From Big Medical Encyclopedia

SYSTEM OF MONONUCLEAR PHAGOCYTES (synonym: macrophagic system, monocytic and macrophagic system) — the system combining cells to-rye have ability to endocytosis, have homogeny, morphological, cytochemical and functional similarity. S.'s concept of m f. it is for the first time offered in 1969 at a conference in Leiden instead of the outdated concept of reticuloendothelial system (see. Reticuloendothelial system ). At the subsequent conferences in Leiden (1973, 1978) of idea of S. of m f. continued to be improved, and now this concept is accepted by most of researchers.

Fig. 1. The cells which are logging in mononuclear phagocytes: the origin, localization in bodies and fabrics, is normal of a kind of macrophages, and also at an inflammation depending on its character [according to R. van Furth, 1980].

In a basis of the concept of S. of m f. modern ideas of a community of an origin and kinetics of these cells, their morphological, cytochemical and functional similarity are put. Mononuclear phagocytes are present at all fabrics, but in normal conditions proliferation of their predecessors happens only in marrow (see). Most early recognizable predecessors of a number of a differentiation of these cells are monoblasts — direct «descendants» of the switched stem cells. Divisions of monoblasts result promonocytes — direct precursors of monocytes (see. Hemopoiesis ). Monocytes come to a circulatory bed, and then migrate in various fabrics and perigastriums where become macrophages (see). Pilot studies confirmed an origin of macrophages of the most different localization from the monocytes circulating in blood. It was also shown that division of macrophages in fabrics of essential value for their updating has no whereas reticular macrophages, dendritic reticular macrophages, fibroblasts, endothelial and mesothelial cells have no predecessors in marrow, and are updated by local division in fabrics. On the scheme the origin of cells, the logging-in mononuclear phagocytes are shown, and their localization in bodies and fabrics, is normal of a kind of macrophages also at an inflammation depending on its character (fig. 1).

Function of system of mononuclear phagocytes is controlled by the difficult regulatory mechanisms providing receipt of macrophages in fabric in the conditions of norm and pathology. For the description of a functional condition of macrophages the various definitions (activated, immune, armed, induced, stimulated, exudative etc. are used). Activation of macrophages happens at cultivation of in vitro, at phagocytosis of bacteria, contact with antigen, cell-bound immune complexes, bacterial lipopolisakhari-da, polynucleotides and at interaction to lymphokines (see. Mediators of cellular immunity ). In particular, in vitro is shown participation in a monocytopoiesis (and a granulocytopoiesis) glycoproteins regulators, or so-called colony stimulating factors, to-rye influence the speed of a differentiation of predecessors of macrophages and treat az globulins with a molecular weight (weighing) from 13 000 to 93 000. At various pathological processes when the need for monocytes increases, products of the last increase at the expense of the introduction in a cycle of not proliferating promonocytes (normal at the person actively proliferates only apprx. 40% of promonocytes) and shortening of a cellular cycle, to-ry normal average apprx. 30 hours. In the conditions of an inflammation macrophages of the center of damage develop and release a factor in a circulator bed, to-ry strengthens a monocytopoiesis and, reaching marrow, stimulates products of monocytes. This factor represents protein with a molecular weight (weight) apprx. 20 000. After elimination of the damaging agent macrophages begin to develop other factor — inhibitor of a monocytopoiesis with a molecular weight (weight) apprx. 50 000.

Elicited macrophages are characterized by the oversizes strengthened by the phagocytal, digesting and bactericidal functions. In them activity of acid hydrolases, exchange processes increase. Morphologically elicited macrophages are characterized by increase in number and the sizes of lysosomes, expansion of a complex of Golgi, increase in a skladchatost of a plasma membrane. Elicited macrophages with the increased number of receptors for IgG are described at the patients suffering sarcoidosis (see), a disease Krone (see. Krone disease ) and tuberculosis (see).

The stimulator possessing expressed and directed by action on macrophages is glucan (complex polysaccharide from covers of yeast cells of Saccharomyces cerevisiae). Administration of glucan to mice leads to sharp increase in phagocytal activity of macrophages, stimulation humoral and cellular immunity (see). At the same time the antineoplastic effect of macrophages is brightly shown. Accumulation of macrophages in a liver, a spleen and lungs is in parallel noted. The researchers applying glucan emphasize absence at experimental animal any by-effects.

