Congenital immunity

Innate immunity (natural, hereditary, nonspecific resistance) to neutralize the antigen uses nonspecific defense factors, in contrast to acquired immunity, which protects against strictly defined antigens.

Nonspecific defense factors, being phylogenetically more ancient, mature and participate in protective-adaptive reactions, outstripping immune factors. They take on the basic function of protection until the final maturation of more perfect immune mechanisms, which is of great importance both in the fetus and in children of the first days and months of life.

Innate immunity includes the presence of anatomical barriers to infection - the skin with its secretory apparatus and bactericidal components of the secretion of sweat and sebaceous glands, mucous membrane barriers with mucociliary clearance in the bronchi, intestinal motility and urinary tract. Nonspecific protective effect is possessed by very many tissue and circulating macrophage cells, as well as natural killers (1MK) and intra-epithelial T-lymphocytes. Circulating with blood phagocytic cells are particularly active in the presence of opsonins and complement factors. Nonspecific anti-infective protection substances can also include metal-binding proteins of blood serum, lysozyme, properdin, interferons, fibronectin, C-reactive protein and other "acute phase reactants".

Nonspecific defense factors are the first to react to the antigen and participate in the formation of acquired (specific) immunity. Further congenital and acquired immunity work synchronously, harmoniously supplementing and strengthening each other.

[1], [2], [3], [4], [5], [6], [7], [8]

Congenital immunity and lysozyme (muromidase)

It is an enzyme that destroys (lysing) mucopolysaccharides of bacterial membranes, especially gram-positive ones. It is contained in tears, saliva, blood, mucous membranes of the respiratory tract, intestines and various tissues of the organs. In humans, the most abundant lysozyme (in grams per 1 kg of body weight) is leukocytes (10) and tears (7), less - saliva (0.2), plasma (0.2). Lizotzym plays an important role in local immunity. It acts in conjunction with secretory immunoglobulins. The high content of lysozyme in the serum of the blood has been proven to be born, which even exceeds its level in an adult.

[9], [10], [11], [12], [13], [14], [15]

Properdin

It is one of the important factors that ensure the stability of the body. He takes part in an alternative way to activate the complementary reaction. The content of the properdin at the moment of birth is low, but literally grows during the first week of life and keeps at a high level throughout the entire childhood.

Of great importance in nonspecific protection is given by interferon. They exist somewhat in accordance with the main producing cells. There are two groups of interferons: Type I (interferon-α, interferon-β and interferon-ω) and type II - interferon-γ. Type I interferons are "pre-immune" interferons involved in antiviral and antitumor protection. Interferon type II (interferon-γ) is an "immune" interferon that activates T and B lymphocytes, macrophages and NK cells.

Previously it was believed that interferon-α ("leukocyte" interferon) is produced by mononuclear phagocytes. It has now been established that mainly lymphoid dendritic cells of the DC2 type are responsible for the synthesis of this type. Interferon-β, or "fibroblast", forms protein structures very similar to interferon-α. Interferon-γ, or immune interferon, in its structure has very little in common with the first two. It occurs (is produced) in T-lymphoid cells (Thl and CD8 + cytotoxic lymphocytes) and NK cells. Interferons can rightfully refer to nonspecific protective factors, since their induction can be caused by a very wide range of both infectious agents and mitogens, and the resistance obtained after induction also has a wide nonspecific character.

Interferons have the property of inhibiting the multiplication of infectious and oncogenic viruses. They have specific specificity and low antigenic activity. Their formation in the body usually goes in parallel with the penetration of the virus and the onset of a febrile reaction. They are produced by cells, primarily affected by viruses. The most active producers of interferon are leukocytes. Interferons exert their effect on the intracellular stage of the virus reproduction. In particular, it is proved that interferons can block the formation of RNA, which is necessary for replication of viruses.

In addition to antiviral, interferon has an effect on intracellular parasites (chlamydia trachoma, plasmodium malaria, toxoplasma, mycoplasma and rickettsia), and also has protective properties for exo and endotoxins. Low doses of interferons contribute to antibody formation, as well as to some degree of activation of the cellular immune system. Interferons strengthen phagocytosis, substantially modify the reactions of specific immunity.

The ability to form interferon immediately after birth is high, but in children 1 year of age it decreases, and only gradually increases with age, reaching a maximum by 12-18 years. The peculiarity of the age-related dynamics of interferon formation is one of the causes of increased susceptibility of young children to viral infection and its more severe course, especially acute respiratory infections.

