Dynamics of production of various types of immunoglobulins. Physiological immunodeficiencies
The ability to form antibodies appears in the prenatal period in a 20-week embryo; After birth, the body’s own production of immunoglobulins begins, which increases until adulthood and decreases somewhat in old age. The dynamics of antibody formation vary depending on the strength of the antigenic effect (dose of the antigen), the frequency of exposure to the antigen, the state of the body and its immune system. During the initial and repeated administration of an antigen, the dynamics of antibody formation are also different and occur in several stages. There are latent, logarithmic, stationary and decreasing phases.
In the latent phase The antigen is processed and presented to immunocompetent cells, a clone of cells specialized for the production of antibodies to this antigen is multiplied, and antibody synthesis begins. During this period, antibodies are not detected in the blood.
During the logarithmic phase synthesized antibodies are released from plasma cells and enter the lymph and blood.
In stationary phase the number of antibodies reaches a maximum and stabilizes, then comes decline phase antibody level. During the initial administration of an antigen (primary immune response), the latent phase is 3-5 days, the logarithmic phase is 7-15 days, the stationary phase is 15-30 days, and the decline phase is 1-6 months or more. A feature of the primary immune response is that IgM is initially synthesized, and then IgG.
In contrast to the primary immune response, with the secondary introduction of an antigen (secondary immune response), the latent period is shortened to several hours or 1-2 days, the logarithmic phase is characterized by a rapid increase and a significantly higher level of antibodies, which in subsequent phases is retained for a long time and slowly, sometimes has been declining for several years. In a secondary immune response, unlike the primary one, mainly IgG is synthesized.
This difference in the dynamics of antibody formation during the primary and secondary immune response is explained by the fact that after the initial introduction of an antigen, a clone of lymphocytes is formed in the immune system, bearing the immunological memory of this antigen. After a second encounter with the same antigen, a clone of lymphocytes with immunological memory quickly multiplies and intensively turns on the process of antibody genesis.
Very fast and energetic antibody formation upon repeated encounter with an antigen is used for practical purposes when it is necessary to obtain high titers of antibodies in the production of diagnostic and therapeutic sera from immunized animals, as well as for the emergency creation of immunity during vaccination
Answer: Immunoglobulins:
Immunoglobulins are proteins that are synthesized under the influence of an antigen and react specifically with it. During electrophoresis they are localized in globulin fractions.
Immunoglobulins consist of polypeptide chains. There are four structures in the immunoglobulin molecule:
Primary is the sequence of certain amino acids. It is built from nucleotide triplets, is genetically determined and determines the main subsequent structural features.
The secondary one is determined by the conformation of polypeptide chains.
Tertiary determines the nature of the location of individual sections of the chain that create a spatial picture.
Quaternary is characteristic of immunoglobulins. A biologically active complex arises from four polypeptide chains. The chains in pairs have the same structure.
Any immunoglobulin molecule is Y-shaped and consists of 2 heavy (H) and 2 light (L) chains linked by disulfide bridges. Each Ig molecule has 2 identical antigen-binding fragments Fab (Fragment antigen binding) and one Fc fragment (Fragment cristalisable), with the help of which IGs complementarily bind to Fc receptors of the cell membrane.
The terminal sections of the light and heavy chains of the IG molecule are quite diverse (variable), and individual regions of these chains are particularly diverse (hypervariable). The remaining sections of the IG molecule are relatively low-lying (constant). Depending on the structure of the constant regions of the heavy chains, IGs are divided into classes (5 classes) and subtypes (8 subtypes). It is these constant regions of heavy chains, significantly different in amino acid composition among different classes of IGs, that ultimately determine the special properties of each class of antibodies:
lgM activate the complement system;
IgE binds to specific receptors on the surface of mast cells and basophils, releasing allergy mediators from these cells;
IgA is secreted into various body fluids, providing secretory immunity;
IgD functions primarily as membrane receptors for antigen;
IgG exhibits a variety of activities, including the ability to penetrate the placenta.
Immunoglobulin classes.
Immunoglobulins G, IgG
Immunoglobulins G are monomers that include 4 subclasses (IgGl - 77%; IgG2 - 11%; IgG3 - 9%; IgG4 - 3%), which differ from each other in amino acid composition and antigenic properties. Their content in blood serum ranges from 8 to 16.8 mg/ml. The half-life is 20-28 days, and 13 to 30 mg/kg is synthesized during the day. They account for 80% of the total content of ISIS. They protect the body from infections. Antibodies of the IgGl and IgG4 subclasses specifically bind through Fc fragments to the pathogen (immune opsonization), and thanks to Fc fragments they interact with Fc receptors of phagocytes (macrophages, polymorphonuclear leukocytes), thereby promoting phagocytosis of the pathogen. IgG4 is involved in allergic reactions and is not able to fix complement.
IgG class antibodies play a fundamental role in humoral immunity in infectious diseases, causing the death of the pathogen with the participation of complement and opsonizing phagocytic cells. They penetrate the placenta and form anti-infective immunity in newborns. They are able to neutralize bacterial exotoxins, fix complement, and participate in the precipitation reaction.