The drugs blocking, or eliminiruyushchy, macrophages, prezht all interfere with their participation in various immune responses. So, particles of the taken colloid coal lead to loss of ability of macrophages in development of an immune response to process antigen or to prepare it for interaction with the corresponding lymphocytes. At the heart of an immunodepressive effect on macrophages of karraginan (high-molecular polygalactoses) and particles of quartz their selective toxic effect lies. The same agents are used for studying of participation of macrophages in these or those processes.

Ways of migration of monocytes to fabrics are various and not up to the end studied. In lungs, e.g., monocytes are directly differentiated in alveolar macrophages, passing a phase of maturing in an interstitium. A part of macrophages comes to an abdominal cavity from lacteal spots (see) where they are differentiated from monocytes. Ability of macrophages to recirculation via veins is very limited, however is proved that they hmonut to migrate in nearby limf, nodes where perish.


Fig. 2. Diffraction pattern of an alveolar macrophage: shooters specified the phagolysosomes containing dust particles; X 5 000.
Fig. 3. The diffraction pattern of an alveolar macrophage received in the help of the scanning microscope: shooters specified the superficial folds and crests formed by a plasma membrane of a macrophage; X 5 000.

Characteristic qualities inherent in S.'s cells of m f., in particular to macrophages (see), are ability to the endocytosis including phagocytosis (see) and pinocytic (see), adhesions, migrations. Macrophages of fabrics and serous cavities have more or less spherical shape, a folded plasma membrane (cytolemma) and are characterized first of all by presence at cytoplasm of numerous lysosomes (see) and phagolysosomes, or digestive vacuoles (fig. 2). In the scanning supermicroscope (see. Submicroscopy ) superficial folds and crests of macrophages (fig. 3) are well visible. Having the expressed ability to adhesion, in culture conditions macrophages are strongly spread on the surface of substrate and get the flattened form. During the movement on substrate they form a set of polymorphic pseudopodiums (see the Cell), and on skanogramma the folded leading edge directed towards movement of a cell and the long shoots fixing a cell to substrate are visible. Along with it macrophages of various localization, even within one body, e.g. limf, a node, differ both morphologically, and is functional. So, macrophages of the light (germinative) centers unlike the fixed and free macrophages of sine limf, nodes do not englobe antigens, but absorb other foreign debris and lymphocytes. They are usually allocated as macrophages with the painted inclusions.

Intracellular metabolism of mononuclear phagocytes depends on a stage of a differentiation, fabric localization, activation and endocytosis. The main sources of energy for mononuclear phagocytes are glycolysis, the gek-sozomonofosfatny shunt and aerobic metabolism. Researches of the last years showed that macrophages are active secretory cells, to-rye release in the environment surrounding them enzymes, inhibitors, factors and components of a complement (see). The key secretory product of macrophages is lysozyme (see), to-ry is developed and cosecretes with constant speed. Unlike a lysozyme nek-ry neutral proteinases cosecrete generally elicited macrophages. Among them are best of all studied elastase (see), a collagenase (see) and plasminogen activators (see. Fibrinolysis ), participating in destruction and reorganization of fabrics (e.g., at a resorption of a bone, involution of mammary glands and puerperal involution of a uterus). As fixed, and free macrophages cosecrete nek-ry factors of a complement, such as S2, SZ, S4, S5, factor In, and also interferon (see).

Methods of a research

Traditional morfol. methods, especially on svetooptichesky and even at the electronic and microscopic level, often happen insufficient for identification of mononuclear phagocytes. Even during the studying of the isolated cells sometimes it is difficult to distinguish a monocyte from a lymphocyte or predecessors of a monocyte (a monoblast and a promonocyte), from predecessors of granulocytes (myeloblasts and promyelocytes). Besides, fabric macrophages often confuse to reticular macrophages, fibroblasts, endothelial and mesothelial cells though division of these cells has basic value since their origin and function are absolutely various.

Only use of specific markers in combination with a submicroscopy allows to identify and estimate reliably participation of mononuclear phagocytes in these or those processes. One of the most reliable markers for identification of mononuclear phagocytes of the person and animals is enzyme esterase (KF 3. 1. 1. 1.), to-ry is defined histochemical during the use as substrate and - naftilbuti-rata or and-naftilatsetata. At the same time almost all monocytes and macrophages are painted though intensity gistokhy. can vary reactions depending on a look and a functional condition of an organism, and also from culture conditions of cells. In mononuclear phagocytes enzyme is localized diffuzno whereas in T lymphocytes comes to light in the form of one-two dot granules.

Other reliable marker — a lysozyme (KF 3. 2. 1. 17.) — the enzyme cosecreted by macrophages to-ry can be revealed with the help of a method to them-munoflyuorestsentnogo with use of antibodies to a lysozyme (see. Immunofluorescence ).

