PHAGOCYTOSIS

From Big Medical Encyclopedia

PHAGOCYTOSIS (phagocytosis, the Greek phagos devouring - j-kytos a receptacle, here — a cell + - osis) — process of recognition, active capture and absorption of microorganisms, the destroyed cells and foreign debris specialized cells of immune system.

Object F. microbes, the alien and changed own cells or their fragments, complexes antigen — an antibody, etc. are. Integral part F. makes the directed movement — a chemotaxis (see the Taxis) — phagocytes to the place of localization of an alien particle.

Definition of efficiency F. it is carried out for assessment of a state by him-munobiol. reactivity of an organism, and also at various medico-biol. researches.

Phenomenon F. as for biological universal response of one-celled, multicellular and higher organisms it was open by I. I. Mechnikov, to-ry in 1883 formulated the theory of phagocytosis. I. I. Mechnikov considered F. as one of forms of food of cells (starting with protozoa). At high-organized organisms this form of food is inherent to the special mesenchymal cells phagocytes absorbing and killing pathogenic microbes and thus performing protective function. I. I. Mechnikov connected immunity to activators with function of these cells inf. diseases. It described phases of phagocytal process and the condition of activation of phagocytes which is characterized by their new properties and the strengthened ability to absorb and destroy bacteria. The key role of phagocytes was proved to them in immunity, at an inflammation, removal of the damaged cells, regeneration, an atrophy, aging.

Granulocytes, generally neutrophilic leukocytes (see), and the mononuclear englobing cells (see System of mononuclear phagocytes), napr, monocytes, macrophages, etc. belong to phagocytes. In the course of recognition by phagocytes of microbes, substances and particles the large role is played by special components of blood serum, to-rye are molecular intermediaries at interaction of microbes with phagocytes and cause strengthening F. These components are called opsonins (see), antibodies of IgGl, IgG3, IgM aggregated by IgAl and IgA2 (see Immunoglobulins), and thermolabile subcomponents of a complement, in the main SZ (see the Complement), and also and-1 and r-globulins, serumal a2 — a HS glycoprotein concern to them. Point out the opsonizing properties S-reaktiv-nogo of protein (see) etc. Antibodies of IgG and IgM specifically contact antigens of the corresponding bacteria and through Fc-receptors fix them to receptors of phagocytes. Phagocytes can connect to an object F. and nonspecific — through hydrophobic bonds of Van der Waals. The subcomponents of a complement arising at a classical or alternative way of its activation are occluded on objects F., the attachment to-rykh to a surface of a phagocyte is carried out through SZ-i S4-receptors.

Opsonizirovanny and neopsoni-zirovanny particles are attached to phagocytes also by means of specific Fc-receptors for IgE, glycoproteins and polysaccharides and nonspecific receptors for alien substances. The majority of neutrophils of the person contain Fc-receptors for the aggregated IgGl and IgG3, and it is possible also for aggregated by I g And; monocytes — receptors for IgGl and IgG3. Receptors for a complement of a vysokoaffinna (have the high durability of connection), they provide sticking of opsonizirovanny particles to not elicited macrophages, absorb such particles only the activated cells. On neutrophils receptors for SZ-, S4-and S5a-subkomponentov of a complement, on macrophages — one receptor for SZ-and S4-, another — for SZ-and Szs1-subkomponentov of a complement are found. If the particle of an opsoniziro-van immunoglobulin and a complement, linkng with a phagocyte is carried out kooperativno through receptors, specific to them, that considerably activates its absorption. There are distinctions between classes of receptors and the reactions mediated by them F. By means of nonspecific and specific to glycoproteins and polysaccharides of receptors F is carried out. bacteria without opsonins. F is known. inert particles — silicon dioxide, coal, etc.

Opsonins not only attach an object F. to a surface of phagocytes, but also activate them, inducing the signals going from a plasma membrane indirectly cause activation of different humoral systems of an organism, strengthening F.

