cells and activation of latent endonucleases, which, turning into an active form, are capable of causing mRNA degradation like a virus. as well as the cell itself. This causes the cells to become insensitive to viral infection, creating a barrier around the site of infection.
The resistance of an organism is understood as its resistance to various pathogenic influences (from Latin resisteo - resistance). The body's resistance to adverse effects is determined by many factors, many barrier devices that prevent the negative effects of mechanical, physical, chemical and biological factors.
Cellular non-specific protective factors
Among the cellular non-specific protective factors include the protective function of the skin, mucous membranes, bone tissue, local inflammatory processes, the ability of the thermoregulation center to change body temperature, the ability of body cells to produce interferon, cells of the mononuclear phagocyte system.
The skin has barrier properties due to the multilayered epithelium and its derivatives (hair, feathers, hooves, horns), the presence of receptor formations, cells of the macrophage system, and the secretion secreted by the glandular apparatus.
Intact skin of healthy animals resists mechanical, physical, chemical factors. It represents an insurmountable barrier to the penetration of most pathogenic microbes, prevents the penetration of pathogens, not only mechanically. It has the ability to self-purify by constantly desquamating the surface layer, secreting secrets from the sweat and sebaceous glands. In addition, the skin has bactericidal properties against many microorganisms in the sweat and sebaceous glands. In addition, the skin has bactericidal properties against many microorganisms. Its surface is an environment unfavorable for the development of viruses, bacteria, fungi. This is due to the acidic reaction created by the secretions of the sebaceous and sweat glands (pH - 4.6) on the surface of the skin. The lower the pH, the higher the bactericidal activity. Skin saprophytes are of great importance. The species composition of the permanent microflora consists of epidermal staphylococci up to 90%, some other bacteria and fungi. Saprophytes are able to secrete substances that have a detrimental effect on pathogenic pathogens. According to the species composition of the microflora, one can judge the degree of resistance of the organism, the level of resistance.
The skin contains cells of the macrophage system (Langerhans cells) capable of transmitting information about antigens to T-lymphocytes.
The barrier properties of the skin depend on the general condition of the body, determined by proper nutrition, care for integumentary tissues, the nature of maintenance, and exploitation. It is known that emaciated calves are more easily infected with microsporia, trichophytosis.
The mucous membranes of the oral cavity, esophagus, gastrointestinal tract, respiratory and urogenital tracts, covered with epithelium, represent a barrier, an obstacle to the penetration of various harmful factors. Intact mucosa is a mechanical obstacle to some chemical and infectious foci. Due to the presence of cilia of the ciliated epithelium from the surface of the respiratory tract, foreign bodies and microorganisms that enter with inhaled air are released into the external environment.
When mucous membranes are irritated by chemical compounds, foreign objects, waste products of microorganisms, protective reactions occur in the form of sneezing, coughing, vomiting, diarrhea, which helps to remove harmful factors.
Damage to the mucous membrane of the oral cavity is prevented by increased salivation, damage to the conjunctiva is prevented by abundant separation of lacrimal fluid, damage to the nasal mucosa is prevented by serous exudate. The secrets of the glands of the mucous membranes have bactericidal properties due to the presence of lysozyme in them. Lysozyme is able to lyse staphylo- and streptococci, salmonella, tuberculosis and many other microorganisms. Due to the presence of hydrochloric acid, gastric juice inhibits the reproduction of microflora. The protective role is played by microorganisms that inhabit the mucous membrane of the intestines, urinary organs of healthy animals. Microorganisms take part in the processing of fiber (infusoria of the proventriculus of ruminants), the synthesis of protein, vitamins. The main representative of the normal microflora in the large intestine is E. coli (Escherichia coli). It ferments glucose, lactose, creates unfavorable conditions for the development of putrefactive microflora. Reducing the resistance of animals, especially in young animals, turns E. coli into a pathogenic agent. The protection of the mucous membranes is carried out by macrophages, which prevent the penetration of foreign antigens. Secretory immunoglobulins are concentrated on the surface of the mucous membranes, the basis of which is class A immunoglobulins.
