Fundamentals of Medical Physiology

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Fundamentals of Medical Physiology provides a concise, in-depth introduction by organ system to the principles of body function and uses emphasis on general models and clinical cases to foster mastery of these principles.

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  • 162

    29 Agranulocytes and Lymphoid Organs

    Monocytes

    Monocytes (Fig. 29.1) are spherical cells. When suspended in isotonic fluid, their diameter is 9 to 12 m, but when flattened in dried blood smears, they measure up to 14 to 18 m in diameter. They have a relatively abundant dull blue cytoplasm with a few azurophilic granules. The nucleus is round or kidneyshaped and is eccentric in position. Its chromatin stains less intensely than that of lymphocytes, and there are one or two nucleoli.

    Monocytes originate in bone marrow and circulate in blood for 3 days before migrating through the walls of postcapillary venules into the connective tissue of various organs, where they differentiate into tissue macrophages. Tissue macrophages do not reenter circulation, but persist in the tissues for another 3 months. Circulating monocytes perform no important function and are only a mobile reserve of cells capable of migrating into tissues and developing into macrophages.

    Monocytosis (an increase in monocyte count, see Table 20.3) occurs in (1) bacterial infections, such as tuberculosis and typhoid; (2) protozoal infections, such as malaria; (3) rickettsial infections; (4) neoplastic diseases, such as infectious mononucleosis, Hodgkin disease, and monocytic leukemia; and (5) chronic inflammatory diseases, such as rheumatoid arthritis, collagen diseases, ulcerative colitis, and regional enteritis.

    Mononuclear Phagocytic SystemTissue macrophages settle at several strategic locations in the body and constitute the tissuemacrophage system. Monocytes and macrophages together constitute the mononuclear phagocytic system. The mononuclear macrophage system was earlier called the reticuloendothelial system (RES), a term

    that encompassed a large collection of phagocytic cells. Any cell capable of taking up a vital dye such as trypan blue and particulate materials like colloidal carbon was called an RES cell. The RES therefore included (1) reticulum cells of the spleen and the lymph nodes; (2) cells lining the lymphatic and blood sinuses of the lymph nodes, spleen, and liver (Kupffer cells); (3) monocytes of blood; and (4) tissue macrophages. The reticuloendothelial system was so named because it included the reticulum cells of the spleen and lymph nodes and also the cells lining the splenic and hepatic sinusoids, which were thought to be endothelial cells. It was later discovered that the true endothelial cells and fibroblasts were also capable of taking up the dye, and although they were weakly phagocytic, they were for some time included under the RES.

    The RES was later renamed the mononuclear phagocytic system (MPS). It includes (1) precursor cells from bone marrow; (2) promonocytes from bone marrow; (3) monocytes from bone marrow and blood; and (4) macrophages in the liver (Kupffer cells), spleen, lymph node, bone marrow, lung (pulmonary alveolar macrophages, also called dust cells), connective tissue (histiocytes), pleura and peritoneum, bones (osteoclasts), and central nervous system (microglial cells). The criteria for identifying a cell of the MPS are vigorous phagocytosis and pinocytosis and its ability to attach firmly to a glass surface. Reticulum cells of the spleen and lymph nodes, endothelial cells, and fibroblasts are not included in the MPS.

    The functions of the MPS are as follows. (1) Macrophages ingest cell debris, broken erythrocytes, fibrin, and bacteria; therefore, they are important in inflammation and healing. (2) Bacteria entering the tissues through blood or lymph are sequestered and destroyed by the macrophages. (3) Macrophag es process antigens and thereby play an important part

    A

    C

    B

    D

    Fig. 29.1 (AC) Range of appearances of typical monocytes with lobed nucleus, gray-blue stained cytoplasm, and fine granulation. (D) Phagocytic monocyte with vacuoles.

  • 29 Agranulocytes and Lymphoid Organs I 163

    in the immune response. Macrophages are also very efficient in pha go cytosing antigenantibodycomplement complexes because they have receptors for immunoglobulins and complement. (4) Macro phages, especially those in the spleen, remove aged erythrocytes. The heme moiety is divested of its iron, which is stored in the macrophages. (5) Macrophages store excess lipids and mucoprotein and become swollen to form foam cells. (6) Twenty or more macrophages can fuse to form a multinu cleate giant cell, up to 50 m in diameter, that engulfs a bacillus, especially the tubercle bacillus.

