Specific immunity: development and establishment

Specific immunological reactions are performed by the body's immune system, which consists of central and peripheral organs of immunogenesis. Specific immunity when exposed to a certain antigen is carried out by T- and B-lymphocytes. The intrauterine period demonstrates intensive dynamics of maturation of the lymphoid system.

The sequential change of various stages of maturation of cells of the B- and T-systems can be controlled by immunological markers of the corresponding stages of maturation or differentiation.

Differentiation markers of cells involved in the immune response

CD marker	Type of cell carrying the marker	Function
CD1	T-lymphocyte	Participation in antigen presentation
CD2	T-lymphocyte	Adhesion of cytotoxic T-lymphocytes to the endothelium, to the epithelial cells of the thymus gland
SDZ	T-lymphocyte	Conduction of the T-cell activation signal, a marker of most mature T-lymphocytes
CD4	T-lymphocyte	Co-receptor for TCR, marker of T-helper cells
CD8	T-lymphocyte	Maturation and selection of GCS-restricted lymphocytes in the thymus gland, a marker of cytotoxic T-lymphocytes
CD25	T-, B-, NK-cells, thymocytes, macrophages	Induction of activity and proliferation of T and B lymphocytes, natural killers, thymocytes and macrophages, α-subunit of the receptor for IL-2
CD28	T-lymphocyte	TCR-independent costimulatory signaling molecule
СDЗ0	T-lymphocyte	Conducting a signal to trigger T-lymphocyte apoptosis
CD5	T and B lymphocyte	Specific for autoimmune diseases
CD9	B-lymphocyte	Present on pre-B cells, responsible for platelet aggregation and activation
CD19, 20, 21	B-lymphocyte	Regulation of B-lymphocyte activation and proliferation
CD22	B-lymphocyte	Responsible for adhesion to erythrocytes, T and B lymphocytes, monocytes and neutrophils
CD40	B-lymphocyte	B-cell activation, proliferation and differentiation
CD16	Natural killer	Activation of antigen-dependent complement-mediated cytotoxicity and cytokine production
CD56	Natural killer	Activation of cytotoxicity and cytokine production
CD94	Natural killer	Inhibition/activation of natural killer cell cytotoxicity
CD11α CD18	Monocyte Granulocyte	Adhesion of leukocytes to endothelium and leukocyte to leukocyte
CD11β CD18	Monocyte Granulocyte	Adhesion of monocytes and neutrophils to the endothelium, opsonization of complement-bound particles
C11c CD18tov	Monocyte Granulocyte	Adhesion of monocytes and granulocytes to the endothelium, phagocytic receptor in inflammation
CD45	Granulocyte	Receptor for tyrosine phosphatase
CD64	Macrophages	Activation of macrophages
CD34	Stem cell or committed colony-forming progenitor	Attachment of lymphocyte L-selectin to endothelium, attachment of stem cells to bone marrow stroma

B-lymphocyte differentiation markers

Pro/pre-B-1 cell	Large pre-B-97-N cell	Small pre-B-97-II cell	Immature B cell	Mature B cell
CD34	CD40	CD40	CD21	CD40
CD40	CD43		CD22	CD19
CD43	CD19		CD80	CD20
B220			CD86
CD25			CD54
			CD79

T-lymphocyte differentiation markers

Pro-T cells TH	Pre-T cells	Immature TN T cells	DP cells	Mature
CD25	CD25	CDZeu	SDZ	CD4
CD44	CDZeu	CD4	CD4+, 8+	CD8
CD117	CD4-	CD8	CD4	SDZ
C3-	CD8-	CD117	CD8	CD4
C4-	CD117			CD8
CD8"
TKP-β
Rearrangement

The development of all systems of both non-specific and specific immunity, primarily cellular, begins at about 2-3 weeks, when multipotent stem cells are formed. The common stem cell-predecessor of all subpopulations of lymphocytes, neutrophilic leukocytes and monocytes can be identified as a CD34+ T-cell.

T-precursors undergo a maturation cycle in the thymus gland and undergo negative and positive selection processes there, the result of which is the elimination of more than 90% of lymphoid cells that are potentially dangerous to the body in terms of the risk of developing autoimmune reactions. The cells remaining after selection migrate and populate the lymph nodes, spleen and group lymphatic follicles.