Bone tissue performs a variety of protective functions. One of them is the protection of the central nervous formations from mechanical damage. The vertebrae protect the spinal cord from injury, and the bones of the skull protect the brain and integumentary structures. Ribs, sternum perform a protective function in relation to the lungs and heart. Long tubular bones protect the main hematopoietic organ - the red bone marrow.
Local inflammatory processes, first of all, tend to prevent the spread, generalization of the pathological process. A protective barrier begins to form around the focus of inflammation. Initially, it is due to the accumulation of exudate - a fluid rich in proteins that adsorb toxic products. Subsequently, a demarcation shaft of connective tissue elements is formed on the border between healthy and damaged tissues.
The ability of the thermoregulatory center to change body temperature is essential for combating microorganisms. High body temperature stimulates metabolic processes, the functional activity of the cells of the reticulomacrophage system, leukocytes. Young forms of white blood cells appear - young and stab neutrophils, rich in enzymes, which increases their phagocytic activity. Leukocytes in increased quantities begin to produce immunoglobulins, lysozyme.
Microorganisms at high temperatures lose their resistance to antibiotics and other drugs, and this creates conditions for effective treatment. Natural resistance in moderate fevers increases due to endogenous pyrogens. They stimulate the immune, endocrine, nervous systems that determine the body's resistance. At present, purified bacterial pyrogens are used in veterinary clinics, which stimulate the body's natural resistance and reduce the resistance of pathogenic microflora to antibacterial drugs.
The central link of cellular defense factors is the system of mononuclear phagocytes. These cells include blood monocytes, connective tissue histiocytes, Kupffer cells of the liver, pulmonary, pleural and peritoneal macrophages, free and fixed macrophages, free and fixed macrophages of lymph nodes, spleen, red bone marrow, macrophages of the synovial membranes of the joints, osteoclasts of bone tissue, microglial cells nervous system, epithelioid and giant cells of inflammatory foci, endothelial cells. Macrophages carry out bactericidal activity due to phagocytosis, and they are also able to secrete a large amount of biologically active substances that have cytotoxic properties against microorganisms and tumor cells.
Phagocytosis is the ability of certain cells of the body to absorb and digest foreign substances (substances). Cells that resist pathogens, freeing the body from its own, genetically alien cells, their fragments, foreign bodies, were named by I.I. Mechnikov (1829) phagocytes (from Greek phaqos - to devour, cytos - cell). All phagocytes are divided into microphages and macrophages. Microphages include neutrophils and eosinophils, macrophages - all cells of the mononuclear phagocyte system.
The process of phagocytosis is complex, multi-layered. It begins with the approach of the phagocyte to the pathogen, then adherence of the microorganism to the surface of the phagocytic cell is observed, further absorption with the formation of a phagosome, intracellular association of the phagosome with the lysosome, and, finally, digestion of the object of phagocytosis by lysosomal enzymes. However, cells do not always interact in this way. Due to the enzymatic deficiency of lysosomal proteases, phagocytosis may be incomplete (incomplete), i.e. proceeds only three stages and microorganisms can remain in the phagocyte in a latent state. Under unfavorable conditions for the macroorganism, bacteria become capable of reproduction and, destroying the phagocytic cell, cause infection.
Humoral non-specific protective factors
Complement, lysozyme, interferon, properdin, C-reactive protein, normal antibodies, bactericidin are among the humoral factors that provide resistance to the organism.
Complement is a complex multifunctional system of blood serum proteins that is involved in such reactions as opsonization, stimulation of phagocytosis, cytolysis, neutralization of viruses, and induction of an immune response. There are 9 known complement fractions, designated C 1 - C 9, which are in the blood serum in an inactive state. Complement activation occurs under the action of the antigen-antibody complex and begins with the addition of C 1 1 to this complex. This requires the presence of Ca and Mq salts. The bactericidal activity of complement is manifested from the earliest stages of fetal life, however, during the neonatal period, complement activity is the lowest compared to other age periods.
