Immunoglobulins, structure and functions. Classes of immunoglobulins, their characteristics
The structure of immunoglobulins
According to its chemical structure immunoglobulins are glycoproteins.
According to physicochemical and antigenic properties, immunoglobulins are divided into classes: G, M, A, E, D.
Immunoglobulin moleculeG built from 2 heavy (H-chains) and 2 light polypeptide chains (L-chains).
Each polypeptide chain consists of a variable (V), stable (constant, C) and so-called hinge parts.
The heavy chains of immunoglobulins of different classes are built from different polypeptides (gamma, mu, alpha, delta, epsilon peptides) and therefore are different antigens.
Light chains are represented by 2 types of polypeptides - kappa and lambda peptides.
Variable regions are much shorter than constant regions. Each pair of light and heavy polypeptide chains in their C-parts, as well as the heavy chains, are linked to each other by disulfide bridges.
Neither heavy nor light chains have the properties of antibodies (interaction with haptens). When hydrolyzed by papain, the immunoglobulin G molecule breaks down into 3 fragments - 2 Fab fragments and an F c fragment.
The latter represents the remnants of heavy chains, their constant parts. It does not have the property of an antibody (does not interact With antigen), but has an affinity for complement and is able to fix and activate it. In this regard, the fragment is designated as F c -fragment (complement fragment). The same F c fragment ensures the passage of immunoglobulins G through the blood-brain or placental barriers.
The other two fragments of immunoglobulin G are the heavy and light chain residues with their variable parts. They are identical to each other and have the property of antibodies (interact with the antigen), therefore these fragments And denoted as F ab ,-(antibody fragment).
Since neither heavy nor light chains have the property of an antibody, but it is detected in F a b fragments, it is obvious that it is the variable parts of the heavy and light chains that are responsible for the interaction with the antigen. They form a structure unique in structure and spatial organization - active center of the antibody. Each active center of any immunoglobulin corresponds to the determinant group of the corresponding antigen like a “key to a lock.”
The immunoglobulin G molecule has 2 active centers. Since the structure of the active centers of immunoglobulins of one
class, but different specificities are not the same, then these molecules (antibodies of the same class, but different specificities) are different antibodies. These differences are referred to as idiotypic immunoglobulin differences, or idiotypes.
Immunoglobulin molecules of other classes are built on the same principle as IgG, i.e. from monomers having 2 heavy and 2 light chains, but class M immunoglobulins are pentamers (built from 5 such monomers), and class A immunoglobulins are dimers or tetramers.
The number of monomers that make up a molecule of a particular class of immunoglobulin determines its molecular weight. The heaviest are IgM, the lightest are IgG, as a result of which they pass through the placenta.
It is also obvious that immunoglobulins of different classes have a different number of active centers: IgG has 2, and IgM has 10. In this regard, they are able to bind a different number of antigen molecules, and the rate of this binding will be different.
The rate of binding of immunoglobulins to antigen is their avidity.
The strength of this connection is denoted as affinity.
IgM is high-avidity, but low-affinity; IgG, on the contrary, is low-avid, but high-affinity.
If there is only one active center in an antibody molecule, it can contact only one antigenic determinant without the subsequent formation of a network structure of antigen-antibody complexes. Such antibodies are called incomplete. They do not give visible reactions, but they inhibit the reaction of the antigen with full antibodies.
Incomplete antibodies play an important role in the development of Rh conflict, autoimmune diseases (collagenosis), etc. and are detected using the Coombs test (antiglobulin test).
The protective role of immunoglobulins of different classes also not the same.
Immunoglobulins class E (reagins) realize the development of immediate-type allergic reactions (immediate-type hypersensitivity - IHT). Allergens (antigens) entering the body are attached to the F ab fragments of reagins fixed in tissues (the F c fragment is associated with tissue basophil receptors), which leads to the release of biologically active substances that trigger the development of allergic reactions. During allergic reactions, tissue basophils are damaged by the antigen-antibody complex and secrete granules containing histamine and other biologically active substances.