The complement system

The complement system consists of three parallel systems: classical, alternative (subsystemperdine) and lectin. Cascade activation of these systems has a multidirectional function. The activated components of the complement system enhance the phagocytosis and lysis of bacterial cells both in the independent mode of nonspecific immune defense and in the regime of combination with the action of antigen-specific antibodies. The system consists of 20 protein components, 5 membrane regulatory proteins and 7 membrane receptors. Nonspecific activation of the classical pathway occurs under the influence of C-reactive protein and trypsin-like enzymes, an alternative pathway is activated by endotoxins and fungal antigens. The pectinic pathway of activation is initiated by a manoso-binding protein, a blood lectin, structurally similar to the complement component C1q. Contact of the manic surface of microbes with blood lectin leads to the formation of C3-convertase (C4β2a) along the classical pathway of activation of the complement system. The complement system makes its main formation in the interval between the 8th and 15th weeks of gestation, but at the time of birth, the total content of complement in the umbilical cord blood is only half of its content in the mother's blood. Components C2 and C4 are synthesized by macrophages, C3 and C4 in the liver, lungs and peritoneal cells, C1 and C5 in the intestine, and the C inhibitor in the liver.

The proteins of the complement system are capable of deploying cascade reactions of mutual activation, approximately analogous to cascade reactions in proteins of the blood coagulation system, in the fibrinolysis or kininogenesis system. The main participants of the classical activation path system are designated as "components" of the system - the letter "C"; participants of the alternative path of activation are called "factors". Finally, a group of regulatory proteins of the complement system is isolated.

Components, factors and regulatory proteins of the complement system of blood serum 

Complement Components	Amount, mg / l
Components of the classical path:
	70
C1q	34
C1r	31
C4	600
C2	25
NW	1200
Alternative path factors:
Properdin	25
Factor B	1
Factor D	1
Membrane tangling complex:
C5	85
C6	75
C7	55
C8	55
C9	60
Regulatory proteins:
C1 inhibitor	180
Factor H	500
Factor I	34

The first complement component includes three subcomponents: C1q, C1r and Cβ. The components of complement are in the blood in the form of precursors, which do not combine with free antigens and antibodies. The interaction between C1q and aggregated immunoglobulins in or M (antigen + antibody complex) triggers the activation of the classical pathway of the complementary reaction. Another complement activation system is an alternative pathway based on properdin.

As a result of the activation of the entire complement system, its cytolytic action is manifested. At the final stage of activation of the complement system, a membrane-coagulating complex consisting of complement components is formed. Membrane-tangling complex is introduced into the cell membrane with the formation of channels with a diameter of 10 nm. Along with cytolytic components, C3a and C5a are anaphyllatoxins, since they cause histamine release by mast cells and enhance neutrophil chemotaxis, and C3c enhances the phagocytosis of complement-loaded cells. An alternative way to activate the complement system is to eliminate the viruses and altered erythrocytes from the body.

The complement system has a protective function, but it can also damage the body's own tissues, for example, with glomerulonephritis, systemic lupus erythematosus, myocarditis, etc. General complementary activity is expressed in hemolytic units. The activity of the complement system in newborns is low and, according to some data, is about 50% of the activity in adults (this applies to C1, C2, C3, C4). However, in the first week of life, the content of complement in the serum rapidly increases, and from the age of 1 month it does not differ from that in adults.

At present, a number of diseases are described, which are based on genetically determined deficiency of various complement components. Inheritance is more often autosomal recessive (C1r, C2, C3, C4, C5, C6, C7, C3β-inhibitor); only the deficiency of the C1 inhibitor is autosomal dominant.

The deficiency of the C1-inhibitor is clinically manifested by angioedema, which is usually painless. In this case, as a rule, there is no redness of the skin. If the edema is localized in the larynx, it can cause respiratory failure due to obstruction. If a similar pattern occurs in the intestine (more often in the small intestine), the patient has pain, vomiting (often with bile), frequent watery stools. With the deficiency of C1r, C2, C4, C5, clinical manifestations are characteristic of systemic lupus erythematosus (SLE), hemorrhagic vasculitis (Shenlaine-Henoch disease), polymyositis, arthritis. Reducing the content of C3, C6 is manifested by recurrent purulent infections, including pneumonia, sepsis, otitis.

Below we will consider the risk structures of various diseases associated with the deficiency of factors, components or regulatory proteins of the complement system.

Phagocytosis and natural immunity

The doctrine of phagocytosis is associated with the name of II Mechnikov. Phagocytosis is phylogenetically one of the most ancient defense reactions of the body. In the process of evolution, the phagocytic reaction has become much more complicated and improved. Phagocytosis is, apparently, an early protective mechanism of the fetus. The system of nonspecific immunity is represented by phagocytes circulating (leukocytes polymorphonuclear, monocytes, eosinophils), as well as fixed in tissues (macrophages, spleen cells, stellate reticuloendotheliocytes of the liver, alveolar macrophages of the lungs, macrophages of the lymph nodes, microglia cells of the brain). Cells of this system appear in the relatively early periods of fetal development - from the 6th to the 12th week of gestation.

There are microphages and macrophages. Microphages are neutrophils, and macrophages are large mononuclear cells, either fixed tissue or circulating, related to monocytes. Somewhat later, a macrophagal reaction is formed in the fetus.