In the 3rd month, a positive blast transformation reaction to phytohemagglutinin is already noted, which coincides with the division of the thymus gland into the cortex and the medullary part. By the 9th-15th week of life, signs of functioning of cellular immunity appear. The delayed-type hypersensitivity reaction is formed at later stages of intrauterine development and reaches its greatest functioning after birth - by the end of the first year of life.

The primary lymphoid organ, the thymus gland, is laid down at about 6 weeks and finally matures histomorphologically by the gestational age of about 3 months. From 6 weeks, HLA antigens begin to be typed in the fetus. This means that already from this period the fetus becomes an "immunological personality" with its individual antigen constitutional "portrait" and many constitutional features in all reactions of the immune system. From the 8th-9th week, small lymphocytes appear in the thymus gland. They are recognized as descendants of lymphoid cells that migrated first from the yolk sac, and later from the liver or bone marrow. Then there is an intensive increase in the number of lymphocytes in the peripheral blood of the fetus - from 1000 in 1 mm3 ^at the 12th week to 10,000 in 1 mm3 ^by the 20th-25th week.

Under the influence of humoral stimulators and partially the local microenvironment, T-lymphocytes can assume the functions of cytotoxic cells, helpers, suppressors, and memory cells. By the time of birth, the absolute number of T-lymphocytes in a child is higher than in an adult, and functionally this system is quite capable, although many characteristics of the T-lymphocyte function are at a lower level than in older children and adults. They have a weakened ability to produce interleukins 4 and 5, interferon-γ, and the CD40β antigen, which is necessary for organizing the interaction of the T- and B-systems in the immune response, is weakly expressed.

The characteristics of the features of the immune response are largely determined by the ability of the cells involved to produce humoral communication substances and regulate cytokines or interleukins. Several dozen such information and regulatory molecules have already been identified and quantitatively studied in scientific research. In clinical immunology, the greatest importance is given to identifying 10-15 biologically active substances of this group.

Early morphological and functional maturation of the thymus gland coincides with the advanced development of the T-cell system. Reactions of transplant rejection have been described, starting from 12 weeks of gestation. By the time of birth, the lymphoid tissue of the thymus gland already has significant dimensions.

The first peripheral lymphatic glands are formed starting from the 3rd month of gestation, but their "population" with lymphoid elements occurs during the following (4th) month. Lymph nodes and formations of the gastrointestinal tract are formed only after the 21st week of gestation.

Differentiation of B cells also begins in the liver or bone marrow, and there is a close connection of this differentiation with the Bruton tyrosine kinase gene. In the absence of this gene, differentiation is impossible and the child will suffer from agammaglobulinemia. During the differentiation of B lymphocytes, deletional recombination with immunoglobulin genes occurs. This allows B cells to present the structure of immunoglobulin M on their surface and, as a result, migrate and repopulate in the spleen and lymph nodes. During a long period of intrauterine development, the dominant B cells in the liver and peripheral blood remain pre-B lymphocytes, which contain heavy M globulin chains in their cytoplasm, but do not carry surface receptors for immunoglobulins. The number of these cells decreases significantly by the time of birth. The transformation of pre-B cells into cells capable of producing immunoglobulins is carried out under the influence of thymus factors. For the final maturation of B cells with the possibility of their transformation into plasma cells, the participation of the immediate microenvironment is necessary, i.e., stromal elements of the lymph nodes, group lymphatic follicles of the intestine, and the spleen.

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Specific immunity and interleukins

