Monocytes, Macrophages, and Their Diseases in Man

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Monocytes, Macrophages, and Their Diseases in Man oo22-202X/ 78/ 7101-0056$02.oo/ 0 THE Jo fiNA L O F INVESTIGATIVE DERMATOLOGY, 71:56-58,1978 Vol. 71, NO.1 Copyright © 1978 by The Williams & Wilkins Co. Printed in U.S.A. I Monocytes, Macrophages, and Their Diseases in Man MARTiN J. CLINE, M.D. Division of Hematology-Oncology, Department of Medicine, University of California School of Medicine, Los Angeles, California, U.S.A. Mononuclear phagocytes are a widely distributed sys­ pool in a ratio of 1:3, (iii) monocytes leave the blood exponen­ tem of cells involved in host defense functions, immu­ tially with a half life of 8.4 hr, (iv), the half life may be prolonged nologic reactions, disposal of unwanted organic and in­ in patients with monocytosis and shortened in patients with \ organic materials, and synthesis of biologically active acute infection or splenomegaly, and (v) the normal monocyte compounds such as complement components and pros­ turnover rate averages 7 X lOG cells pel' hour pel' kilogram of taglandins. The system includes early precursor cells in body weight. the bone marrow, blood monocytes, alveolar and peri­ Available data suggest that there is no significant reentry of toneal macrophages, sinusoidal lining cells in the spleen, monocytes into the bloodstream once they have left the circu­ and Kupffer cells in the liver. We have recently come to lation. They enter the tissues and mature to macrophages. The understand the biology of these interesting cells and the major source of mononuclear phagocytes accumulating at in­ diseases they produce. flammatory foci is the monocyte precursors of the bone marrow [6]. Under noninflammatory conditions tissue macrophages may also arise from endogenous replicating cell populations, as Mononuclear phagocytes constitute a cell line that includes well as from man-ow precursors [7]. monoblasts and promonocytes in the bone marrow, the mono­ cyte as a cell of intermediate differentiation in the blood, and METABOLISM OF MONONUCLEAR PHAGOCYTES mature macrophages in the tissues. Tissue macrophages are The metabolism and enzymatic activities of mononuclear \ heterogeneous and include free alveolar and peritoneal macro­ phagocytes change profoundly with cell maturation and with phages, Kupffer cells, and the macrophages of the splenic changes in cellular environment [2,8]. The principal energy sinusoids. The concept of a continuum of cells from bone source for human monocytes and for most tissue macrophages marrow precursors to the mature tissue macro phages is impor­ is glycolysis, even under aerobic conditions. In contrast, the tant to an understanding of the function and metabolism of metabolism of the nonphagocytic human alveolar macrophage these cells. appears to be primaril'y aerobic [2,9]. MATURATION OF MONONUCLEAR PHAGOCYTES Macrophages have an active lipid metabolism, and phospho­ lipid synthesis is increased during phagocytosis. The more Mononuclear phagocytes share a common progenitor cell mature cells of the series have abundant rough endoplasmic with the granulocytic series. The earliest cells of these series reticulum and a high rate of protein synthesis. Much of this are undifferentiated lymphocyte-like cells [1]. When undiffer­ synthetic activity is directed toward the production oflysosomal entiated monoblasts mature and form a complex Golgi appa­ enzymes, but other biologically active compounds, such as ratus and a definite granule population, they are identifiable complement components, are also made in these cells. and are designated promonocytes. The promonocyte has a high The many hydrolytic enzymes localized within the lysosomal I nucleus-to-cytoplasm ratio, basophilic cytoplasm, and some cell fraction [2] probably have a major role in the digestion of peroxidase activity. The cell generally shows little phagocytic phagocytized organic materials, including erythrocytes and mi- \ activity. With maturation to the monocyte level, the activity of croorganisms. Some lysosomal enzymes may also be secreted certain acid hydrolases and the phagocytic ability increase by macro phages [10]. [2,3]. The transformation from monoblast to mature macrophage Tissue macrophages (synonym: histiocytes) are later stages is associated with changes in cellular composition and m e­ of maturation of monocytes. They are large cells 20 to 80 !Lm in tabolism. With maturation, the number of cytoplasmic lyso­ diameter, with one or more large vesicular nuclei and abundant somes and mitochondria increases, and the activity levels of cytoplasmic lysosomes, numerous mitochondria, and other in­ associated lysosomal and mitochondrial enzymes change Cor- \ clusions. The cells move slowly, and the movement appears to respondingly. Differentiation to mature macrophages and the