Immunoglobulins class A may be:
- serum (synthesized in plasma cells of the spleen, lymph nodes, have a monomeric and dimeric molecular structure and make up 80% of the IgA contained in serum);
- secretory (synthesized in the lymphatic elements of the mucous membranes).
The latter are distinguished by the presence of a secretory component (beta-globulin), which attaches to the immunoglobulin molecule as it passes through the epithelial cells of the mucosa.
Secretory immunoglobulins play a significant role in local immunity, preventing the adhesion of microorganisms on mucous membranes, stimulating phagocytosis and activating complement, and can penetrate into saliva and colostrum.
Immunoglobulins class M
are the first to be synthesized in response to antigenic stimulation. They are capable of binding a large number of antigens and play an important role in the formation of antibacterial and antitoxic immunity. The majority of serum antibodies are class G immunoglobulins, which account for up to 80% of all immunoglobulins. They are formed at the height of the primary and secondary immune response and determine the intensity of immunity against bacteria and viruses. In addition, they are able to penetrate the placental and blood-brain barriers.
Immunoglobulin classD
unlike immunoglobulins of other classes, they contain N-acetylgalactosamine and are unable to fix complement. IgD levels increase in myeloma and chronic inflammatory processes.
Immunoglobulins according to their structure, antigenic and immunobiological properties are divided into five classes: IgM, IgG, IgA, IgE, IgD.
Immunoglobulin class G. Isotype G makes up the bulk of Ig in blood serum. It accounts for 70-80% of all serum Ig, with 50% contained in tissue fluid. The average IgG content in the blood serum of a healthy adult is 12 g/l. The half-life of IgG is 21 days.
IgG is a monomer, has 2 antigen-binding centers (can simultaneously bind 2 antigen molecules, therefore, its valency is 2), a molecular weight of about 160 kDa and a sedimentation constant of 7S. There are subtypes G1, G2, G3 and G4. Synthesized by mature B lymphocytes and plasma cells. It is well detected in blood serum at the peak of the primary and secondary immune response.
Has high affinity. IgG1 and IgG3 bind complement, with G3 being more active than G1. IgG4, like IgE, has cytophilicity (tropism, or affinity, for mast cells and basophils) and is involved in the development of type I allergic reaction. In immunodiagnostic reactions, IgG can manifest itself as an incomplete antibody.
Easily passes through the placental barrier and provides humoral immunity to the newborn in the first 3-4 months of life. It is also capable of being secreted into the secretions of mucous membranes, including into milk by diffusion.
IgG ensures neutralization, opsonization and marking of the antigen, triggers complement-mediated cytolysis and antibody-dependent cell-mediated cytotoxicity.
Immunoglobulin class M. The largest molecule of all Igs. This is a pentamer that has 10 antigen-binding centers, i.e. its valency is 10. Its molecular weight is about 900 kDa, its sedimentation constant is 19S. There are subtypes M1 and M2. The heavy chains of the IgM molecule, unlike other isotypes, are built from 5 domains. The half-life of IgM is 5 days.
It accounts for about 5-10% of all serum Igs. The average IgM content in the blood serum of a healthy adult is about 1 g/l. This level in humans is reached by the age of 2-4 years.
IgM is phylogenetically the most ancient immunoglobulin. Synthesized by precursors and mature B lymphocytes. It is formed at the beginning of the primary immune response, and is also the first to be synthesized in the body of a newborn - it is determined already at the 20th week of intrauterine development.
It has high avidity and is the most effective complement activator via the classical pathway. Participates in the formation of serum and secretory humoral immunity. Being a polymer molecule containing a J-chain, it can form a secretory form and be secreted into mucous secretions, including milk. Most normal antibodies and isoagglutinins are IgM.
Does not pass through the placenta. The detection of specific antibodies of the M isotype in the blood serum of a newborn indicates a former intrauterine infection or placental defect.
IgM ensures neutralization, opsonization and marking of the antigen, triggers complement-mediated cytolysis and antibody-dependent cell-mediated cytotoxicity.
Immunoglobulin class A. Exists in serum and secretory forms. About 60% of all IgA is contained in mucosal secretions.