Lysozyme is an enzyme from the group of glycosidases. Lysozyme was first described by Fletting in 1922. It is secreted constantly and is found in all organs and tissues. In animals, lysozyme is found in the blood, lacrimal fluid, saliva, nasal mucous membrane secretions, gastric and duodenal juice, milk, amniotic fluid of fetuses. Leukocytes are especially rich in lysozyme. The ability to lysozymalize microorganisms is extremely high. It does not lose this property even at a dilution of 1:1000000. Initially, it was believed that lysozyme is active only against gram-positive microorganisms, but it has now been established that, with respect to gram-negative bacteria, it acts cytolytically together with complement, penetrating through the bacterial cell wall damaged by it to the objects of hydrolysis.
Properdin (from lat. perdere - to destroy) is a globulin-type blood serum protein with bactericidal properties. In the presence of a compliment and magnesium ions, it exhibits a bactericidal effect against gram-positive and gram-negative microorganisms, and is also able to inactivate influenza and herpes viruses, and exhibits bactericidal activity against many pathogenic and opportunistic microorganisms. The level of properdin in the blood of animals reflects the state of their resistance, sensitivity to infectious diseases. A decrease in its content was revealed in irradiated animals with tuberculosis, with streptococcal infection.
C-reactive protein - like immunoglobulins, has the ability to initiate reactions of precipitation, agglutination, phagocytosis, complement fixation. In addition, C-reactive protein increases the mobility of leukocytes, which gives reason to talk about its participation in the formation of nonspecific resistance of the body.
C-reactive protein is found in the blood serum during acute inflammatory processes, and it can serve as indicators of the activity of these processes. This protein is not detected in normal blood serum. It does not pass through the placenta.
Normal antibodies are almost always present in the blood serum and are constantly involved in nonspecific protection. Formed in the body as a normal component of serum as a result of contact of the animal with a very large number of various environmental microorganisms or some dietary proteins.
Bactericidin is an enzyme that, unlike lysozyme, acts on intracellular substances.
Non-specific factors natural resistance protect the body from microbes at the first meeting with them. These same factors are also involved in the formation of acquired immunity.
Areactivity of cells is the most persistent factor of natural protection. In the absence of cells sensitive to this microbe, toxin, virus, the body is completely protected from them. For example, rats are insensitive to diphtheria toxin.
Skin and mucous membranes represent a mechanical barrier to most pathogenic microbes. In addition, secretions from sweat and sebaceous glands containing lactic and fatty acids have a detrimental effect on microbes. Clean skin has stronger bactericidal properties. Desquamation of the epithelium contributes to the removal of microbes from the skin.
In the secretions of the mucous membranes contains lysozyme (lysozyme) - an enzyme that lyses the cell wall of bacteria, mainly gram-positive. Lysozyme is found in saliva, conjunctival secretion, blood, macrophages, and intestinal mucus. Opened for the first time by P.N. Lashchenkov in 1909 in the protein of a chicken egg.
Epithelium of the mucous membranes of the respiratory tract is an obstacle to the penetration of pathogenic microbes into the body. Dust particles and liquid droplets are thrown out with mucus secreted from the nose. From the bronchi and trachea, the particles that have got here are removed by the movement of the cilia of the epithelium, directed outward. This function of the ciliated epithelium is usually impaired in heavy smokers. A few dust particles and microbes that have reached the lung alveoli are captured by phagocytes and rendered harmless.
The secret of the digestive glands. Gastric juice has a detrimental effect on microbes that come with water and food, due to the presence of hydrochloric acid and enzymes. Reduced acidity of gastric juice helps to weaken resistance to intestinal infections such as cholera, typhoid fever, dysentery. Bile and enzymes of intestinal contents also have a bactericidal effect.
The lymph nodes. Microbes that have penetrated the skin and mucous membranes are retained in the regional lymph nodes. Here they undergo phagocytosis. The lymph nodes also contain the so-called normal (natural) killer-lymphocytes (English, killer - killer), carrying the function of antitumor surveillance - the destruction of the body's own cells, altered due to mutations, as well as cells containing viruses. Unlike immune lymphocytes, which are formed as a result of an immune response, natural killer cells recognize foreign agents without prior contact with them.