Immunoglobulins M, IgM
Immunoglobulins M are the “earliest” of all classes of IG, including 2 subclasses: IgMl (65%) and IgM2 (35%). Their concentration in blood serum ranges from 0.5 to 1.9 g/l or 6% of the total IG content. 3-17 mg/kg is synthesized per day, and their half-life is 4-8 days. They do not cross the placenta. IgM appears in the fetus and is involved in anti-infective defense. They are able to agglutinate bacteria, neutralize viruses, and activate complement. IgM play an important role in the elimination of the pathogen from the bloodstream and in the activation of phagocytosis. A significant increase in the concentration of IgM in the blood is observed in a number of infections (malaria, trypanosomiasis) in both adults and newborns. This is an indicator of intrauterine infection with the causative agent of rubella, syphilis, toxoplasmosis, and cytomegaly. IgM are antibodies formed in the early stages of the infectious process. They are highly active in the reactions of agglutination, lysis and binding of endotoxins of gram-negative bacteria.
Immunoglobulins A, IgA
Immunoglobulins A are secretory IGs, including 2 subclasses: IgAl (90%) and IgA2 (10%). The content of IgA in blood serum ranges from 1.4 to 4.2 g/l or 13% of the total amount of IgA; 3 to 50 mcg/kg is synthesized daily. The half-life of antibodies is 4-5 days. IgA is found in milk, colostrum, saliva, lacrimal, bronchial and gastrointestinal secretions, bile, and urine. IgA contains a secretory component consisting of several polypeptides, which increases the resistance of IgA to the action of enzymes. This is the main type of IG involved in local immunity. They prevent bacteria from attaching to the mucosa, neutralize enterotoxin, and activate phagocytosis and complement. IgA is not detectable in newborns. It appears in saliva in children aged 2 months, with the secretory component SC being the first to be detected. And only later the complete SigA molecule. Age 3 months Many authors define it as a critical period; this period is especially important for diagnosing congenital or transient deficiency of local immunity.
Immunoglobulins E, IgE
Immunoglobulins D, IgD
Immunoglobulins D are monomers; their content in the blood is 0.03-0.04 g/l or 1% of the total amount of IG; per day they are synthesized from 1 to 5 mg/kg, and the half-life ranges from 2-8 days. IgDs are involved in the development of local immunity, have antiviral activity, and in rare cases activate complement. Plasma cells secreting IgD are localized mainly in the tonsils and adenoid tissue. IgD is detected on B cells and is absent on monocytes, neutrophils and T lymphocytes. It is believed that IgD is involved in the differentiation of B cells, contributes to the development of an anti-idiotypic response, and is involved in autoimmune processes.
Table of contents of the topic "Humoral immune reactions. Main types of antibodies. Dynamics of antibody formation.":On the rate of antibody formation (AT) is influenced by a number of factors: the dose of Ag (the strength of the Ag effect), the frequency of Ag stimulation and the state of the individual’s immune system (that is, his immune status). If the body encounters Ag for the first time, a primary immune response develops, and upon repeated contact, a secondary response develops (Fig. 10-11).
Primary immune response
The appearance of antibodies(AT) is preceded by a latent period lasting 3~5 days. At this time, Ag recognition and the formation of plasma cell clones occurs. Then comes the logarithmic phase corresponding to the arrival antibodies(AT) into the blood; its duration is 7-15 days. Gradually credits antibodies (AT) reach a peak and a stationary phase begins, lasting 15-30 days. It is replaced by a phase of decreasing AT titers, lasting 1-6 months. The proliferation of AT producing cells is based on the principle of selection. In the dynamics of antibody formation, the titers of high-affinity AT gradually increase: after immunization, the affinity of AT to Ag constantly increases. Initially, IgM is formed, but gradually their formation decreases and the synthesis of IgG begins to predominate. Since the switching of syntheses from IgM to IgG does not change the AT idiotype (that is, its specificity in relation to a particular Ag), it is not associated with clonal selection. Features of the primary response are a low rate of antibody formation and the appearance of relatively low AT titers.
Rice. 10-11. Dynamics of antibody (AT) formation during primary and secondary immune responses. The abscissa axis is time (days), the ordinate axis is AT titer (dilution).Secondary immune response
After antigenic stimulation, some B and T lymphocytes circulate in the form of memory cells. Features of the secondary immune response - high rate of antibody formation, the appearance of maximum titers antibodies (AT) and long-term (sometimes multi-year) circulation.
Basic characteristics of the secondary immune response:
antibody formation(AT) is induced by significantly lower doses of Ag;
inductive phase reduced to 5-6 hours;
among antibodies(AT) IgG dominates with high affinity, the peak of their formation occurs earlier (3-5 days);
Antibodies(AT) are formed in higher titers and circulate in the body for a long time.
The composition of immunoglobulin G includes antibodies that play a leading role in protection against many viral (measles, smallpox, rabies, etc.) and bacterial infections caused mainly by gram-positive microorganisms, as well as against tetanus and malaria, anti-Rh hemolysins, antitoxins (diphtheria, staphylococcal and etc.). IgG antibodies have a destructive effect through complement, opsonization, activation of phagocytosis, and have virus-neutralizing properties. Immunoglobulin G subfractions and their ratios can not only be determined by the specificity of the antigenic stimulus (infection), but also be evidence of incomplete immunological competence. Thus, a deficiency of immunoglobulin G2 may be associated with a deficiency of immunoglobulin A, and an increase in the concentration of immunoglobulin G4 for many children reflects the likelihood of an atopic predisposition or atopy, but of a different type than the classic one, based on the production and reactions of immunoglobulin E.