Serum IgA: It accounts for about 10-15% of all serum Ig. The blood serum of a healthy adult contains about 2.5 g/l IgA, the maximum is reached by the age of 10. The half-life of IgA is 6 days.
IgA is a monomer, has 2 antigen-binding centers (i.e., 2-valent), a molecular weight of about 170 kDa and a sedimentation constant of 7S. There are subtypes A1 and A2. Synthesized by mature B lymphocytes and plasma cells. It is well detected in blood serum at the peak of the primary and secondary immune response.
Has high affinity. May be an incomplete antibody. Does not bind complement. Does not pass through the placental barrier.
IgA ensures neutralization, opsonization and marking of the antigen, and triggers antibody-dependent cell-mediated cytotoxicity.
Secretory IgA: Unlike serum, secretory sIgA exists in polymeric form as a di- or trimer (4- or 6-valent) and contains J- and S-peptides. Molecular mass 350 kDa and higher, sedimentation constant 13S and higher.
It is synthesized by mature B-lymphocytes and their descendants - plasma cells of the corresponding specialization only within the mucous membranes and is secreted into their secretions. The production volume can reach 5 g per day. The slgA pool is considered the most numerous in the body - its quantity exceeds the total content of IgM and IgG. Not detected in blood serum.
The secretory form of IgA is the main factor in the specific humoral local immunity of the mucous membranes of the gastrointestinal tract, genitourinary system and respiratory tract. Thanks to the S-chain, it is resistant to proteases. slgA does not activate complement, but effectively binds to antigens and neutralizes them. It prevents the adhesion of microbes on epithelial cells and the generalization of infection within the mucous membranes.
Immunoglobulin class E. Also called reagin. The content in blood serum is extremely low - approximately 0.00025 g/l. Detection requires the use of special highly sensitive diagnostic methods. Molecular weight - about 190 kDa, sedimentation constant - approximately 8S, monomer. It accounts for about 0.002% of all circulating Igs. This level is reached by 10-15 years of age.
It is synthesized by mature B lymphocytes and plasma cells mainly in the lymphoid tissue of the bronchopulmonary tree and the gastrointestinal tract.
Does not bind complement. Does not pass through the placental barrier. It has a pronounced cytophilicity - tropism for mast cells and basophils. Participates in the development of immediate type hypersensitivity - type I reaction.
Immunoglobulin class D. There is not much information about Ig of this isotype. Almost completely contained in blood serum at a concentration of about 0.03 g/l (about 0.2% of the total circulating Ig). IgD has a molecular weight of 160 kDa and a sedimentation constant of 7S, monomer.
Does not bind complement. Does not pass through the placental barrier. It is a receptor for B-lymphocyte precursors.
50.Immunocompetent cells: T- and B-lymphocytes, macrophages, their cooperation
Immunocompetent cells- cells that can specifically recognize an antigen and respond to it with an immune response. Such cells are T- and B-lymphocytes (thymus-dependent and bone marrow lymphocytes), which, under the influence of foreign agents, differentiate into a sensitized lymphocyte and plasma cell.
T lymphocytes are a complex group of cells that originate from a pluripotent stem cell in the bone marrow and mature and differentiate from precursors in the thymus. T lymphocytes are divided into two subpopulations: immunoregulators and effectors. The task of regulating the immune response is performed by T helper cells. The effector function is carried out by T-killers and natural killer cells. In the body, T lymphocytes provide the cellular forms of the immune response and determine the strength and duration of the immune reaction.
B lymphocytes are predominantly effector immunocompetent cells. Mature B lymphocytes and their descendants, plasma cells, are antibody producers. Their main products are immunoglobulins. B lymphocytes are involved in the formation of humoral immunity, B-cell immunological memory and immediate hypersensitivity.
Macrophages are connective tissue cells capable of actively capturing and digesting bacteria, cell debris and other particles foreign to the body. The main function of macrophages is to combat those bacteria, viruses and protozoa that can exist inside the host cell, using powerful bactericidal mechanisms. The role of macrophages in immunity is extremely important - they provide phagocytosis, processing and presentation of antigen to T cells.