Allows to reveal various stages of a differentiation of mononuclear phagocytes peroxidase (see). The granules containing enzyme are painted positively only in monoblasts, promonocytes, monocytes and macrophages of exudate; resident (i.e. constantly present at normal fabrics) macrophages are not painted.

As enzymes markers of mononuclear phagocytes are used also 51 nucleotidases, (KF 3. 1. 3. 5), leucineaminopeptidase (KF 3. 4. 11. 1.), phosphodiesterase I (KF 3. 1. 4. 1.), localized in a plasma membrane. Activity of these enzymes is defined or in homogenates of cells, or by tsitokhimichesk. Identification Б^нук-леотидазы allows to distinguish normal (resident) macrophages from activated (activity of this enzyme is high in the first and is low secondly). Activity a leucine aminopeptidase and phosphodiesterases, on the contrary, increases in process of activation of macrophages.

Components of a complement, in particular SZ, can also be a marker as this protein is synthesized only by monocytes and macrophages. It can be revealed in cytoplasm by means of immunocytochemistry methods; components of a complement at different types of animals differ on antigenic properties.

Existence immunol is very characteristic of mononuclear phagocytes. receptors for a Fc-fragment of JgG (see Immunoglobulins) and for the SZ component of a complement. Mononuk-learny phagocytes bear the called receptors at all stages of development, but among unripe cells the number of mononuclear phagocytes with receptors are lower, than among mature (monocytes and macrophages). Mononuclear phagocytes have ability to endocytosis. Therefore absorption of opsonizirovanny bacteria or the covered IgG of erythrocytes (immune phagocytosis) is the important criterion allowing to carry a cell to S. of m f. However absorption of the erythrocytes covered with a complement does not happen if mo-nonuklearny phagocytes were not previously activated. Except phagocytosis, all mononuklear-ny phagocytes are characterized by an intensive pinocytic. In macrophages prevails makropinotsitoz, to-ry is the cornerstone of capture of all solutions; the vesicles which are formed as a result of internalization of a membrane (emboly of the site of a membrane in a cell), transport substances and out of limits of a cell. Pi-notsitoz is marked out also at other cells (e.g., at fibroblasts), but in weaker degree. Nontoxic vital stains and colloid coal are suitable a little for the characteristic of endocytotic activity of mononuclear phagocytes as are absorbed also by other types of cells.

For identification of antigens, specific to mononuclear phagocytes, antiserums, however receiving the antibodies specific to these cells can be used, still presents great difficulties since many of antiserums contain the antibodies which are cross reacting with other types of cells.

At the cellular level about ability of cells to division judge by inclusion of the marked predecessor of DNA of 3H-thymidine or by the content of DNA in kernels.

A role of system of mononuclear phagocytes in physiological and pathological processes

Mononuclear phagocytes — multifunctional cells, to-rye, having the expressed ability to endocytosis, perform protective function in an organism, take part in processes of an inflammation, immune responses, have antineoplastic activity, participate in regulation of a hemopoiesis and metabolism.

Protective function

is the cornerstone of protective function of mononuclear phagocytes their ability to absorb and destroy selectively various alien agents. The term «professional phagocytes» as absorption (endocytosis) — their main function was assigned to them. Monocytes and macrophages are capable to the directed movement determined by specific chemotactic factors. Regulation of these factors is difficult; in blood serum of the person their inhibitors and inactivators are revealed. In vivo a chemotaxis (see. Taxis ) is caused by components of a complement of SZ and S4, kallikrein, components of a fibrinolysis, products of lymphocytes — lymphokines. Macrophages also are attracted by the substances which are released from bacteria. Thanks to a chemotaxis macrophages migrate in the centers of an infection and an inflammation. After phagocytosis of microorganisms there is their killing and digestion. In process of advance of phagocytal vacuoles in a cell in them the substances which are in lysosomes capable to hydrolyze proteins, the lipids and carbohydrates which are a part of microorganisms are released. Nek-rye from the released components of macrophages, such as peroxidase, a lysozyme, etc., have antimicrobic activity. The lysozyme is an antibacterial agent and out of cells. Wednesday in phagolysosomes becomes acid that promotes manifestation of optimum activity of enzymes of lysosomes. At the same time in the englobing cells there is a sharp increase in metabolism. Digestion comes to the end within one-two hours. Elicited macrophages like neutrophils release hydrogen peroxide and anions of superoxide to the environment and with their help various target cells can lyse. Macrophages take also viruses, and nek-ry of them come to a cell by a pinocytic. The main function of cells of Kupfer of a liver is the clearance (clarification) of blood from bacteria and viruses. The old or damaged erythrocytes are englobed by macrophages of marrow, spleen and liver, and then are exposed to intracellular digestion (erythrophagocytosis).