Immunoglobulin M
Immunoglobulin M plays an important role in protecting the body from infections. It contains antibodies against gram-negative bacteria (Shigella, typhoid fever, etc.), viruses, as well as hemolysins of the ABO system, rheumatoid factor, and anti-organ antibodies. Antibodies belonging to the immunoglobulin M class have high agglutinating activity and are capable of activating complement through the classical pathway.
Immunoglobulin A
The role and significance of serum immunoglobulin A is still not well understood. It is not involved in the activation of complement or in the lysis of bacteria and cells (for example, red blood cells). At the same time, it is substantiated that serum immunoglobulin A is the main source for the synthesis of secretory immunoglobulin A. The latter is formed by lymphoid cells of the mucous membranes of the digestive and respiratory systems and, thus, participates in the local immune system, preventing the invasion of pathogens ( viruses, bacteria, etc.) into the body. This is the so-called first line of defense of the body against infection.
Immunoglobulin D
Little is known about the function of antibodies related to immunoglobulin D. Immunoglobulin D is found in the tissue of the tonsils and adenoids, which suggests its role in local immunity. Immunoglobulin D is located on the surface of the B lymphocyte (together with monomeric IgM) in the form of mIg, controlling its activation and suppression. It has also been established that immunoglobulin D activates alternative complement and has antiviral activity. In recent years, interest in immunoglobulin D has been increasing due to the description of an acute febrile illness similar to rheumatic fever (enlarged lymph nodes, polyserositis, arthralgia and myalgia) in combination with hyperimmunoglobulinemia D.
Immunoglobulin E
Immunoglobulin E, or reagins, is associated with the idea of immediate allergic reactions. The main method for recognizing specific sensitization to a wide variety of allergens is the study of total or total immunoglobulin E in blood serum, as well as titers of immunoglobulin E antibodies in relation to specific household allergens, nutrients, pollen, etc. Immunoglobulin E also activates macrophages and eosinophils , which may enhance phagocytosis or microphage (neutrophil) activity.
In the postnatal period, very significant dynamics are observed in the content of immunoglobulins of different classes in the blood of children. It is due to the fact that during the first months of life, the decay and removal of those class B immunoglobulins that were transferred transplacentally from the mother continues. At the same time, there is an increase in the concentrations of immunoglobulins of all classes, already produced in-house. During the first 4-6 months, maternal immunoglobulins are completely destroyed and the synthesis of one’s own immunoglobulins begins. It is noteworthy that B lymphocytes synthesize predominantly immunoglobulin M, the content of which reaches the levels characteristic of adults more quickly than other classes of immunoglobulins. The synthesis of your own immunoglobulin occurs more slowly.
As stated, at birth the child does not have secretory immunoglobulins. Their traces begin to be detected from the end of the first week of life. Their concentration gradually increases, and the content of secretory immunoglobulin A reaches its maximum values only by 10-12 years.
Immunoglobulin E in blood serum, kE/l
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Age of children |
Healthy children |
In adults with illnesses |
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Maximum |
Maximum |
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Newborns |
Allergic rhinitis |
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Atopic asthma |
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Atopic dermatitis |
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Bronchopulmonary aspergillosis: |
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remission |
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Adults |
exacerbation |
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Hyper-IgE syndrome |
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IgE myeloma |
More than 15,000 |
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Serum immunoglobulins in children, g/l
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Immunoglobulin G |
Immunoglobulin A |
Immunoglobulin M |
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Maximum |
Maximum |
Maximum |
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Low levels of secretory immunoglobulin A are found in children of the first year of life in the secretions of the small and large intestines, as well as in feces. In nasal lavages of children in the first month of life, secretory immunoglobulin A is absent and increases very slowly in subsequent months (up to 2 years). This explains the milder incidence of respiratory infections in young children.
Immunoglobulin D in the blood serum of newborns has a concentration of 0.001 g/l. Then it increases after the 6th week of life and reaches values characteristic of adults by 5-10 years.
Such complex dynamics create changes in quantitative relationships in the blood serum, which cannot be ignored when assessing the results of diagnostic studies of the immune system, as well as in interpreting the characteristics of morbidity and immunological constitution in different age periods. The low content of immunoglobulins during the first year of life explains the slight susceptibility of children to various diseases (respiratory, digestive, pustular skin lesions). With an increase in contact between children in the second year of life, against the background of a relatively low level of immunoglobulins during this period, their incidence is particularly high compared to children of other periods of childhood.
Heterohemagglutinins, belonging to the class of immunoglobulins M, are detected by the 3rd month of life, then their content increases, but more noticeably at 2-2 1/2 years. In newborns, the content of staphylococcal antitoxin is equal to that of an adult, and then it decreases. Again, its significant increase is observed at 24-30 months of life. The dynamics of the concentration of staphylococcal antitoxin in the child’s blood suggests that its initially high level is due to its transplacental transmission from the mother. Its own synthesis occurs later, which explains the high frequency of pustular skin lesions (pyoderma) in young children. When suffering from intestinal infections (salmonellosis, coli-enteritis, dysentery), antibodies to their pathogens are rarely detected in children in the first 6 months of life; at the age of 6 to 12 months - only in 1/3 of patients, and in children in the second year of life - almost in 60%.
When suffering from acute respiratory infections (adenovirus, parainfluenza), seroconversion in children of one year of life is detected only in 1/3 of those who have had them, and in the second year - already in 60%. This once again confirms the peculiarities of the formation of the humoral component of immunity in young children. It is no coincidence that in many manuals on pediatrics and immunology, the described clinical and immunological syndrome or phenomenon receives the rights of a nosological form and is designated as “physiological transient hypoilshunoglobulinemia of young children.”
