Innate immunity

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

Non-specific defense factors, being phylogenetically more ancient, mature and participate in defense-adaptive reactions, ahead of immune factors. They take on the main function of defense until the final maturation of more advanced 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 penetration - the skin with its secretory apparatus and bactericidal components of sweat and sebaceous gland secretion, barriers of mucous membranes with mucociliary clearance in the bronchi, intestinal motility and urinary tract. A non-specific protective effect is possessed by many tissue and circulating macrophage cells, as well as natural killers (NK) and intraepithelial T-lymphocytes. Phagocytic cells circulating with the blood are especially active in the presence of opsonins and complement factors. Metal-binding proteins of blood serum, lysozyme, properdin, interferons, fibronectin, C-reactive protein and other "acute phase reactants" can also be classified as substances of non-specific anti-infective protection.

Non-specific protective factors are the first to react to the antigen and participate in the formation of acquired (specific) immunity. Subsequently, innate and acquired immunity work synchronously, harmoniously complementing and reinforcing each other.

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Innate immunity and lysozyme (muromidase)

It is an enzyme that destroys (lyses) mucopolysaccharides of bacterial membranes, especially gram-positive ones. It is contained in tears, saliva, blood, mucous membranes of the respiratory tract, intestines and in various tissues of organs. In humans, leukocytes (10) and tears (7) are the richest in lysozyme (in grams per 1 kg of body weight), saliva (0.2) and blood plasma (0.2) are less rich. Lysozyme plays an important role in local immunity. It acts in collaboration with secretory immunoglobulins. High levels of lysozyme in blood serum have been proven by birth, which even exceeds its level in adults.

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Properdin

It is one of the important factors that ensure the body's resistance. It takes part in the alternative pathway of activation of the complementary reaction. The content of properdin at the moment of birth is low, but literally during the first week of life it quickly increases and remains at a high level throughout childhood.

Interferon plays a major role in non-specific protection. There are several of them, depending on the main producer 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. Type II interferon (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 lymphoid dendritic cells of the DC2 type are mainly responsible for the synthesis of this type. Interferon-β, or "fibroblastic", forms protein structures very similar to interferon-α. Interferon-γ, or immune interferon, has very little in common with the first two in its structure. It arises (is produced) in T-lymphoid cells (Thl and CD8+ cytotoxic lymphocytes) and NK cells. Interferons can rightfully be classified as non-specific defense factors, since their induction can be caused by a very wide range of both infectious agents and mitogens, and the resistance achieved after induction is also of a broad non-specific nature.

Interferons have the property of suppressing the reproduction of infectious and oncogenic viruses. They have species specificity and low antigenic activity. Their formation in the body usually occurs 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 interferon producers are leukocytes. Interferons exert their effect at the intracellular stage of virus reproduction. In particular, it has been proven that interferons can block the formation of RNA, which is necessary for the replication of viruses.

In addition to antiviral, interferon also has an effect on intracellular parasites (trachoma chlamydia, malaria plasmodia, toxoplasma, mycoplasma and rickettsia), and also has protective properties against exo- and endotoxins. Low doses of interferons promote antibody formation, as well as, to some extent, activation of the cellular link of immunity. Interferons enhance phagocytosis, significantly modify the reactions of specific immunity.

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

Complement system

The complement system consists of three parallel systems: classical, alternative (properdin subsystem) and lectin. Cascade activation of these systems has a multidirectional function. Activated components of the complement system enhance the reactions of phagocytosis and lysis of bacterial cells both in an independent mode of non-specific immune protection and in a mode of combination with the action of antigen-specific antibodies. The system consists of 20 protein components, 5 membrane regulatory proteins and 7 membrane receptors. Non-specific activation of the classical pathway occurs under the influence of C-reactive protein and trypsin-like enzymes, the alternative pathway is activated by endotoxins and fungal antigens. The lectin pathway of activation is initiated by manose-binding protein - a blood lectin similar in structure to the complement component C1q. Contact of the microbial manose surface with blood lectin leads to the formation of C3 convertase (C4β2a) via the classical pathway of complement system activation. The complement system undergoes its main formation between the 8th and 15th week of gestation, but even by the time of birth the total complement content in 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.

Proteins of the complement system are capable of developing 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 pathway are designated as "components" of the system - by the letter "C"; participants of the alternative activation pathway are called "factors". Finally, a group of regulatory proteins of the complement system is distinguished.

Components, factors and regulatory proteins of the serum complement system

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

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

As a result of activation of the entire complement system, its cytolytic action is manifested. At the final stage of activation of the complement system, a membrane attack complex is formed, consisting of complement components. The membrane attack complex penetrates into the cell membrane, forming channels with a diameter of 10 nm. Along with the cytolytic components, C3a and C5a are anaphylatoxins, since they cause the release of histamine by mast cells and enhance neutrophil chemotaxis, and C3c enhances the phagocytosis of complement-loaded cells. An alternative pathway for activation of the complement system ensures the elimination of viruses and altered erythrocytes from the body.

The complement system has a protective function, but can also contribute to damage to the body's own tissues, for example, in glomerulonephritis, systemic lupus erythematosus, myocarditis, etc. The total complement 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 complement content in the blood serum increases rapidly, and from the age of 1 month does not differ from that in adults.

Currently, a number of diseases have been described that are based on genetically determined deficiency of various complement components. Inheritance is most often autosomal recessive (C1r, C2, C3, C4, C5, C6, C7, C3β-inhibitor); only C1-inhibitor deficiency is autosomal dominant.