Process of absorption of an opsoniziro-bathing particle begins with interaction of receptors of a phagocyte with the opsonins localized on a surface of a particle. Further there is an interaction of the next free receptors of a phagocyte to nearby free opsonins of a particle until all opsonins covering a particle on the periphery are connected, and it completely will not plunge into cytoplasm of a phagocyte together with the surrounding site of a plasma membrane, forming a phagosoma. Interaction of a particle with a plasma membrane of a phagocyte by means of the formed complexes opsonin receptor starts the difficult mechanism F., the main role in Krom belongs to work of sokratitelny proteins. Process of absorption begins with formation of a pseudopodium — a pulling of the site of cytoplasm of a phagocyte in the direction of a particle. During the formation of a pseudopodium the nondirectional octynic threads (filaments) which are in it become parallel that is followed by passing change of viscosity of cytoplasm. The hypothesis of rigidity (gelatinization) — the reduction of cytoplasm changing its state and generating the mechanical force of the movement of the phagocyte regulated by calcium ions is formulated. At gelatinization octynic threads cross communicate the aktinsvyazyvayushchy protein turning cytoplasm into gel owing to formation of an octynic lattice. This process is suppressed osobykhm kaltsiyzavisimy actin - regulatory protein — the gelsoli-number which is fiziol. regulator of gelatinization of actin. Further the myosin forms cross bridges with actin and gel begins to be reduced, especially in the presence of ions of the magnesium, ATP and a cofactor which is the kinase phosphorylating a heavy chain of a myosin. Rigidity of cytoplasmatic structures (gelatinization of the site of cytoplasm) increases in the place of contact of a plasma membrane and particle. Process goes continuously; constantly from a plasma membrane soluble aktinsvyazyvayu-shchy protein is secreted and the membrane moves towards a particle. In the field of sticking of a particle to a plasma membrane ion concentration of calcium increases, to-rye «dissolve» an octynic lattice, reduce rigidity of cytoplasm in this site, and it moves towards the increased rigidity on the end of a pseudopodium since threads of a myosin pull octynic threads in the direction of area of the greatest rigidity of a lattice.

In the course of F. at neutrophils the energy reserved in the form of ATP, formed as a result of reaction of glycolysis (see) is consumed. At alveolar macrophages energy for F. more (perhaps, generally) it is removed from ATP, formed in the course of oxidizing phosphorylation (see biological oxidation). It is established that a metabolic indicator in macrophages is not the absolute content of ATP, but the speed of updating. The amount of ATP in the englobing macrophages partially is supported by phosphorylation of ADF at the expense of creatine phosphate (see Creatine), to-rogo in macrophages in 3 — 5 times more, than ATP, and consumption significantly increases at F. Kre-atinfosfat in macrophages serves, thus, for

F. F. the shunt is followed the major reserve and the supplier of chemical energy metabolic, or respiratory, by explosion, the shown increase in oxygen consumption and oxidation of glucose through hexosemonophosphate-ny (see. Carbohydrate metabolism). At the same time key products of recovery of oxygen — superoxidic anion and hydrogen peroxide due to oxidation of nicotinamide adenine dinucleotides and-kotinamidadenin-dinukleotidfosfa-tov by means of corresponding to NADN-and NADFN-oksidaz are formed; the collecting oxidized coenzymes cause strengthening of the geksozomonofos-fatny shunt due to their recovery with the help glyukozo-6-phosphate-II of 6-phosphogluconates-dehydrogenases. Phagocytes have a complex system for destruction of hydrogen peroxide. This system protects components of a cell from destruction and is presented by a catalase, myeloperoxidase, glu-tation-peroxidase, the recovered glutathione. Respiratory explosion is followed by strengthening of metabolism of carbohydrates, lipids, synthesis of RNA, increase in level of a cyclic guanozinmonofosfat, decrease in synthesis of protein and transport of amino acids.