The passage of a limited amount of antigenic food material across the intestinal barrier is not in itself a pathological phenomenon. In healthy children of any age, as well as in adults, trace amounts of dietary proteins can enter the blood, causing the formation of specific antibodies. Almost all infants fed cow's milk develop precipitating antibodies. Feeding with cow's milk leads to an increase in the concentration of antibodies against milk proteins within 5 days after the introduction of the formula. The immune response is especially pronounced in children who received cow's milk from the neonatal period. Previous breastfeeding results in a lower level of antibodies and a slower increase in antibody levels. With age, especially after 1-3 years, parallel to the decrease in the permeability of the intestinal wall, a decrease in the concentration of antibodies to food proteins is determined. The possibility of food antigenemia in healthy children has been proven by direct isolation of food antigens found in the blood in free form or as part of an immune complex.
The formation of relative impermeability to macromolecules, the so-called intestinal block, in humans begins in utero and occurs very gradually. The younger the child, the higher the permeability of his intestines to food antigens.
A specific form of protection against the harmful effects of food antigens is the immune system of the gastrointestinal tract, consisting of cellular and secretory components. The main functional load is borne by dimeric immunoglobulin A (SIgA). The content of this immunoglobulin in saliva and digestive secretions is much higher than in serum. From 50 to 96% of it is synthesized locally. The main functions in relation to food antigens are to prevent the absorption of macromolecules from the gastrointestinal tract (immune exclusion) and regulate the penetration of food proteins through the epithelium of the mucous membrane into the internal environment of the body. Relatively small antigenic molecules penetrating the epithelial surface stimulate local synthesis of SIgA, which prevents subsequent entry of antigens by forming a complex on the membrane. However, the gastrointestinal tract of a newborn is deprived of this specific form of protection, and all of the above will not be fully realized very soon, as the SIgA synthesis system fully matures. In an infant, the period of minimally sufficient maturation can range from 6 months to 1 "/2 years or more. This will be the period for the formation of an “intestinal block.” Until this period, the system of local secretory protection and blocking of food antigens can be provided only and exclusively by colostrum and mother's milk. The final maturation of secretory immunity can occur after 10-12 years.
The biological meaning of a significant increase in the content of immunoglobulin A in colostrum immediately before birth lies in its specialized function of immune exclusion of antigens (infectious and food) on the mucous membranes.
The content of SIgA in colostrum is very high and reaches 16-22.7 mg/l. With the transition of colostrum milk to mature milk, the concentration of secretory immunoglobulins decreases significantly. The implementation of the protective functions of SIgA is facilitated by its pronounced resistance to the proteolytic action of enzymes, due to which SIgA retains its activity in all parts of the gastrointestinal tract, and in a breast-fed child, it is almost completely excreted unchanged in the feces.
The participation of SIgA in human milk in immune processes associated with food antigens has been proven by the discovery in human milk of immunoglobulin A antibodies against a number of food proteins: α-casein, β-casein, β-lactoglobulin from cow's milk.
In second place in the concentration of immunoglobulins is immunoglobulin G, and the relatively high content of immunoglobulin G4 is of particular interest. The ratio of the concentration of immunoglobulin G4 in colostrum to the content in blood plasma exceeds the ratio of the concentration of immunoglobulin G in colostrum to the content in blood plasma by more than 10 times. This fact, according to researchers, may indicate local production of immunoglobulin G4 or its selective transport from peripheral blood to the mammary glands. The role of colostrum immunoglobulin G4 is unclear, but its participation in the processes of interaction with food antigens is confirmed by the detection of specific immunoglobulin C4 antibodies against β-lactoglobulin, bovine serum albumin and α-gliadin in both plasma and colostrum. It has been suggested that immunoglobulin G4 enhances the antigenic activation of mast cells and basophils, leading to the release of mediators necessary for chemotaxis and phagocytosis.
Thus, the state of immunoglobulin synthesis not only determines the readiness of a young child for infections, but also turns out to be a causal mechanism for the penetration of a wide flow of allergenic substances through the intestinal barrier and the barrier of other mucous membranes. Together with other anatomical and physiological characteristics of young children, this forms a special and completely independent form of “transient atopic constitution, or diathesis of young children.” This diathesis can have very bright, primarily skin manifestations (eczema, allergic dermatosis) up to 2-3 years of age, with rapid subsequent remission of skin changes or complete recovery in subsequent years. In many children with a hereditary predisposition to atopy, increased permeability of the mucous membranes during the period of transient atopic diathesis contributes to the implementation of the hereditary predisposition and the formation of a long chain of persistent allergic diseases.
Thus, age-related physiological characteristics of immunity in young children determine a significant increase in their sensitivity to both infectious environmental factors and exposure to allergens. This determines many requirements for caring for children and preventing their diseases. This includes the need for special control over the risk of contact with infections, the advisability of individual or mini-group education, control over the quality of food products and their tolerance to the symptoms of allergic reactions. There is also a way out of the situation, developed by the millennia-long evolution of mammals - this is full breastfeeding of children. Colostrum and native human milk, containing a large amount of immunoglobulin A, macrophages and lymphocytes, seem to compensate for the immaturity of general and local immunity in children in the first months of life, allowing them to safely bypass the age of a critical or borderline state of the immune system.