Deficiency of C1 inhibitor is clinically manifested by angioedema, which is usually painless. As a rule, there is no reddening of the skin. If the edema is localized in the larynx, it can cause respiratory failure due to obstruction. If a similar picture occurs in the intestine (usually in the small intestine), the patient experiences pain, vomiting (often with bile), frequent watery stools. With deficiency of C1r, C2, C4, C5, clinical manifestations occur that are characteristic of systemic lupus erythematosus (SLE syndrome), hemorrhagic vasculitis (Schonlein-Henoch disease), polymyositis, arthritis. A decrease in 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 deficiency of factors, components or regulatory proteins of the complement system.

Phagocytosis and natural immunity

The theory of phagocytosis is associated with the name of I. I. Mechnikov. Phylogenetically, phagocytosis is one of the most ancient reactions of the body's defense. In the process of evolution, the phagocytic reaction has become significantly more complex and improved. Phagocytosis is apparently an early defense mechanism of the fetus. The non-specific immunity system is represented by phagocytes, circulating (polymorphonuclear leukocytes, 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, microglial cells of the brain). The cells of this system appear at a relatively early stage of fetal development - from the 6th to the 12th week of gestation.

A distinction is made between microphages and macrophages. Microphages are neutrophils, and macrophages are large mononuclear cells, either fixed tissue or circulating, related to monocytes. A macrophage reaction is formed in the fetus somewhat later.

Leukocytes with polymorphic nuclei have a half-life of only 6-10 hours. Their function is to capture and intracellularly digest pyogenic bacteria, some fungi and immune complexes. However, to implement this function, a whole complex of factors regulating and "guiding" or aiming the migration of polymorphonuclear leukocytes is necessary. This complex includes adhesion molecules: selectins, integrins and chemokines. The actual process of destroying microorganisms is carried out by turning on oxidase systems, including superoxides and peroxides, as well as hydrolytic enzymes of granules: lysozyme and myeloperoxidase. Short peptides called "defensins" also play an important role. Their molecule consists of 29-42 amino acids. Defensins contribute to the disruption of the integrity of membranes of bacterial cells and some fungi.

Throughout the fetal period and even those obtained from peripheral umbilical cord blood, newborn leukocytes have a low capacity for phagocytosis and low mobility.

If the absorption capacity of phagocytes in newborns is sufficiently developed, then the final phase of phagocytosis is not yet perfect and is formed at a later stage (after 2-6 months). This applies primarily to pathogenic microorganisms. In children of the first 6 months of life, the content of non-enzymatic 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. Throughout life, the percentage of phagocytosis, starting from the 1st month of life, fluctuates slightly, amounting to about 40. It turned out that pneumococci, Klebsiella pneumoniae, Haemophilus influenzae are not subject to phagocytosis, which probably explains the higher incidence of pneumonia in children, especially at an early age, with its more severe course, often giving complications (destruction of the lungs). In addition, it was found that staphylococci and gonococci even retain the ability to reproduce in the protoplasm of 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. Bone marrow produces up to (1...3)x10 ¹⁰ neutrophils per day, their full maturation period is about 2 weeks. During infection, the production of neutrophilic leukocytes can increase significantly and the maturation period can decrease. In addition, infection leads to the "recruitment" 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 reorganization of the processes of metabolism, migration, adhesion, the release of the charge of short-chain proteins - defensins, the implementation of an oxygen "explosion", absorption of the object, the formation of a digestive vacuole (phagosome) and secretory degranulation. The activity of phagocytosis increases the effect of opsonization, in which the phagocyte itself, the object of phagocytosis and proteins with opsonizing properties cooperatively participate. The role of the latter can be performed by immunoglobulin G, C3, C-reactive protein and other proteins of the "acute phase" - haptoglobin, fibronectin, acidic α-glycoprotein, α2- macroglobulin. The opsonizing role of factor H of the complement system is very important. The deficiency of this factor is associated with the insufficient effectiveness of phagocytic protection in newborns. The vascular endothelium also plays a significant role in regulating phagocytosis reactions. Adhesion molecules act as regulators of its participation in this process: selectins, integrins and chemokines.

Long-lived tissue macrophages derived from monocytes are activated primarily by interferon-γ and T-lymphocytes. The latter react with the CD40 cross-antigen of the phagocyte membrane, leading to the expression of nitric oxide synthesis, CD80 and CD86 molecules, and the production of interleukin 12. These chains are necessary for antigen presentation in the chain of formation of specific cellular immunity. Thus, at present, the phagocytosis system cannot be considered only as an evolutionarily primitive line of primary non-specific protection.

Children may have primary and secondary phagocytosis disorders. Primary disorders may affect both microphages (neutrophils) and macrophages (mononuclear cells). They may be transmitted from generation to generation, i.e. inherited. Transmission of phagocytic reaction disorders may be linked to the X chromosome (chronic granulomatous disease) or autosomal, more often of the recessive type, which is manifested by a decrease in the bactericidal properties of the blood.

Usually, disturbances of phagocytic reactions are manifested by enlarged lymph nodes, frequent skin and lung infections, osteomyelitis, hepatosplenomegaly, etc. In this case, children are especially susceptible to diseases caused by Staphylococcus aureus, Escherichia coli, Candida albicans (thrush).

The study 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, the mobility of micro- and macrophages) can be an argument for the assumption that the pathological process is based on a disorder of phagocytosis. Secondary disorder of phagocytosis, as a rule, of an acquired nature, develops against the background of drug treatment, for example, long-term use of cytostatic drugs. Both primary and secondary disorders of phagocytosis can be defined as predominant disorders of chemotaxis, adhesion, intracellular cleavage of the object. Hereditary or acquired after severe diseases or intoxications disorders of the phagocytosis system can determine an increase in the frequency of some diseases and the peculiarity of their clinical manifestations.