Cooperation of immunocompetent cells. The body's immune reaction can have a different character, but it always begins with the capture of antigen by macrophages of the blood and tissues or with binding to the stroma of lymphoid organs. Often the antigen is also adsorbed on the cells of parenchymal organs. In macrophages it can be completely destroyed, but more often it undergoes only partial degradation. In particular, most antigens in the lysosomes of phagocytes undergo limited denaturation and proteolysis within an hour. The remaining peptides (usually two or three amino acid residues) are complexed with MHC molecules expressed on the outer membrane of macrophages.
Macrophages and all other auxiliary cells that carry antigens on the outer membrane are called antigen-presenting; it is thanks to them that T- and B-lymphocytes, performing the function of presentation, allow rapid recognition of the antigen.
An immune response in the form of antibody formation occurs when B cells recognize an antigen, which induces their proliferation and differentiation into plasma cells. Only thymus-independent antigens can have a direct effect on the B cell without the participation of T cells. In this case, B cells cooperate with T helper cells and macrophages. Cooperation on a thymus-dependent antigen begins with its presentation on a macrophage to a T-helper. In the mechanism of this recognition, MHC molecules play a key role, since T-helper receptors recognize the nominal antigen as a complex as a whole or as MHC molecules modified by the nominal antigen that have acquired foreignness. Having recognized the antigen, T helper cells secrete γ-interferon, which activates macrophages and helps destroy the microorganisms they have captured. The helper effect on B cells is manifested by their proliferation and differentiation into plasmacytes. In the recognition of antigen in the cellular nature of the immune response, in addition to T-helper cells, T-killer cells are also involved, which detect the antigen on those antigen-presenting cells where it is complexed with MHC molecules. Moreover, T-killers that cause cytolysis are able to recognize not only the transformed, but also the native antigen. Having acquired the ability to cause cytolysis, killer T cells bind to the complex antigen + MHC class 1 molecules on target cells; attract cytoplasmic granules to the place of contact with them; damage target membranes after exocytosis of their contents.
As a result, lymphotoxins produced by T-killers cause the death of all transformed cells of the body, and cells infected with the virus are especially sensitive to it. At the same time, along with lymphotoxin, activated killer T cells synthesize interferon, which prevents the penetration of viruses into surrounding cells and induces the formation of lymphotoxin receptors in cells, thereby increasing their sensitivity to the lytic action of killer T cells.
By cooperating in the recognition and elimination of antigens, T-helper and T-killer cells not only activate each other and their predecessors, but also macrophages. These, in turn, stimulate the activity of various subpopulations of lymphocytes.
The regulation of the cellular immune response, as well as the humoral one, is carried out by T-suppressors, which affect the proliferation of cytotoxic and antigen-presenting cells.
Cytokines. All processes of cooperative interactions of immunocompetent cells, regardless of the nature of the immune response, are determined by special substances with mediator properties that are secreted by T-helper cells, T-killer cells, mononuclear phagocytes and some other cells involved in the implementation of cellular immunity. All their diversity is usually called cytokines. Cytokines are proteins in structure, and mediators in their effect. They are produced during immune reactions and have a potentiating and additive effect; Being quickly synthesized, cytokines are consumed in a short time. When the immune response subsides, the synthesis of cytokines stops.
51. Antibody formation: primary and secondary immune response.
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 multiplies, 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 the stationary phase, the amount of antibodies reaches a maximum and stabilizes, then a phase of decreasing antibody levels begins. 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. and 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.
Characteristics of the main classes of immunoglobulins.
Basic biological characteristics of antibodies.
1. Specificity- the ability to interact with a specific (own) antigen (correspondence between the epitope of the antigen and the active center of the antibodies).
2 . Valence- the number of active centers capable of reacting with the antigen (this is due to the molecular organization - mono- or polymer). Immunoglobulins can be divalent(IgG) or polyvalent(IgM pentamer has 10 active sites). Bi- or more valent antibodies emerge full antibodies. Incomplete antibodies have only one active center involved in interaction with the antigen (blocking effect on immunological reactions, for example, on agglutination tests). They are detected in the Coombs antiglobulin test, the reaction of inhibition of complement fixation.