The dynamics of antibody production in response to antigenic stimulation is determined to a large extent by the species affiliation of the individual, since it is genetically determined (Vershigora A.V., 1990). Nevertheless, general patterns of antibody formation have been discovered that are characteristic of various animal species and humans. The latter are as follows.
The intensity of antibody formation depends on the structural features of the antigen, the method of administration of the antigen and the route of its penetration into the body.
The production of antibodies depends on the state of the immunological reactivity of the body, determined, in turn, by the level of representativeness of the clone of lymphocytes that is capable of receiving a given antigen, the presence or absence of mutations of this clone that can affect the quantity and quality of synthesized immunoglobulins.
The nature of the immune response is, of course, determined by the functional activity of macrophage elements, including various populations of classical phagocytes with a less pronounced ability to present antigen in the reactions of the primary immune response, as well as antigen-presenting macrophages with slightly expressed phagocytic activity.
The intensity of antibody formation depends on the hormonal status and functional activity of the central nervous system. Excessive hormonal levels created by ACTH, glucocorticoids, as well as insulin deficiency can adversely affect the processes of antibody formation.
The strength of the immune response also depends on the general condition of the body, the duration of previous diseases of an infectious and non-infectious nature, the nature of the impact of stress stimuli, the state of the electrolyte balance of the body, the acid-base state, the degree of intensification of free radical oxidation of lipids in biological membranes.
It is well known that with the development of various typical pathological processes, nonspecific destabilization of the biological membranes of cells of various organs and tissues, swelling of mitochondria, ATP deficiency, suppression of all energy-dependent reactions in cells, including the synthesis of antibodies of various classes of immunoglobulins, occur.
It has been established that human immunization with protein antigens, viral antigens, and lipopolysaccharide antigens of enterobacteria stimulates the formation of antibodies predominantly of the IgG class, and in guinea pigs similar antigens mainly enhance the synthesis of antibodies of the IgM class. A relatively large number of antibodies are synthesized per molecule of the introduced antigen. Thus, for each molecule of diphtheria toxoid administered, over a million molecules of antitoxin are synthesized within 3 weeks.
For each antigen there are optimal doses for influencing the immune system. Small doses induce a weak response, extremely large doses can cause the development of immunological tolerance or have a toxic effect on the body.
During primary antigenic exposure, 4 phases of the immune response develop.
1st phase of antibody production
1st phase of antibody production (resting phase, lag phase, induction phase, or latent phase), that is, the period between the time the antigen enters the body and before the start of the exponential growth of antibodies (Yeger L., 1986; Ice- Vanov M.Yu., Kirichuk V.F., 1990).
The duration of this phase may vary depending on the nature of the antigen: from several minutes and hours to a month.
The essence of this phase is the development of the macrophage reaction, phagocytosis or endocytosis of the antigen by antigen-presenting or phagocytic macrophages, the formation of highly immunogenic antigen fractions in complex with MHC class I and II antigens, presentation of the antigen to B and T lymphocytes, cooperative interaction of macrophage cells - precise elements and antigen-sensitive subpopulations of T- and B-lymphocytes, the development of plasmatization of lymphoid tissue. As mentioned above, one of the features of lymphoid cells is the preservation in them of the unique chromosome-repairing enzyme of a hematopoietic stem cell - telomerase, which provides the possibility of repeated cyclic proliferation throughout life against the background of antigenic stimulation.
As is known, there are two mechanisms for activating resting B lymphocytes with their subsequent involvement in proliferation and differentiation.
For the main subpopulation of B2 lymphocytes differentiating in the bone marrow, inclusion in the immune response is ensured by their interaction with T-helpers restricted by the main histocarcinoma complex, as well as various cytokines - growth and proliferation factors.
The selected clone of B-lymphocytes enters the proliferation phase, which ensures an increase in the representation in the lymphoid tissue of the antigen-sensitive clone of B-lymphocytes, capable of further transformation.
The VI (CD5) subpopulation of lymphocytes, which leaves the bone marrow in the early period of embryonic development and differentiates outside the bone marrow, is capable of T-independent activation under the influence of a certain group of antigens - bacterial polysaccharides. In the process of plasmatization of the VI subpopulation of lymphocytes against the background of antigenic stimulation, class M immunoglobulins with wide cross-reactivity are formed.
2nd phase of antibody production
2nd phase of antibody production (logarithmic phase, log phase, productive phase). This phase is called the phase of exponential growth of antibodies. It takes a period of time from the appearance of antibodies to reaching their maximum amount in the blood, on average lasting from 2 to 4 days. In some cases, the duration of the phase increases to 15 days.
An exponential increase in the number of antibodies, doubling their titers, occurs initially every 2-4 hours, and then every 4-6 hours. However, the rate of antibody formation slows down by the end of the second or third day, remaining at a certain level for different periods of time.
3rd phase of antibody production
The 3rd phase of antibody production is the stabilization phase, or the stationary period, during which the antibody titer remains stably high. During this period, the transition of cells from the class of activated precursors to the class of antibody-forming cells stops.
The duration of the stabilization phase is largely determined by the structural features of allergen antigens. In some cases it continues for several days, weeks, months. Antibodies to some microbial antigens continue to be synthesized in fairly high titers for a number of years.