After completion of absorption of a particle the arisen phagosoma and primary lysosomes (see), primary azurophilic and secondary specific granules of phagocytes mutually approach and merge, forming a phagolysosome. This process is followed by disappearance in phagocytes of the isolated granules. From lysosomes a large amount of hydrolases gets to a phagosoma. T. it is also connected with secretion from phagocytes of a number of enzymes — (Z-glucuronidases, N-atsetil-R-glyukoz-aminidazy, acid and alkaline phosphatase, cathepsine, myeloperoxidase, lactoferrin, the plazminogenny activator. Similar secretion is accompanied by activation of the geksozomono-phosphatic shunt and process F lasts much longer, than directly.

After penetration of bacteria in phagocytes the difficult mikrobotsid-ny mechanism presented by antimicrobic systems as demanding oxygen not depending on it begins to function. The antimicrobic system demanding oxygen functions in two options — with participation and without participation of myeloperoxidase. The option with participation of myeloperoxidase is highly active concerning bacteria, fungi, miko-silt zm and viruses. Interaction of myeloperoxidase and hydrogen peroxide is followed by formation of oxidizers, oxidation of haloids and the galogenization which is in iodination, chlorination, booking of various bacterial components that leads to death of bacteria. At the described reactions bactericidal ions of chlorine, iod, chloroamines, nitrites, bactericidal aldehydes, singlet oxygen are formed, to-rye block many fermental systems of bacteria. The option of ashtshikrobny system of phagocytes which is not depending on myeloperoxidase causes formation of intermediate forms, toxic for microbes, of the recovered oxygen — superoxidic anion, hydrogen peroxide, the hydroxylic radical and singlet oxygen. Hydrogen peroxide is most active from them.

To antimicrobic system F., not depending on oxygen, carry: the lysozyme (see) splitting pepti-doglikana of cell walls of nek-ry gram-positive bacteria to the disaccharides consisting from muramino-howl to - you and a glycosamine; lactoferrin, to-ry in unsaturated iron to a form has bacteriostatic effect in phagosomas due to binding of the iron which is a growth factor for a row from them; various cationic proteins. The deep acidulation which is also forming in phagolysosomes to pH 6,5 — 3,75 has a certain bactericidal effect.

Acidulation, besides, activates lizosomalny hydrolases of primary lysosomes, inactive at alkalescent pH.

Mikrobotsidny systems of phagocytes function in cooperation. They possess various potentiality, but all together have vzaimope-rekryvayushchy effect therefore have high reliability and efficiency even at defects F.

At disturbance of a chemotaxis F. bacteria it is suppressed that promotes development and a malignant current of a row inf. diseases. The substances inducing a chemotaxis are called chemoattractants and are subdivided into several groups: 1) products specific, generally immunol. reactions — SZA-, S5a-subkomponenta of a complement, the activated G567 complex, SZ-convertase of an alternative way of complement activation, lymphokines (see Mediators of cellular immunity), a transfer factor of lymphocytes, cytophilic antibodies; 2) nonspecific endogenous chemoattractants — products of the damaged cells, kallikrein (see Ki-niny), the plazminogenny activator, fibrinopeptide B hydrolyzed or aggregated by IgG, collagen, and - and R-casein of milk, cyclic adenosinemonophosphate, etc.; 3) exogenous chemoattractants — the fragments of protein of bacteria containing N-formilmetionin, peptides, lipids or lipoproteids which are allocated in the course of bacterial activity in an organism.

On a surface of phagocytes specific receptors for chemoattractants — eicosathetas-rayenovoy to - you are found, synthetic for - it is lovely - methionyls-peptides, S5a-subkom-ponenta a kokhmplement. Apparently, the number of these receptors is unequal at different types of phagocytes, napr, the circulating neutrophils of a rabbit 8 times weaker connected chemo-taksichesky peptides, than peritoneal neutrophils. Reaction of sokratitelny system of a cell to action of chemoattractants is proved. Its orientation to a gradient of chemoattractants is caused by work of the microtubules which are carrying out a role of a cytoskeleton of a cell — they keep the polarized shape of a cell extended on a gradient of chemoattractants. However directly the movement of a phagocyte is carried out by system of microfilaments. Assume that blood proteins — albumine and IgG are regulators of locomotory function of phagocytes. Activation of phagocytes by chemoattractants in many respects is followed by the same changes, to-rye occur at F. — metabolic explosion, secretion from cells of enzymes, etc. A certain regulating role belongs to cyclic nucleotides: cyclic adenosinemonophosphate suppresses, and cyclic guanozinmono-phosphate stimulates a chemotaxis.