depend on the complex of microfllaments. Immature macro­ accompanying increase in specific activity of certain lysosomal phages are capable of DNA synthesis and cell division, but enzymes are dependent on intact protein synthesis. When mac­ ultimately immature cells give rise to mature nondividing mac­ rophages are cultivated in vitro under circumstances in which rophages. These macrophages may form multinucleate giant pinocytic activity is reduced, the many secondary lysosome cells, probably by the process of cell fusion. These giant cells, gradually disappear from the cytoplasm. Such influence of \ seen in chronic granulomatous reactions, are rich in lysosomes environmental factors on the cellular level oflysosomal enzymes and hyd.rolytic enzymes. seen in vitro probably reflects the situation in the intact animal in which the functional status of the macrophages is adaptable. KINETICS OF MONONUCLEAR PHAGOCYTES This phenomenon is most clearly demonstrated in macro phages The studies of Meuret, Bammert, and Hoffmann [4,5] indi­ "activated" by infection with an intracellular parasite, such a cate the following: (i) normally blood monocyte counts oscillate Mycobacterium tuberculosis. These mononuclear phagocyte with a cycle frequency of 3 to 6 days, (ii) the total blood are larger, spread more readily on a sUlface, and have increased \ monocyte pool comprises a circulating pool and a marginated metabolic and microbicidal activity. Activation is thought to be mediated by products of sensitized lymphoid cells [11]. \ Supported by USPHS Grant CA 15688. Dr. Cline is a recipient of an endowment from the Ambrose and Gladys Bowyer Foundation. FUNCTIONS OF MONONUCLEAR PHAGOCYTES Reprint requests to: Martin J. Cline, M.D., Division of Hematology­ Oncology, Department of Medicine, University of California School of Five major areas of mononuclear phagocyte function have Medicine, Los Angeles, California 90024. been identified: (i) defense against microorganisms, (ii) removal Abbreviation: of dead or damaged cells, cell debris, and inorganic material , \ eSA: colony stimulating activity (iii) cooperative and effector functions in immune responses, \ 56 July 1978 MONOCYTES, MACROPHAGES, AND THEIR DISEASES IN MAN 57 (iv) regulatory interactions in hematopoiesis, and (v) synthesis proliferative response to mitogen and the generation of helper of other biologically active compounds, such as complement T cells requires interaction with macro phages [20]. Macrophage components and prostaglandins. These cells may also play a interactions with T cells are complex and require cells that are role in wound repair and remodeling of embr~'onic tissues. genetically compatible. In summary, it is apparent that lymphoid cells may activate DEFENSE AGAINST MICROORGANISMS macrophages and that macrophages may activate and direct Monocytes and macrophages have an important role in the lymphocytes. defense against a variety of infectious organisms [2,8,12]. They are the principal cells involved in killing intracellulaj' parasites CELL-MEDIATED CYTOTOXICITY AND ANTITUMOR such as Mycobacteria, Listeria, and Toxoplasma [13]. Macro­ IMMUNITY phages participating with immunocompetent cells may also kill virus and virus-infected cells, and have been demonstrated to The role of monocytes and macrophages in the control of produce interferon and to enhance lymphocyte production of neoplasia is of considerable interest but is still uncertain [21]. interferon. It is thought that mononuclear phagocytes may act as effector Mononuclear phagocytes are chemotactically attracted to an cells in various cytotoxic reactions. One form is referred to as infective focus, where they phagocytize the invading organism. antibody-dependent, cell-mediated cytotoxicity (ADCC). This The activated fifth component of complement, as well as factors mechanism depends on the coating of target cells with specific released by mitogen- and antigen-stimulated lymphocytes are antibody and subsequent identification and destruction by ef­ chemotactic for monocytes. fector cells. Mononuclear phagocytes, as well as granulocytes, Macrophages may accumulate at an infective focus under the can function in ADCC [22]. Macrophage recognition of anti­ influence of another lymphocyte-derived factor, migration-in­ body-coated target cells depends on membrane receptors for hibiting factor. This factor may be the same molecule that the Fc portion of subclasses of IgG antibody. activates macrophages (macrophage-activating factor) and is Monocytes and macrophages also participate in cytotoxic probably one of the inducers of the complex series of metabolic reactions mediated by humoral antibody (cytophilic antibody) changes that result in the "activated" state [14]. that attaches first to the effector cells. This type of antitumor The precise mechanisms by
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