Interleukin	Source of education	Functions
IL-1	Macrophages, dendritic cells, fibroblasts, NK cells, endothelial cells	Acceleration of antigen presentation, stimulates production of IL-2 by Th cells, maturation of B lymphocytes, pro-inflammatory and pyrogenic action
IL-2	Activated T lymphocytes (predominantly Th1)	Growth factor for T and B lymphocytes, activates differentiation of Th and cytotoxic T lymphocytes, stimulates NK cells and Ig synthesis by B lymphocytes
IL-3	T cells and stem cells	Plasma cell growth factor, multicolony stimulating factor
IL-4	Th2 cells, mast cells	Differentiation of Th0 into Th2 cells, B-differentiation, acceleration of IgE synthesis, growth of plasma cells, suppresses the formation of cytotoxic lymphocytes and NK cells, suppresses the formation of interferon-γ
IL-5	Th2 cells	Acceleration of the synthesis of immunoglobulins, especially IgA, acceleration of the production of eosinophils
IL-6	T and B lymphocytes, macrophages, fibroblasts, endothelial cells	Acceleration of immunoglobulin synthesis, stimulates proliferation of B-lymphocytes, hepatocyte growth factor, antiviral protection
IL-7	Stromal cells, fibroblasts, endothelial cells, T lymphocytes, bone marrow cells	Acceleration of pre-T and pre-B cell growth
IL-8	T cells, macrophages, endothelial cells, fibroblasts, hepatocytes	Neutrophil activation, chemoattractant for lymphocytes, neutrophils, macrophages and eosinophils
IL-9	Th2 cells	Synergism with IL-4 in increasing IgE synthesis, plasma cell growth, stimulates proliferation of T-lymphocytes and basophils
IL-10	Th0 and Th2 cells, CD8+, macrophages, dendritic cells	Factor inhibiting the synthesis of proinflammatory cytokines, suppressing the functions of macrophages, accelerating the growth of B-lymphocytes and mast cells
IL-12	Macrophages, neutrophils, B lymphocytes and dendritic cells	Stimulation of natural killers, maturation of lymphocyte cytotoxicity, stimulates growth and differentiation of TM- into Th1 cells, inhibits the synthesis of IgE, a proinflammatory cytokine
IL-13	Th2 cells and mast cells	Acceleration of IgE synthesis, acceleration of B-lymphocyte growth, inhibition of macrophage activation
IL-14	T and B lymphocytes	Reduces Ig production, increases proliferation of B-lymphocytes
IL-15	Monocytes and epithelial cells	Growth factor for T-lymphocytes, activates differentiation of Th- and cytotoxic T-lymphocytes, stimulates NK-cells and Ig synthesis by B-lymphocytes
IL-16	Eosinophils, CD8+, mast cells	Activates chemotaxis of Th cells, eosinophils and monocytes
IL-17	Memory T cells and NK cells	Enhances the production of IL-6, IL-8, enhances the expression of ICAM-1, stimulates the activity of fibroblasts
IL-18	Macrophages	Acceleration of interferon-γ synthesis
IL-19	Monocytes	IL-10 homolog
IL-20	Keratinocytes	Participates in skin inflammation in psoriasis
IL-21	T lymphocytes and mast cells	Enhances proliferation of T, B lymphocytes and NK cells
IL-22	T-lymphocytes	IL-10 homolog
IL-23	Activated dendritic cells	Increases the proliferation of CD4+ memory T-lymphocytes and stimulates the production of interferon-γ
IL-24	Activated monocytes, T lymphocytes	IL-10 homolog
IL-25	Bone marrow stromal cells	Increases production of Th2 cytokines
IL-26	Activated monocytes, T lymphocytes, NK cells	IL-10 homolog
Interferon-γ	T cells	Activation of macrophages, inhibition of IgE synthesis, antiviral activity
Tumor necrosis factor	Monocytes, macrophages, T and B lymphocytes, neutrophils, NK cells, endothelial cells	Induces the synthesis of IL-1 and IL-6 by macrophages, the formation of acute phase proteins, stimulates angiogenesis, induces apoptosis, hemorrhagic necrosis of tumors
Chemokines (RANTES, MIP, MCP)	T cells, endothelium	Chemoattractant (chemokine) for monocytes, eosinophils, T-cells

Relatively mature B-lymphocytes are identified by the presence of immunoglobulin antigen receptors on their surface. In the liver, such cells begin to be detected after 8 weeks. At first, these are receptors for immunoglobulins G and M, later - for A. After the 20th week, cells with receptors are already detected in the spleen and peripheral blood.

The ability to produce antibodies by the B-system cells themselves has been confirmed in the fetus starting from the 11th-12th week. The earliest the fetus acquires the ability to form immunoglobulin M (from the 3rd month), somewhat later immunoglobulin B (from the 5th month) and immunoglobulin A (from the 7th month). The timing of immunoglobulin D synthesis in the prenatal period has not been sufficiently studied. The fetus's own production of immunoglobulin E is detected from the 11th week in the lungs and liver, and from the 21st week - in the spleen. Many lymphocytes carrying immunoglobulin E are found in the umbilical cord blood, but the content of immunoglobulin E itself is very low. Up to the 37th week of gestational age, it is no more than 0.5 IU / ml. At the age of 38 weeks, immunoglobulin E is determined in 20% of newborns, and after the 40th week - in 34%.