3. Affinity - the strength of the connection between the antigen epitope and the active center of antibodies depends on their spatial correspondence.
4. Avidity - an integral characteristic of the strength of the connection between antigen and antibodies, taking into account the interaction of all active centers of antibodies with epitopes. Since antigens are often multivalent, communication between individual antigen molecules is carried out by several antibodies.
5. Heterogeneity - due to the antigenic properties of antibodies, the presence of three types of antigenic determinants:
- isotypic- antibodies belong to a certain class of immunoglobulins;
- allotypic- caused by allelic differences in immunoglobulins encoded by the corresponding alleles of the Ig gene;
- idiotypal- reflect the individual characteristics of immunoglobulin, determined by the characteristics of the active centers of antibody molecules. Even when antibodies to a particular antigen are
one class, subclass and even allotype, they are characterized by specific differences from each other ( idiotic). This depends on the structural features of the V-regions of the H- and L-chains, and the many different variants of their amino acid sequences.
The concept of polyclonal and monoclonal antibodies will be given in the following sections.
Ig G. Monomers include four subclasses. Concentration in the blood is from 8 to 17 g/l, half-life is about 3-4 weeks. This is the main class of immunoglobulins that protect the body from bacteria, toxins and viruses. The largest quantities of IgG antibodies are produced at the stage of recovery after an infectious disease (late or 7S antibodies), during the secondary immune response. IgG1 and IgG4 specifically (through Fab fragments) bind pathogens ( opsonization), thanks to the Fc fragments of IgG, they interact with the Fc receptors of phagocytes, promoting phagocytosis and lysis of microorganisms. IgG is capable of neutralizing bacterial exotoxins and fixing complement. Only IgG is able to be transported across the placenta from mother to fetus (pass through the placental barrier) and provide protection by maternal antibodies to the fetus and newborn. Unlike IgM antibodies, IgG antibodies belong to the late category - they appear later and are detected in the blood for a longer time.
IgM. The molecule of this immunoglobulin is a polymeric Ig of five subunits connected by disulfide bonds and an additional J-chain, and has 10 antigen-binding centers. Phylogenetically, this is the most ancient immunoglobulin. IgM is the earliest class of antibodies formed when an antigen initially enters the body. The presence of IgM antibodies to the corresponding pathogen indicates a fresh infection (current infectious process). IgM is the main class of immunoglobulins synthesized in newborns and infants. IgM in newborns is an indicator of intrauterine infection (rubella, CMV, toxoplasmosis and other intrauterine infections), since maternal IgM does not pass through the placenta. The concentration of IgM in the blood is lower than IgG - 0.5-2.0 g/l, half-life is about a week. IgM is capable of agglutinating bacteria, neutralizing viruses, activating complement, activating phagocytosis, and binding endotoxins of gram-negative bacteria. IgM has greater avidity than IgG (10 active centers), affinity (affinity for antigen) is less than that of IgG.
IgA. There are serum IgA (monomer) and secretory IgA (IgAs). Serum IgA is 1.4-4.2 g/l. Secretory IgAs are found in saliva, digestive juices, secretions of the nasal mucosa, and colostrum. They are the first line of defense for mucous membranes, providing their local immunity. IgAs consist of an Ig monomer, a J chain, and a glycoprotein (secretory component). There are two isotypes: IgA1 predominates in serum, subclass IgA2 in extravascular secretions.
The secretory component is produced by epithelial cells of the mucous membranes and attaches to the IgA molecule as it passes through the epithelial cells. The secretory component increases
resistance of IgAs molecules to the action of proteolytic enzymes. The main role of IgA is to provide local immunity to the mucous membranes. They prevent the attachment of bacteria to mucous membranes, ensure the transport of polymeric immune complexes with IgA, neutralize enterotoxin, activate phagocytosis and the complement system.