Inflammation (vascular-cellular reaction) is one of the phylogenetically ancient protective reactions. In response to the penetration of microbes, a local inflammatory focus is formed as a result of complex changes in the microcirculation, blood system and connective tissue cells. The inflammatory response promotes the removal of microbes or delays their development and therefore plays a protective role. But in some cases, when the agent that caused the inflammation is re-entered, it can take on the character of a damaging reaction.
Humoral protective factors . In the blood, lymph and other body fluids (Latin humor - liquid) there are substances that have antimicrobial activity. The humoral factors of nonspecific protection include: complement, lysozyme, beta-lysins, leukins, antiviral inhibitors, normal antibodies, interferons.
Complement - the most important humoral protective factor of the blood, is a complex of proteins, which are designated as C1, C2, C3, C4, C5, ... C9. Produced by liver cells, macrophages and neutrophils. In the body, complement is in an inactive state. When activated, proteins acquire the properties of enzymes.
Lysozyme It is produced by blood monocytes and tissue macrophages, has a lysing effect on bacteria, and is thermostable.
Beta Lysine secreted by platelets, has bactericidal properties, thermostable.
Normal antibodies contained in the blood, their occurrence is not associated with the disease, they have an antimicrobial effect, promote phagocytosis.
Interferon - a protein produced by cells in the body, as well as cell cultures. Interferon inhibits the development of the virus in the cell. The phenomenon of interference is that in a cell infected with one virus, a protein is produced that inhibits the development of other viruses. Hence the name - interference (lat. inter - between + ferens - transferring). Interferon was discovered by A. Isaac and J. Lindenman in 1957.
The protective effect of interferon turned out to be non-specific in relation to the virus, since the same interferon protects cells from different viruses. But it has species specificity. Therefore, the interferon that is formed by human cells acts in the human body.
Later it was found that the synthesis of interferon in cells can be induced not only by live viruses, but also by killed viruses and bacteria. Interferon inducers can be some drugs.
Currently, several interferons are known. They not only prevent the reproduction of the virus in the cell, but also retard the growth of tumors and have an immunomodulatory effect, that is, they normalize immunity.
Interferons are divided into three classes: alpha interferon (leukocyte), beta interferon (fibroblast), gamma interferon (immune).
Leukocyte a-interferon is produced in the body mainly by macrophages and B-lymphocytes. Donor alpha-interferon preparation is obtained in cultures of donor leukocytes exposed to an interferon inducer. It is used as an antiviral agent.
Fibroblast beta-interferon in the body is produced by fibroblasts and epithelial cells. The preparation of beta-interferon is obtained in cultures of human diploid cells. It has antiviral and antitumor activity.
Immune gamma-interferon in the body is produced mainly by T-lymphocytes stimulated by mitogens. The preparation of gamma-interferon is obtained in a culture of lymphoblasts. It has an immunostimulating effect: it enhances phagocytosis and the activity of natural killers (NK cells).
The production of interferon in the body plays a role in the process of recovery of a patient with an infectious disease. With influenza, for example, the production of interferon increases in the first days of the disease, while the titer of specific antibodies reaches a maximum only by the 3rd week.
The ability of people to produce interferon is expressed to varying degrees. "Interferon status" (IFN-status) characterizes the state of the interferon system:
2) the ability of leukocytes obtained from the patient to produce interferon in response to the action of inductors.
In medical practice, alpha, beta, gamma interferons of natural origin are used. Recombinant (genetically engineered) interferons have also been obtained: reaferon and others.
Effective in the treatment of many diseases is the use of inductors that promote the production of endogenous interferon in the body.
II Mechnikov and his doctrine of immunity to infectious diseases. Phagocytic theory of immunity. Phagocytosis: phagocytic cells, stages of phagocytosis and their characteristics. Indicators for characterizing phagocytosis.