Participation in an inflammation

the Damaging agents (agents irritants) of various nature cause generally the same reaction of an organism — inflammation (see). The single short-term irritation induces migration of neutrophils and their accumulation in a zone of damage. In 6 hours inflow of neutrophils gradually weakens then migration of macrophages begins, edges continues approximately during Zsut., and then decreases. Macrophages in the center of an acute inflammation are formed only of the circulating monocytes. At a subacute and chronic inflammation macrophages often become the dominating cells and if acute inflammatory process passes in hron. a form, the local proliferation and selection of long-living macrophages directed to maintenance of number of macrophages in the center of an inflammation are observed.

Fig. 4. The diffraction pattern of epithelial cells from the center of an aseptic inflammation: 1 — excentricly located kernels; 2 — borders between the next epithelial cells; 3 — bubbles, vacuoles and granules in cytoplasm; X 5 000.
Fig. 5. The diffraction pattern of the site of multinucleate colossal cell of a foreign body from the center of an aseptic inflammation: shooters specified the kernels which are a part of one cell; X 5 000.

By nature irritating agent removability of macrophages in the center of damage depends. In case of elimination of the provocative agent they disappear (perish or migrate in limf. nodes). At preservation of operation of the activator of an inflammation macrophagic infiltrate remains. If in the course of the response directed to elimination of a toxic and steady irritant (e.g., silicon dioxides, bacteria), there is a loss of a large number of macrophages, then the granuloma forms (see) with a high level of removability of cells. If the irritant is steady against action of macrophages and at the same time is non-toxical, there is a granuloma with low level of removability of cells; in such granuloma long-living macrophages prevail. In many specific granulomas (e.g., at tuberculosis, a sarcoidosis, a leprosy) mononuclear phagocytes turn into epithelial cells (fig. 4) with weak phagocytal activity, but strongly expressed pinocytic and ability to secretion. In the centers hron. inflammations mononuclear phagocytes at merge give rise to so-called macrophagic polykarionums, or multinucleate colossal cells of foreign bodys (fig. 5) and cells like Pirogov — Langkhansa (see. Colossal cells ). The last usually keep very weak phagocytal activity, napr, in relation to bacteria of tuberculosis. In hron. the granulomas caused by particles of quartz continuous death of macrophages results from destruction of lysosomes and self-digestion of cells. At the same time from cells the fibrogenny factor stimulating synthesis of collagen with fibroblasts is released. Besides, elicited macrophages produce fibronectin — the glycoprotein with high molecular weight which is, in particular, the chemoattractant (attracting with the agent) for fibroblasts.

Participation in immune processes

S.'s Cells of m f. take part in immune processes. Primary interaction of a macrophage with antigen (see) — an indispensable condition of development of the directed and maximum immune response (see Immunity). As a result of such interaction antigen is absorbed and processed in a macrophage (processing) then cosecretes in an immuno-gene form, being fixed on its plasma membrane. Immune stimulation of lymphocytes results from their direct contact with macrophages. Further the immune response proceeds with participation of V-lymphocytes, T lymphocytes and macrophages (see. Immunocompetent cells).

Antineoplastic activity

Macrophages have antineoplastic activity and show specific and nonspecific cytotoxic properties thanks to presence of the cytophilic antibodies or factors produced by sensibilized T lymphocytes. Destruction of target cells is usually estimated on release of the related radioactive chrome after an itskubation with cytotoxic macrophages — effectors. The cytotoxicity shown by macrophages is related to a number of immune responses, such as rejection of allotransplants (see. Immunity transplant ) and atrepsy (see. atrepsy ).

Cytotoxic properties two categories of macrophages — effectors have: immune, or so-called armed, the macrophages who are actively destroying specific klet-ki-targets, and nonspecific elicited macrophages with less selective properties. Cytotoxicity of immune macrophages in relation to tumor cells is shown in experiences of in vitro, in to-rykh macrophages from mice, immunizirovanny sin-gene (genetically identical) tumor cells used. At the same time macrophages were not capable to destroy tumor cells if were received from mice, immunizirovanny by the allogenic tumor cells (taken from other animal same look). Specific training (arms) of macrophages depends on products of a specific factor sensibilized T lymphocytes. The exact mechanism of destruction of cells the armed macrophages is still unknown. The contact between them and macrophages is necessary for a lysis of tumor cells. Process of destruction of tumor cells includes a stop of their proliferation and lysis. After a specific immune response between a macrophage and a tumoral target cell the macrophage can lose specificity. In this case it turns into a nonspecific cell effector. Nonspecific cytotoxicity can be observed after an incubation of macrophages with various substances: endotoxin, two-chained RNA and a Freund's adjuvant (see. Adjuvants ).