IgE. It is a monomer and is found in low concentrations in blood serum. The main role is that with its Fc fragments it attaches to mast cells (mastocytes) and basophils and mediates immediate hypersensitivity reactions. IgE refers to “allergy antibodies” - reagins. The level of IgE increases in allergic conditions and helminthiasis. The antigen-binding Fab fragments of the IgE molecule specifically interact with the antigen (allergen), the formed immune complex interacts with the receptors of the Fc fragments of IgE embedded in the cell membrane of the basophil or mast cell. This is a signal for the release of histamine and other biologically active substances and the development of an acute allergic reaction.
IgD. IgD monomers are found on the surface of developing B lymphocytes and are found in extremely low concentrations in serum. Their biological role has not been clearly established. 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.
In order to determine the concentrations of immunoglobulins of individual classes, several methods are used, most often method of radial immunodiffusion in gel (according to Mancini) - a type of precipitation reaction and ELISA.
Determination of antibodies of various classes is important for the diagnosis of infectious diseases. Detection of antibodies to antigens of microorganisms in blood serum is an important criterion when making a diagnosis - serological diagnostic method. Antibodies of the IgM class appear in the acute period of the disease and disappear relatively quickly; antibodies of the IgG class are detected at a later date and persist for a longer period (sometimes for years) in the blood sera of those who have recovered from the disease; in this case, they are called anamnestic antibodies.
The concepts are distinguished: antibody titer, diagnostic titer, studies of paired sera. The most important is the detection of IgM antibodies and a fourfold increase in antibody titers (or seroconversion- antibodies are detected in the second sample with negative results with the first blood serum) during the study doubles- samples taken during the dynamics of the infectious process with an interval of several days or weeks.
Reactions of interaction of antibodies with pathogens and their antigens ( “antigen-antibody reaction”) manifests itself in the form of a number of phenomena - agglutination, precipitation, neutralization, lysis, complement fixation, opsonization, cytotoxicity and can be identified by various serological reactions.
The primary response is upon initial contact with the pathogen (antigen), the secondary response is upon repeated contact. Main differences:
Duration of the latent period (longer during the primary period);
The rate of growth of antibodies (faster in secondary);
The amount of antibodies synthesized (more with repeated contact);
The sequence of synthesis of antibodies of different classes (in the primary, IgM predominates for a longer time, in the secondary, IgG antibodies are quickly synthesized and predominate).
The secondary immune response is due to the formation immune memory cells. An example of a secondary immune response is an encounter with a pathogen after vaccination.
Immunoglobulins are divided into classes depending on the structure, properties and antigenic characteristics of their heavy chains. Light chains in immunoglobulin molecules are represented by two isotypes - lambda (λ) and kappa (κ), which differ in the chemical composition of both variable and constant regions, in particular the presence of a modified amino group at the M-end of the k-chain. They are the same for all classes. Heavy chains of immunoglobulins are divided into 5 isotypes (γ, μ, α, δ, ε), which determine their belonging to one of five classes of immunoglobulins: G, M, A, D, E, respectively. They differ from each other in structure, antigenic and other properties.
Thus, the molecules of different classes of immunoglobulins include light and heavy chains, which belong to different isotypic variants of immunoglobulins.
Along with them, there are allotypic variants (allotypes) of immunoglobulins that carry individual antigenic genetic markers that serve for their differentiation.
The presence of an antigen-binding site specific to each immunoglobulin, formed by the hypervariable domains of the light and heavy chains, determines their different antigenic properties. These differences form the basis for the division of immunoglobulins into idiotypes. The accumulation of any antibodies that carry in the structure of their active centers antigenic epitopes (idiotypes) new to the body leads to the induction of an immune response to them with the formation of antibodies called anti-idiotypic.
Properties of immunoglobulins
Molecules of immunoglobulins of different classes are built from the same monomers, having two heavy and two light chains, which are capable of combining into di- and polymers.
Monomers include immunoglobulins G and E, pentamers include IgM, and IgA can be represented by monomers, dimers and tetramers. The monomers are connected to each other by a so-called connecting chain, or j-chain.