Ways and methodical approaches to assessment F. are various and depend on specific objectives of a research. They allow to define efficiency of processes of absorption of particles, death and digestion of live microorganisms and metabolic changes of phagocytes. Important data about F. can be also received at a research of a chemotaxis and opsonization.

For assessment F. use various microorganisms — staphylococcus (see), escherichias (see), salmonellas (see the Salmonella), etc. Use as live, and ubi-

ty microbes, but as live bacteria quite often allocate toxic products, overwhelming F., it is better to use the killed.

T. amplifies in the presence of the serum opsonizing bacteria. For strengthening and standardization F. use a predopsoniza-tion, i.e. preliminary (before phagocytosis) processing of a microbe opsonins — specific antibodies — or fresh serum, in a cut microbes activate system of a complement and adsorb the appearing subcomponents of a complement facilitating F. Odnako in experiments with live microbes apply only those, to-rye are not killed with the opsonizing serum. Speed F. analyze at joint incubation of phagocytes and live bacteria. Through different time terms take away tests, by means of differential centrifuging are exempted from phagocytes and sow nadosa-dochny liquid on cups with an agar that allows to define reduction of number of live bacteria in the course of F. During the work with fungi of the sort Candida drug is counted in Goryaev's camera, defining at the same time number vnekletochno of the located fungi.

For the analysis F. by determination of percent of the phagocytes which absorbed bacteria (a phagocytal index of the Hamburger), or a median number of the bacteria absorbed by one phagocyte (phagocytal number of District-hectare), speeds F. use particles of latex, starch, zymosan, a carmine, coal, etc. The method of a research F is offered., at Krom use droplets of the paraffine oil containing special dye and stabilized by protein. The absorbed material is defined by spektrofotometrichesk (see. With a pektrofotometriya). Also use particles or microbes, marked radioisotopes (see. Marked connections). The method is characterized by speed of performance, however does not allow to get rid completely of the stuck bacteria that overestimates indicators F. Other option consists in addition by Wednesday with phagocytes and particles of marked serum proteins, to-rye at F. get to a phagosoma that allows to estimate quantitatively F. Primenyayut's intensity also xenogenic intact or the singen-ny damaged or opsoniziro-bathing erythrocytes, analyzing their absorption visually or on an exit of hemoglobin.

At a research of absorption of live bacteria, especially with the subsequent accounting of quantity of the killed bacteria it is necessary to remove the stuck microbes from a surface of phagocytes. For this purpose apply various antibiotics, the killing extracellular bacteria but not getting into phagocytes the special drugs (phenylbutazone) interrupting at certain moments F. and intracellular inactivation of microbes. The method allowing to distinguish stuck and the absorbed killed fungi of the sort Candida on coloring of drug three-panovym is developed by blue.

Death and digestion of the absorbed microbes reveal by incubation of suspension of phagocytes with microbes, the subsequent washing of phagocytes of of the stuck microbic cells, calculation of the live microbes which remained in tests of the phagocytes which are taken away in various terms of an incubation. Number of live bacteria determine by serial crops from tests of phagocytes on Petri dishes with an agar. Number of live fungi count in a lysate of phagocytes after an incubation by means of coloring by methylene blue. Intracellular digestion of bacteria is studied also by means of inclusion of 3H-uridine in them. For this purpose the culture of the phagocytes which absorbed bacteria is processed Actinomycinum of D, adding to the environment of 3H-Uri-dynes. Tag, joining in live intracellular bacteria, does not get in killed and phagocytes.