Leukocytes with polymorphic nuclei have a half-life of only 6-10 hours. Their function is to capture and intracellular digestion of pyogenic bacteria, certain fungi and immune complexes. However, in order to realize this function, a whole set of factors of regulation and "targeting" or targeting the migration of polymorphonuclear leukocytes is necessary. This complex includes adhesion molecules: selectins, integrins and chemokines. Actually, the process of destruction of microorganisms is carried out by including oxidase systems, including superoxides and peroxides, as well as hydrolytic enzymes of granules: lysozyme and myeloperoxidase. An important role is played also by short peptides, called "defensins". Their molecule consists of 29-42 amino acids. Defensins contribute to the disruption of the integrity of membranes of bacterial cells and certain fungi.

Throughout the fetal period and even derived from peripheral umbilical cord blood, the newborn's leukocytes have a low ability for phagocytosis and low mobility.

If the absorptive capacity of phagocytes in newborns is sufficiently developed, the final phase of phagocytosis is not yet complete and is formed at a later date (2-6 months). This is relevant in the first place to pathogenic microorganisms. In children of the first 6 months of life, the content of non-enzyme cationic proteins participating in the final stage of phagocytosis is low (1.09 ± 0.02), then it increases (1.57 ± 0.05). Cationic proteins include lysozyme, lactoferrin, myeloperoxidase, etc. During life, the percentage of phagocytosis, ranging from the 1st month of life, varies slightly, amounting to about 40. It turned out that pneumococci, Klebsiella pneumoniae, Haemophilus influenzae do not undergo phagocytosis than probably , and explains the higher incidence of children, especially the early age, pneumonia with its more severe course, often causing complications (destruction of the lungs). In addition, it was found that staphylococci and gonococci even retain the ability to multiply in proto-phagocytic phagocytes. At the same time, phagocytosis is a very effective mechanism of anti-infective protection. This effectiveness is also determined by the large absolute number of both tissue and circulating macrophages and microphages. The bone marrow produces up to (1 ... 3) x10 ¹⁰ neutrophils per day, the full term of their maturation is about 2 weeks. With infection, the production of neutrophilic leukocytes can significantly increase and the maturation period decreases. In addition, the infection leads to "recruiting" of leukocytes deposited in the bone marrow, the number of which is 10-13 times greater than in the circulating blood. The activity of the stimulated neutrophil is manifested in the restructuring of metabolic processes, migration, adhesion, the release of short-chain proteins - defensins, the oxygen "explosion", the absorption of the object, the formation of the digestive vacuoles (phagosomes) and secretory degranulation. The activity of phagocytosis is enhanced by the opsonization effect, in which the phagocyte itself, the phagocytosis object and proteins with opsonizing properties participate co-operatively. The role of the latter can carry immunoglobulin G, C3, C-reactive protein and other proteins of the "acute phase" - haptoglobin, fibronectin, acid α-glycoprotein, α2-macroglobulin. Very important is the opsonizing role of factor H of the complement system. Deficiency of this factor is associated with insufficient effectiveness of phagocyte protection in newborn children. In the regulation of the reactions of phagocytosis, the endothelium of the vessels also takes an important part. Regulators of its participation in this process are adhesion molecules: selectins, integrins and chemokines.

Tissue long-living macrophages derived from monocytes are activated mainly by interferon-γ and T-lymphocytes. The latter react with the cross antigen of the CD40 envelope of the phagocyte, resulting in expression of the synthesis of nitric oxide, CD80 and CD86 molecules, as well as production of interleukin 12. These chains are necessary for the presentation of the antigen in the chain of formation of specific cellular immunity. Thus, at present, the phagocytosis system can not be regarded only as an evolutionarily primitive line of primary non-specific protection.

In children, primary and secondary disorders of phagocytosis can be observed. Primary disorders can concern both microphages (neutrophils) and macrophages (mononuclear cells). They can be passed on from generation to generation, ie, inherited. Transmission of violations of the phagocytic reaction can be linked to the X-chromosome (chronic granulomatous disease) or autosomal, more often recessive, which is manifested by a decrease in the bactericidal properties of the blood.

Usually, violations of phagocytic reactions are manifested by an increase in lymph nodes, frequent cutaneous and pulmonary infections, osteomyelitis, hepatosplenomegaly, and others. In this case, the tendency of children to diseases caused by Staphylococcus aureus, Escherichia coli, Candida albicans is especially high.

Investigation of the relative and absolute number of morphological features of phagocytic cells, cytochemical characteristics-the activity of myeloperoxidase, glucose-6-phosphate dehydrogenase, and functional features (for example, mobility of micro- and macrophages) may be an argument for the assumption that phagocytosis is the basis of the pathological process. A secondary disorder of phagocytosis, as a rule, acquired character, develops on the background of drug treatment, for example, prolonged use of cytotoxic drugs. Both primary and secondary disorders of phagocytosis can be defined as preferential disorders of chemotaxis, adhesion, intracellular splitting of the object. Hereditary or acquired after serious illnesses or intoxications, disorders of the phagocytosis system may determine an increase in the frequency of certain diseases and the originality of their clinical manifestations.