Immunoglobulins of different classes differ from each other in biological properties. First of all, this relates to their ability to bind antigens. In this reaction, monomers of IgG and IgE involve two antigen-binding sites (active centers), which determine the bivalence of antibodies. In this case, each active center binds to one of the epitopes of the polyvalent antigen, forming a network structure that precipitates. Along with bi- and polyvalent antibodies, there are monovalent antibodies, in which only one of the two active centers functions, capable of contacting only a single antigenic determinant without the subsequent formation of a network structure of immune complexes. Such antibodies are called incomplete; they are detected in blood serum using the Coombs test.
Immunoglobulins are characterized by different avidity, which refers to the speed and strength of binding to the antigen molecule. Avidity depends on the immunoglobulin class. In this regard, pentamers of class M immunoglobulins have the most pronounced avidity. The avidity of antibodies changes during the immune response due to the transition from the synthesis of IgM to the predominant synthesis of IgG.
Different classes of immunoglobulins differ from each other in their ability to pass through the placenta, bind and activate complement. The individual domains of the Fc fragment of immunoglobulin, formed by its heavy chain, are responsible for these properties. For example, the cytotropicity of IgG is determined by the Cγ3 domain, complement binding by the Cγ2 domain, etc.
Immunoglobulin class G (IgG) constitute about 80% of serum immunoglobulins (average 12 g/l), with a molecular weight of 160,000 and a sedimentation rate of 7S. They are formed at the height of the primary immune response and upon repeated administration of the antigen (secondary response). IgG have a fairly high avidity, i.e. relatively high rate of binding to antigen, especially of a bacterial nature. When the active centers of IgG bind to epitopes of the antigen in the region of its Fc fragment, the area responsible for fixation of the first fraction of the complement system is exposed, followed by activation of the complement system along the classical pathway. This determines the ability of IgG to participate in protective reactions of bacteriolysis. IgG is the only class of antibodies that penetrates the placenta into the fetus. Some time after the birth of a child, its content in the blood serum drops and reaches a minimum concentration by 3-4 months, after which it begins to increase due to the accumulation of its own IgG, reaching the norm by 7 years of age. About 48% of IgG is contained in tissue fluid into which it diffuses from the blood. IgG, like immunoglobulins of other classes, undergoes catabolic breakdown, which occurs in the liver, macrophages, and inflammatory focus under the action of proteinases.
There are 4 known subclasses of IgG, differing in the structure of the heavy chain. They have different abilities to interact with complement and pass through the placenta.
Immunoglobulins class M (IgM) are the first to begin to be synthesized in the fetal body and the first to appear in the blood serum after immunization of people with most antigens. They make up about 13% of serum immunoglobulins with an average concentration of 1 g/l. In terms of molecular weight, they significantly exceed all other classes of immunoglobulins. This is due to the fact that IgM are pentamers, i.e. consist of 5 subunits, each of which has a molecular weight close to IgG. IgM belongs to most of the normal antibodies - isohemagglutinins, which are present in blood serum in accordance with people's belonging to certain blood groups. These allotypic IgM variants play an important role in blood transfusion. They do not pass through the placenta and have the highest avidity. When interacting with antigens in vitro, they cause their agglutination, precipitation or complement fixation. In the latter case, activation of the complement system leads to lysis of corpuscular antigens.
Immunoglobulin class A (IgA) found in blood serum and in secretions on the surface of mucous membranes. Blood serum contains IgA monomers with a sedimentation constant of 7S at a concentration of 2.5 g/l. This level is reached by the age of 10 years. Serum IgA is synthesized in plasma cells of the spleen, lymph nodes and mucous membranes. They do not agglutinate or precipitate antigens, are not able to activate complement along the classical pathway, and as a result do not lyse antigens.
Secretory immunoglobulins of the IgA class (SIgA) differ from serum ones by the presence of a secretory component associated with 2 or 3 monomers of immunoglobulin A. The secretory component is β-globulin with a molecular weight of 71 KD. It is synthesized by secretory epithelial cells and can function as their receptor, and joins IgA as it passes through epithelial cells.
Secretory IgA plays a significant role in local immunity, since it prevents the adhesion of microorganisms on the epithelial cells of the mucous membranes of the mouth, intestines, respiratory and urinary tracts. At the same time, SIgA in aggregated form activates complement along the alternative pathway, which leads to stimulation of local phagocytic defense.