Regarding the significance of this stabilization phase, it should be noted that antibodies not only ensure the inactivation of bacterial, toxic, allergic pathogenic factors in various reactions of agglutination, precipitation, complement activation, and antibody-dependent cytolysis, but also act as autoregulators of immunopoiesis.
4th phase of decreased antibody production
The duration of this phase varies and depends on the preservation of the antigen in the tissues.
The dynamics of antibody formation described above occurs in the case of primary immunization. Repeated immunization several months later changes the dynamics of the immune response. The latent period and the period of increase in antibody titer become significantly shorter, the amount of antibodies reaches a maximum faster and remains at a high level longer, and the affinity of antibodies increases.
In the development of a secondary immune response, an important role is played by the increase in the level of immunological memory cells to a given antigen. With increasing duration of immunization, the specificity of antibodies to soluble antigens increases.
It should be noted that the formation of antigen-antibody complexes during multiple immunization increases the strength of the antigenic effect and the intensity of antibody formation.
As has been established over the past decades, the synthesis of immunoglobulins is a self-regulating process. Proof of this is the inhibitory effect on the production of antibodies of specific immunoglobulins introduced into the bloodstream, and the higher the affinity of the antibodies, the more intense their inhibitory effect on the processes of immunopoiesis. Antibodies can have an inhibitory effect on the synthesis of not only homologous, but also related immunoglobulins. The formation of antibodies can also be inhibited by large doses of nonspecific β-globulins.
Structure and functional significance of immunoglobulins.
Proteins belonging to the immunoglobulin family have the same structural principle: their molecules include light and heavy polypeptide chains (Dolgikh R.T., 1998).
According to the WHO nomenclature (1964), there are 5 classes of immunoglobulins: IgG, IgA, IgM, IgE, IgD. Each class of immunoglobulins is characterized by its own specific heavy H-chains, designated according to the class of immunoglobulins (m, g, a, d, e). It is the structural features of the H-chains that determine the belonging of an immunoglobulin to one class or another.
Immunoglobulins are formed by at least four polypeptide chains interconnected by disulfide bridges. Two of them are represented by heavy H-chains, and two by light L-chains. There are two types of light chains k and l, which can be found in immunoglobulins of each of the 5 classes. Immunoglobulins of classes G, D and E are monomers, while IgM is found mainly in the form of a pentamer, and IgA - in the form of a mono-, di- and tetramer. Polymerization of monomers in molecules of immunoglobulins of classes A and M is ensured by the presence of additional J-chains (Vershigora A.V., 1990; Royt A., 1991; Stefani D.F., Veltishchev Yu.E., 1996).
In both heavy and light chains, there is a variable V region, in which the sequence of amino acids is not constant, as well as a constant C region.
The variable regions of the light and heavy chains take part in the formation of the active center of antibodies and determine the specificity of the structure of the anti-determinant of antibodies, which ensures the binding of the antigen determinant.
One antibody molecule can have unambiguous light chains (k or l).
Antibodies of different specificities can be contained in any of the classes of immunoglobulins. In lymphoid tissue, in response to the action of the same antigen, the synthesis of polypeptide chains of various classes of immunoglobulins occurs simultaneously.
What is common in the structure of immunoglobulins of different classes is the presence of so-called Fab fragments (Fragment antigen binding), Fc fragment (Fragment crystalline) and Fd fragment (Fragment difficult).
The Fab fragment includes antigen-sensitive receptor groups capable of specifically binding antigen. The CD region (amino-terminal part of the heavy chain) and, possibly, a fragment of the variable part of the light chain also takes part in the formation of the Fab fragment.
The Fc fragment determines the nonspecific functions of antibodies: fixation of complement, the ability to pass through the placenta, fixation of immunoglobulins on cells.
Studying the structure of immunoglobulins is difficult due to their heterogeneity. The heterogeneity of immunoglobulins is due to the fact that immunoglobulin molecules are carriers of different sets of determinants. There are three main types of antibody heterogeneity: isotypy, allotypy, idiotypy.
Isotypic variants of antibodies are found in all individuals. These include subclasses of various types of immunoglobulins.
In the IgG class, 4 isotypes are known (IgG1, IgG2, IgG3, IgG4), in the classes IgA, IgM and IgD there are 2 isotypes, or subclasses.
The isotypic determinants of antibodies of one class and subclass in individuals of a given species are identical. Isotypic differences are determined by the amino acid sequence in the constant part of the heavy chains, as well as the number and position of disulfide bridges. Thus, IgG1 and IgG4 have four interchain disulfide bonds, two of which connect the H chains. The IgG2 molecule has six disulfide bridges, four of which link polypeptide chains.
Isotypic variants include k and l - types and subtypes of L-chains.
Variable regions of light chains of a certain type can be divided into subgroups. K-type L-chains have 4 subgroups, and l-type L-chains have 5 subgroups. Chains of different subgroups, in addition to differences in the primary structure, are characterized by variations in the sequence of twenty N-terminal amino acids.
For the variable part of the H chain, 4 subgroups are described.
Allotypic variants of immunoglobulins in humans and animals are genetically determined, their frequency varies among individuals of different species. Allotypes are allelic variants of polypeptide chains that arise through the process of mutation. The synthesis of allotypes is controlled by various gene alleles. There are six allotypes of rabbit globulins. Currently, many systems of allotypic markers of human immunoglobulins are known, located in the C-region of the L and H chains. The existence of some of these markers is due to the development of a point mutation and the replacement of only one amino acid in the polypeptide sequence. If a mutation affects the structure of a region specific to a certain class and subclass of immunoglobulins, an allotypic variant is formed.