In general, the synthesis of immunoglobulins during intrauterine development is very limited and is enhanced only by antigen stimulation (for example, by intrauterine infection). The humoral immune response of the fetus and newborn differs significantly from the response of an older child or an adult, both qualitatively and quantitatively.

At the same time, during the period of intrauterine development, some maternal immunoglobulins are transferred transplacentally to the fetus. Among the latter, immunoglobulin B has this ability. The transfer of maternal immunoglobulin M to the fetus is possible only due to increased permeability of the placenta. As a rule, this is observed only in gynecological diseases of the mother, for example, in endometritis. Other classes of maternal immunoglobulins (A, E, D) do not transfer transplacentally.

The presence of selective transport of maternal immunoglobulin B through the placenta can be considered a significant factor in perinatal adaptation. This transition begins after the 12th week of gestation and increases with its duration. It is very important that the child receives from the mother a wide range of specific antibodies, both antibacterial and antiviral, aimed at protecting him from the range of pathogens that his mother encountered and that are important in the local environment. The transition of immunoglobulin B2 through the placenta is especially easy.

It is obvious that the reverse transition of fetal immunoglobulins and even the child's lymphocytes into the mother's blood is possible, although in an insignificant amount, which creates a risk of her immunization to alloantigens of fetal immunoglobulins. It is believed that this mechanism may be important in the formation of the mechanism of suppression of alloantigen synthesis by the fetus. Immunodepression of a woman and mutual immunological tolerance during pregnancy are evolutionarily developed adaptations that allow, despite the antigenic difference between the mother and fetus, to ensure the normal course of pregnancy and the birth of children on time.

After birth, the ratio of T- and B-cells in the blood of newborns fluctuates significantly. The content of T- and B-lymphocytes in the peripheral blood of newborns is higher, and it decreases with age. A more pronounced blast transformation reaction is also noteworthy - both spontaneous and stimulated by phytohemagglutinin. However, in functional terms, lymphocytes are less active, which is explained, on the one hand, by immunodepression by substances transferred from the woman's body during pregnancy, and on the other hand, by the absence of antigenic stimulation of the fetus in utero. Evidence of the latter position is an increase in the content of immunoglobulins A and, to a lesser extent, immunoglobulins M in newborns who have had an intrauterine infection or are suffering from it.

A very complex mechanism of differentiation and "learning" is presented in the selection of clones capable of producing antibodies to factors of the normal habitat, or in the active prolongation of reactions of this kind. We can talk about perinatal aspects of the formation of allergenic tolerance or allergic predisposition (atopic diathesis). The development of tolerance to allergens (atopenes) in the intrauterine period is carried out under the influence of the allergens themselves, easily penetrating the placental barrier, but mainly - through the penetration of allergen-antibody immune complexes. The inability of allergens and immune complexes to cause tolerance often becomes the cause of intrauterine sensitization. In recent decades, there has been a widespread prevalence of food allergies, and the importance of intrauterine sensitization is convincingly confirmed.

During the development of allergic reactivity, the characteristics of the first "contacts" of the immune system with antigens or allergens of the external environment may have a possible and significant impact. It has been revealed that already in the first hours of life, acquaintance with antigens related to the competence of the response chains emanating from cytokines of one of the T-helper subpopulations - Th1 or Th2, may be decisive regarding the subsequent development of atopic diathesis. The dominance of Th2 production at the end of intrauterine life is adaptive in nature and is aimed at protecting the placenta from potential Th toxicity. This dominance may persist for some time after birth. During this period, the phenomenon of an "open window" for external sensitization and the launch of a stereotype for reactions of atopic reactivity is noted. According to preliminary data, protecting a child from contact with atopenes or competitive exposure to antigens including Th helper populations may become an example of “organized early experience” for the immunocompetent system, leading to the most effective prevention of allergic diseases.

There is also sufficient evidence of the importance of specific allergens that affect the newborn in the first hours and days of life. The consequence of such "early experience" or acquaintance with an allergen may be the establishment of clinically significant sensitization with its detection after many years of life. In the complex immunological restructuring of the primary adaptation of the newborn, the role of another participant or mechanism of adaptation is evolutionarily determined - these are the peculiarities of the newborn's nutrition, special functions of maternal colostrum and milk from the very first hours of postnatal life.