Participation in regulation of a hemopoiesis

S.'s Cells of m f. take part in regulation myeloid and lymphoid hemopoiesis (see). In red marrow, a spleen, a liver and a vitellicle of an embryo the so-called central macrophage surrounded with one-two rows of erythroblasts is described. Thin cytoplasmatic shoots of the central macrophage get between erythroblasts, and sometimes completely surround them. The central macrophage always becomes the center of an erythrogenesis, together with erythroblasts, adjacent to it, he received the name of an erythroblastic island, to-ry is considered as functional and anatomic unit of the centers of an erythrogenesis. The central macrophage absorbs kernels of erythroblasts, digests old erythrocytes and transfers the accumulated iron to the developing erythroblasts. Nek-ry decomposition products of the absorbed kernels can reutilizirovatsya for new synthesis of DNA by the hemopoietic cells. The central macrophage differs in high resistance to impact of the ionizing radiation and a hypoxia. The central macrophages are stromal elements and perform the regulating function during the maturing of erythroidal cells-predshestvenni-kov, e.g. at fenilgidrazino-howl anemias (see Anemia, anemia experimental). Emergence of new intravaskulyarny erythroblastic islands in marrow, a liver and a spleen is always connected with presence of the englobing macrophages who are differentiated from the monocytes circulating in blood.

Kupfer's cells of a liver participate in regulation of an erythrogenesis by means of development erythropoetin (see).

By means of agar cultures it is established that monocytes and macrophages develop the factors stimulating products of monocytes, neutrophils and eosinophils, and also proliferation of macrophages therefore there are discrete cellular colonies. On the other hand, they can render the inhibiting effect on growth of colonies, synthesizing prostaglandin E (see. Prostaglandins ).

In marrow and an internal zone of cortical substance of segments of a thymus gland and timuszavisimy zones of all peripheral limf, bodies (limf, nodes, a spleen, accumulations limf, fabrics went. - kish. a path) rather so-called interdigitiruyushchy cells were described recently. They are characterized by irregular shape of kernels and existence in cytoplasm of tubulovesicular structures. Their plasma membrane forms the numerous protrusions getting between similar formations of the next cells of the same type or lymphocytes. These cells are morphologically very similar to macrophages, and also Langergans's cells which are localized in epidermis (see Skin). Now most of researchers inclines that interdigitiruyushchy cells — the specific stromal elements of timuszavisimy zones responsible for migration and differentiation T-lim-fotsitov.

Macrophages participate in synthesis of the substances modulating proliferation and a differentiation of lymphoid cells. The factor activating lymphocytes and providing the mitogenetic (blastogenic) answer of T lymphocytes to lectin and histocompatibility antigens (see Blastotransformation of lymphocytes), and also the factors strengthening helper function of T lymphocytes concerns to them (strengthening of antibodyformation in V-lymphocytes). By means of cloning of V-lymphocytes it is shown that macrophages develop the diffusion factor promoting formation of colonies subpopulation of V-lymphocytes. The excess number of macrophages, on the contrary, leads to suppression of growth of colonies as a result of production of prostaglandin E.

Exchange function

Exchange process, in Krom is authentically proved a role of macrophages, exchange of iron is. As a result of an erythrophagocytosis in macrophages of marrow and spleen there is an accumulation of iron in the form of specific needle or rhabdoid inclusions of ferritin and hemosiderin. Ferritin then comes by a pinocytic (see) to adjacent erythroblasts. At fe-nilgidrazinovy anemia in macrophages increase in the rhabdoid inclusions containing ferritin is observed.

Bibliography: Mononuclear phagocytes, ed. by R. van Furth, Oxford — Edinburgh, 1970; Mononuclear phagocytes, In immunity, infection and pathology, ed. by R. van Furth, Oxford a. o., 1975; Mononuclear phagocytes, Functional aspects, ed. by R. van Furth, pt 1 — 2, Hague a. o., 1980.

H. G. Hrushchov, V. I. Starostin.