Several allotype markers can be detected in the serum of one individual.
Idiotypic antibody differences essentially reflect antibody specificity. They are associated with variable regions of polypeptide chains, do not depend on the structural features of various classes of immunoglobulins, and are identical in different individuals if they have antibodies to the same antigen.
There are approximately as many idiotypic variants as there are antibodies of varying specificity. The belonging of an antibody to a certain idiotype of immunoglobulins determines the specificity of its interaction with the antigen. It is generally accepted that the presence of 5,000 to 10,000 different variants of antibody specificity is sufficient to associate any of the possible types of antigenic determinants with greater or lesser affinity. Currently, antigenic determinants of V regions are also commonly called idiotypes.
Affinity and avidity are the most important properties of antibodies of various classes of immunoglobulins, and affinity reflects the strength of the connection between the active center of antibodies and the determinant of the antigen, while avidity characterizes the degree of binding of the antigen to the antibody, determined by the affinity and number of active centers of the antibody.
A heterogeneous population of antibodies has a set of antideterminants of different affinities; therefore, when determining its avidity, we determine the average affinity. With equal affinity, the avidity of IgM can be greater than the avidity of IgG, since IgM functionally has five valencies, and IgG is divalent.
Genetics of antibody formation
As mentioned above, immunoglobulins of various classes and subclasses are represented by heavy and light polypeptide chains, each of which has variable and constant regions. It has now been established that the synthesis of the variable region is under the control of many V genes, the number of which is approximately 200.
In contrast, a limited number of C genes are known for the constant region in accordance with its insignificant variability (class, subclass, type, subtype).
At the initial stages of the formation of lymphoid tissue, V- and C- genes are located in DNA segments far apart from each other, and in the genome of maturing immunocompetent cells they are combined due to translocation in one sublocus that controls the synthesis of H- and L- chains.
The formation of a variety of antibodies is explained by the hypothesis of somatic hypermutability of V genes, which is unlikely, as well as by the hypotheses of genetic recombination of genes and recombination errors.
General characteristics of individual classes of immunoglobulins
Due to the characteristics of the physicochemical structure, antigenicity and biological functions, 5 main classes of immunoglobulins are distinguished (IgM, IgG, IgA, IgE, IgD).
It should be noted that antibodies of the same specificity may belong to different classes of immunoglobulins; at the same time, antibodies of different specificities may belong to the same class of immunoglobulins.
Immunoglobulins class M
Class M immunoglobulins are the earliest, both phylogenetically and ontogenetically. In the embryonic period and in newborns, mainly IgM is synthesized. IgM accounts for about 10% of the total amount of immunoglobulins, their average concentration in the serum of women is 1.1 g/l, in the serum of men - 0.9 g/l.
Antibodies of the IgM class are pentavalent and have a pronounced ability to agglutinate, precipitate and lyse antigens. Of all types of antibodies, IgM exhibit the greatest ability to bind complement. IgM are found predominantly in blood plasma and lymph, the rate of their biosynthesis is about 7 mg/day, and their half-life is 5.1 days. IgM does not cross the placenta. Detection of high concentrations of IgM in the fetus indicates an intrauterine infection.
Regarding the structural organization of IgM, it should be noted that IgM molecules have a MW of 900–000 with a sedimentation constant of 19S, and include 5 subunits connected by disulfide bonds between heavy chains. Each IgM subunit has a MW of 180–000 and a sedimentation constant of 7S, and is identical in structure to the IgG molecule.
By influencing the IgM molecule with pepsin, trypsin, chymotrypsin, papain, various fragments (Fab, Fd, Fc) can be obtained. IgM contains a J chain, which is involved in the polymerization of the molecule.
Depending on the ability to fix complement with the participation of the Fc fragment, IgM is divided into two subclasses: IgM1 and IgM2. IgM1 binds complement, IgM2 does not bind complement.
During an electrophoretic study, macroglobulins migrate in the zone of the -globulin fraction.
By the end of the 2nd year of a child’s life, the IgM content is 80% of its content in adults. The maximum concentration of IgM is observed at 8 years.
Immunoglobulins class G
IgG is the most studied class of immunoglobulins; they are found in the blood serum at the highest concentration compared to other immunoglobulins (on average 12.0 g/l), making up 70-75% of the total number of immunoglobulins.
The molecular weight of IgG is 150“000, the sedimentation constant is 7S.
Possessing two antigen-binding centers, IgG forms a network structure with polyvalent antigens, causing precipitation of soluble antigens, as well as agglutination and lysis of corpuscular and pathogenic agents.
There are 4 subclasses of IgG: IgG1, IgG2, IgG3, IgG4.
The subclasses IgG3, IgG1 and IgG2 have the maximum ability to activate complement through the classical pathway. The IgG4 subclass is capable of activating complement via the alternative pathway.
Antibodies belonging to the subclasses IgG1, IgG3, IgG4 freely penetrate the placenta; antibodies of the IgG2 subclass have a limited ability of transplacental transport.
IgG form the main line of specific immunological defense mechanisms against various pathogens. Antibodies of the IgG2 subclass are mainly produced against antigens of a polysaccharide nature; anti-Rh antibodies belong to IgG4.
IgG molecules diffuse freely from blood plasma into tissue fluid, where almost half (48.2%) of the IgG present in the body is located.