Secretory IgA prevents the adsorption and reproduction of viruses in the epithelial cells of the mucous membrane, for example, during adenovirus infection, polio, and measles. About 40% of total IgA is found in the blood.
Immunoglobulins class D (lgD). Up to 75% of IgD is contained in the blood, reaching a concentration of 0.03 g/l. It has a molecular weight of 180,000 D and a sedimentation rate of about 7S. IgD does not cross the placenta and does not bind complement. It is still unclear what functions IgD performs. It is believed that it is one of the receptors of B lymphocytes.
Immunoglobulins class E (lgE). Normally found in the blood at a concentration of 0.00025 g/l. They are synthesized by plasma cells in the bronchial and peritoneal lymph nodes, in the mucous membrane of the gastrointestinal tract at a rate of 0.02 mg/kg body weight per day. Class E immunoglobulins are also called reagins, since they take part in anaphylactic reactions, having pronounced cytophilicity.
Immunoglobulins are synthesized by plasma cells, which are formed from transformed, antigen-stimulated B lymphocytes (B immunoblasts). All immunoglobulin molecules synthesized by a single plasma cell are identical and have specific reactivity against a single antigenic determinant. Likewise, all plasma cells produced by transformation and proliferation of a single B lymphocyte precursor are identical; that is, they constitute a clone. Immunoglobulin molecules synthesized by cells of different clones of plasma cells have different amino acid sequences, which determines the different tertiary structure of the molecules and gives different specificity to the antibody, that is, they react with different antigens. These differences in amino acid sequence occur in the so-called V (variable) region of the immunoglobulin molecule.
Regulation of antibody production: Antibody production begins after B cells are activated by antigen. The maximum concentration of antibodies in the serum is observed from 1 to 2 weeks and then begins to decrease. The continued presence of free antigen maintains the response until an increase in antibody levels results in increased clearance of the antigen and thus cessation of B cell stimulation. There are also more subtle mechanisms for regulating the synthesis of immunoglobulins. T helper cells (CD4 positive) play an important role in regulating the response of B cells to a large number of antigens and their constant presence increases the production of antibodies. This effect occurs due to the release of lymphokines. T-suppressors (CD8-positive) have the opposite effect, causing a decrease in the immune response; strong response suppression may be one of the mechanisms underlying tolerance. One additional regulatory mechanism is the production of anti-idiotypes (i.e. antibodies against one's own antibodies (autoantibodies)). It is assumed that in an immune response, the production of a specific antibody is necessarily accompanied by the production of a second antibody (anti-idiotype) with specificity against the variable (V) sequences (idiotypes or antigen-binding regions) of the first antibody. An anti-idiotype antibody is capable of recognizing idiotypes on the B cell antigen receptor (which is constructed from an immunoglobulin identical in structure to the idiotype of the first antibody), thus it competes with the antigen and serves to inhibit B cell activation.
It should be noted that immunoglobulins are synthesized not only during infectious diseases. They are produced continuously in every healthy person. As a result, people have a certain level of various types of antibodies in their bodies, against almost all microbial antigens, including those against pathogens that they have never encountered. This is explained by the fact that the body’s ability to synthesize antibodies was developed in humans during the process of evolutionary development and is genetically determined. These antibodies (immunoglobulins) are called normal. Normal antibodies play a large role in protecting the body from infection at the time pathogens enter the body, as well as during the initial period of the disease (i.e., when immune responses to infection have not yet formed). Typically, the first manifestations of infectious immunity appear no earlier than the 4th day from the moment of illness and reach maximum severity on the 14th day and later.
The fact that antibodies produced by subepithelial lymphocytes are secreted not into the blood, but onto the surface of the mucous membranes deserves special attention. At the same time, antibodies circulating in the blood do not normally penetrate the surface of the mucous membranes. Consequently, lymphoid cells of the mucous membranes function largely autonomously. The antibodies they secrete form the body's first line of defense against pathogens of infectious diseases.