The analysis of the damaging action of phagocytes on microbes can be carried out on extent of coloring of the absorbed microbes by dyes or on coloring methylene blue phagolysosomes of phagocytes. Completeness F. estimate on the relation of a median number of the killed of microbes to live or numbers of phagocytes with the digested microbes to total number of the englobing phagocytes, and also on percent of the destroyed microbes from number fagotsitirovanny or on a median number of the killed microbes on one phagocyte. Expressiveness of metabolic changes at F. analyze on oxygen consumption, chemiluminescence, oxidation of glucose, iodination, etc.

Phagocytes play a key role in formation of the antimicrobic immunity (see Immunity) caused by both specific, and nonspecific factors of protection. In spite of the fact that specific immunity is mediated by specific T-cells, and also the specific antibodies opsonizing bacteria and strengthening F., elimination of pathogenic bacteriums is carried out nonspecific — the phagocytes activated by lymphokines of specific T lymphocytes. The activated phagocytes kill bacteria much more effectively that showed

also. I. Mechnikov. Natural immunity to activators inf. diseases it is also caused by generally phagocytal cells. The key role belongs to them and in a detoxication of the bacterial toxins neutralized by antibodies.

Macrophages, processing antigen and presenting it to lymphocytes, participating in intercellular cooperation, activation and suppression of proliferation of lymphocytes, are a necessary link in formation of unresponsiveness (see unresponsiveness) and transplant immunity (see Immunity transplant). Макрофг^ги participate in atrepsy (cm * atrepsy), having cytostatic and cytotoxic effect on tumor cells.

Damages of phagocytes by various immunosuppressors, blockers (see Immunity, Ymmupo-depressivnye of substance), ionizing radiation (see) cause sharp suppression of antimicrobic stability of an organism. At impact on animals high doses of ionizing radiation phagocytal activity can practically disappear. Phagocytal activity at animals, as a rule, after the 20th day is normalized. At the rabbits irradiated in a dose 600 I am glad (6 Gr), it is recovered only in 40 days. Between an ionizing radiation dose and extent of suppression F. there is a correlation. Doses 10 — 75 I am glad (0,1 — 0,75 Gr) strengthen F. granulocytes, and 350 — 600 I am glad (3,5 — 6 Gr) — sharply he is oppressed, and completeness F decreases., by 3 — 4 times mobility of phagocytes is suppressed, and also their absolute number decreases. The same patterns are characteristic of macrophages, the number and the digesting ability to-rykh at radiation also sharply decrease.

The diseases which are followed by primary (inborn) or secondary (acquired) defects F are revealed. The so-called chronic granulematozny disease arising at children concerns to them, in phagocytes to-rykh because of defect of oxidases formation of peroxides and nadperekpsy and, therefore, process of an inactivation of microbes is broken. Reduced ability to destruction of bacteria is revealed at people, neutrophils to-rykh synthesize insufficient amount of myeloperoxidase, a glyukozo-@-phosphate-dehydrogenase, pyruvatekinase. The slowed-down death of microbes is found in patients with Chediak's syndrome — Higasi (see Trombotsitopatiya), in neutrophils to-rykh is broken allocation in a phagosoma of lizosomalny enzymes because of defect of system of microtubules. The disturbance of polymerization process of actin leading to delay of absorption of particles neutrophils and their mobility is described. Patients with the specified defects of phagocytes often have heavy bacterial and fungal infections.

Primary disturbances F. are observed also at the level of opsonins, napr, at inborn deficit of SZ-and C5 components of a complement, to-ry can lead to development of recurrent infections with damage of lungs, bones, skin.

Secondary defects F. are described at diseases of connecting fabric, kidneys, disturbance of food, viral and recurrent bacterial infections.

Bibliography: Berman V. M. and Glories-with to and I am E. M, Complete phagocytosis, Zhurn. mikr., epid. and immun., No. 3, page 8, 1958; P about d about p r and about r and G. I. and Andreyev V. N. Modern methods of studying of phagocytal activity of leukocytes in vitro, in the same place, No. 1, e. 19, 1976; X r and m-tsov A. V. and Zemskov V. M. Rol of a plasma membrane in activation of lizosomalny enzymes, Dokl. Academy of Sciences of the USSR, t. 271, No. 1, page 241, 1983; Handbook of experimental immunology, ed.

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