The rate of IgG biosynthesis is 32 mg/kg body weight per day, the half-life is 21-23 days. The exception is IgG3, for which the half-life is much shorter - 7-9 days.
The transplacental transfer of IgG is ensured by a special grouping of the Fc fragment. Antibodies passing through the placenta from mother to child are essential for protecting the child’s body from a number of microbes and toxins: pathogens of diphtheria, tetanus, polio, measles. By the end of the first year of a child’s life, the blood contains 50-60% of the IgG content of an adult, and by the end of the 2nd year - about 80% of that in adults.
Deficiency of IgG2 and IgG4 in the first years of life determines the child’s high sensitivity to the pathogenic effects of pneumococci, meningococci and other pathogens.
Immunoglobulins class A
In accordance with the structural features, three types of class A immunoglobulins are distinguished:
serum IgA, which has a monomeric structure and makes up 86% of all IgA contained in serum;
serum dimeric IgA;
secretory IgA, which is a polymer, most often a dimer, is characterized by the presence of an additional secretory component that is absent in serum IgA.
IgA is not detected in the secretions of newborns; they appear in saliva in children aged 2 months. The content of secretory IgA in saliva reaches its level in an adult by the age of 8 years. By the end of the child's first year of life, the blood contains approximately 30% IgA. The plasma level of IgA reaches that in adults by 10-12 years. Class A immunoglobulins make up about 20% of the total number of immunoglobulins.
Normally, in blood serum the IgG/IgA ratio is 5-6, and in secreted biological fluids (saliva, intestinal juice, milk) it decreases to 1 or less. IgA is contained in amounts up to 30 mg per 100 ml of secretion.
In terms of physicochemical properties, IgA is heterogeneous and can occur in the form of monomers, dimers and tetramers with sedimentation constants of 7, 9, 11, 13. In blood serum, IgA is presented predominantly in the monomeric form; Serum IgA is synthesized in the spleen, lymph nodes and mucous membranes.
The biological function of IgA is mainly to locally protect the mucous membranes from infection. Antigens that have penetrated under the epithelium are met by dimeric IgA molecules. The complexes formed in this case are actively transported to the surface of the mucous membranes after their connection with the transport fragment in the epithelial membranes.
It has been suggested that it is possible to activate complement with the participation of IgA in an alternative way and, thus, ensure the processes of opsonization and lysis of bacteria with the participation of IgA.
It is also known that secretory IgA prevents the adhesion of bacteria to epithelial cells, thereby making it difficult for bacteria to colonize mucous membranes.
In addition to secretory IgA, IgM and IgG contained in human secretions are of significant importance, and IgM can be actively secreted due to the presence of a secretory component and play an important role in ensuring local immunity in the digestive tract. IgG can penetrate secretions only passively.
The system of secretory immunoglobulins provides an intense but short-lived immune response and does not form immunological memory cells, prevents the contact of antigens with plasma IgG and IgM, subsequent activation of complement and cytolytic destruction of one’s own tissues.
Immunoglobulins class D
Immunoglobulins class D make up about 2% of the total amount of immunoglobulins in the blood. Their concentration in serum reaches 30 mg/l, MW is, according to various authors, from 160“000 to 180“000; sedimentation constants range from 6.14 to 7.04 S. IgD does not fix complement, does not pass through the placenta and is not bound by tissues. 75% of IgD is contained in blood plasma, the half-life is 2.8 days, the biosynthesis rate is 0.4 mg/kg per day. The biological function of IgD is unclear; at certain stages of B-lymphocyte differentiation, IgD acts as a receptor. The concentration of IgD almost doubles during pregnancy, and also increases in some chronic inflammatory processes.
Immunoglobulins class E
The concentration of IgE in plasma is 0.25 mg/l, the percentage of the total amount of immunoglobulins is 0.003%, the half-life is 2.3 - 2.5 days; biosynthesis rate - 0.02 mg/kg body weight per day.
IgE does not fix complement, does not pass through the placenta, is thermolabile, quickly and firmly binds to allogeneic tissues, and does not precipitate antigens. In allergic diseases, the concentration of IgE increases sharply and reaches an average of 1.6 mg/l.
Plasma cells that synthesize IgE are found mainly in the mucous membranes of the bronchi and bronchioles, gastrointestinal tract, bladder, tonsils and adenoid tissue. The distribution of IgE-producing cells is similar to the distribution of IgA-producing cells.
If the barrier formed by secretory IgA is overcome, the antigen interacts with IgE - antibodies fixed on mast cells, and the development of allergic reactions is induced. IgE concentrations in the blood reach adult levels by approximately 10 years of age. With the participation of the Fc fragment, IgE is fixed on the cell surface due to Fc receptors.
There are classic high-affinity receptors of mast cells and basophils for IgE, and from 30-103 to 400-103 IgE molecules can be fixed on one basophil, as well as low-affinity receptors. The latter are represented mainly on macrophages, eosinophils, and platelets.
Antibodies of the IgE class are responsible for the development of anaphylactic (atopic) allergic reactions of the humoral type.
It should be noted that only about 1% of IgE is present in the blood; more than 99% of IgE is secreted by enterocytes into the intestinal lumen, and IgE secreted into the intestinal lumen creates anthelmintic protection, in particular, due to IgE-dependent cytolysis provided by eosinophils. It is known that eosinophils can produce two toxic proteins - large basic protein and cationic eosinophil protein.