Phagocytosis - the process of active absorption by the cells of the body of microbes and other foreign particles (Greek phagos - devouring + kytos - cell), including the body's own dead cells. I.I. Mechnikov - author phagocytic theory of immunity - showed that the phenomenon of phagocytosis is a manifestation of intracellular digestion, which in lower animals, for example, in amoebas, is a way of feeding, and in higher organisms phagocytosis is a defense mechanism. Phagocytes free the body from microbes, and also destroy the old cells of their own body.
According to Mechnikov, everything phagocytic cells subdivided into macrophages and microphages. Microphages include polymorphonuclear blood granulocytes: neutrophils, basophils, eosinophils. Macrophages are blood monocytes (free macrophages) and macrophages of various body tissues (fixed) - liver, lungs, connective tissue.
Microphages and macrophages originate from a single precursor, the bone marrow stem cell. Blood granulocytes are mature short-lived cells. Peripheral blood monocytes are immature cells and, leaving the bloodstream, enter the liver, spleen, lungs and other organs, where they mature into tissue macrophages.
Phagocytes perform a variety of functions. They absorb and destroy foreign agents: microbes, viruses, dying cells of the body itself, products of tissue decay. Macrophages take part in the formation of the immune response, firstly, by presenting (presenting) antigenic determinants (epitopes on their membranes) and, secondly, by producing biologically active substances - interleukins, which are necessary to regulate the immune response.
AT the process of phagocytosis distinguish several stages :
1) the approach and attachment of a phagocyte to a microbe is carried out due to chemotaxis - the movement of a phagocyte in the direction of a foreign object. Movement is observed due to a decrease in the surface tension of the phagocyte cell membrane and the formation of pseudopodia. Attachment of phagocytes to the microbe occurs due to the presence of receptors on their surface,
2) absorption of the microbe (endocytosis). The cell membrane flexes, an invagination is formed, as a result, a phagosome is formed - a phagocytic vacuole. This process is cross-linked with the participation of complement and specific antibodies. For phagocytosis of microbes with antiphagocytic activity, the participation of these factors is necessary;
3) intracellular inactivation of the microbe. The phagosome merges with the lysosome of the cell, a phagolysosome is formed, in which bactericidal substances and enzymes accumulate, as a result of which the death of the microbe will occur;
4) digestion of the microbe and other phagocytosed particles occurs in phagolysosomes.
Phagocytosis, which leads to microbial inactivation , that is, it includes all four stages, is called complete. Incomplete phagocytosis does not lead to the death and digestion of microbes. Microbes captured by phagocytes survive and even multiply inside the cell (for example, gonococci).
In the presence of acquired immunity to a given microbe, opsonin antibodies specifically enhance phagocytosis. Such phagocytosis is called immune. In relation to pathogenic bacteria with antiphagocytic activity, for example, staphylococci, phagocytosis is possible only after opsonization.
The function of macrophages is not limited to phagocytosis. Macrophages produce lysozyme, complement protein fractions, participate in the formation of the immune response: interact with T- and B-lymphocytes, produce interleukins that regulate the immune response. In the process of phagocytosis, particles and substances of the organism itself, such as dying cells and tissue decay products, are completely digested by macrophages, that is, to amino acids, monosaccharides and other compounds. Foreign agents such as microbes and viruses cannot be completely destroyed by macrophage enzymes. The foreign part of the microbe (determinant group - epitope) remains undigested, is transferred to T- and B-lymphocytes, and thus the formation of an immune response begins. Macrophages produce interleukins that regulate the immune response.
Humoral factors of nonspecific protection
The main humoral factors of nonspecific defense of the body include lysozyme, interferon, the complement system, properdin, lysines, lactoferrin.
Lysozyme refers to lysosomal enzymes, is found in tears, saliva, nasal mucus, secretion of mucous membranes, blood serum. It has the ability to lyse live and dead microorganisms.
Interferons are proteins that have antiviral, antitumor, 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, form a membrane attack complex, followed by an 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 a foreign invading microorganism.
Properdin takes part in the destruction of microbial cells, neutralization of viruses and plays a significant role in non-specific complement activation.
Lysines are blood serum proteins that have the ability to lyse some bacteria.
Lactoferrin is a local immunity factor that protects epithelial integuments from microbes.
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