    Lymphocyte

    Lymphocytes (711 m) have a deeply staining, slightly indented nucleus with a thin rim of clear blue cytoplasm (Fig. 29.2). They contain no specific granules, but may have a few small azurophilic granules.

    Large and small lymphocytes I About 10 to 20% of the lymphocytes in peripheral blood are large lymphocytes (1115 m). These were believed to be in an early stage of development from the lymphoblast, which is larger than the lymphocyte. However, it is now known that these large lymphocytes are actually natural killer (NK) cells. They nonspecifically kill any cell that is coated with immunoglobulin IgG. This phe nomenon is called antigendependent cellmediated cytotoxicity (ADCC). Large lymphocytes require neither any prior sensitization nor major histocompatibility (MHC) molecules (see Chapter 31, Initial Phase of Immune Response section) for antigen re cognition. They are therefore responsible for innate immunity rather than acquired immunity. They are particularly effective against tumor cells and virusinfected cells.

    Small lymphocytes produce acquired immune response. They are classified as B lymphocytes, which mediate humoral immunity, and T lymphocytes, which mediate cellular immunity. These subtypes are not morphologically distinguishable, but have distinctive molecules on their cell membranes (surface markers) that are identifiable by immunocytochemical methods.

    Lymphocytic count I The normal lymphocytic count is giv en in Table 20.3. Lymphocytosis occurs in (1) viral infections (e.g., mumps, measles, chicken pox, influenza, and viral hepatitis), (2) bacterial infections (e.g., typhoid, tuberculosis, and whooping cough), (3) parasitic infections (e.g., toxoplasmosis), (4) malignancies (e.g., lymphocytic leukemia and lymphocytic lymphoma), and (5) autoimmune diseases (e.g., myasthenia gravis and thyrotoxicosis).

    Lymphopenia occurs in (1) acquired immunodeficiency syndrome (AIDS), (2) pancytopenia from any cause (e.g., aplastic anemia, bone marrow infiltration, and hypersplenism), and (3) corticosteroid administration.

    Lymphocytic ProcessingThe committed lymphocytic stem cells soon differentiate into the committed B and T cells. The committed B lymphocytic stem cells are processed (rendered mature and immunocompetent) in the bone marrow (B for bursa of Fabricius, the site of B cell processing in birds). The committed T lymphocytic stem cells are processed in the thymus. The processing involves brisk proliferation with frequent mutations during cell divisions. These mutations may have a role in the development of antibody specificity. In the thymus, a factor called thymosin plays an important role in the processing of T lymphocytes.

    Following processing, the mature T and B cells enter the circulation, where they are present in a 70:30 ratio. Many of them leak out through the postcapillary venules to settle in the peripheral lymphoid tissues (see below). Some of the lymphocytes return again to the circulation through the lymphatics draining these lymphoid tissues. At any given time, only ~2% of the lymphocytes are in the peripheral blood; the rest remains in the lymphoid organs. Within the peripheral lymphoid tissues, the T and B lymphocytes are found in distinct zones, as shown in Table 29.1. After birth, some lymphocytes are still formed in the bone marrow, but most are formed in the lymph nodes, thymus, and spleen from precursor cells that originally came from bone marrow.

    Fig. 29.2 Lymphocytes (arrows).

  • 164 I IV Blood and Immune System

    Lymphoid Tissues

    Lymphocytes occur individually in blood, lymph, and connective tissues. They also occur in densely packed aggregates. The term lymphoid tissue includes all aggregations of lymphocytes and lymphocyterich organs, such as the thymus, lymph nodes, and spleen.

    The lymphoid tissues in which lymphocytes are processed, the thymus and bone marrow, are called central or primary lymphoid tissues. The lymphoid organs in which processed lymphocytes are seeded are called peripheral or secondary lymphoid tissues. They include lymph nodes, the spleen, the lymphoid tissues associated with the alimentary tract (including the tonsils in the oral cavity and the Peyers patches in the terminal ileum), respiratory and urinary tracts, and a portion of lymphocytes in bone marrow.

    ThymusThe thymus is located anterior to the heart. In a small child, it may extend up to the neck, almost to the level of the thyroid gland. The thymus reaches its greatest size during puberty. After puberty, the thymus regresses (thymic involution), during which the thymic lymphocytes and epithelial cells are increasingly replaced by adipose tissue, though some thymic tissue persists throughout life.

    The thymus consists of a cortex and a medulla. The cortex contains lymphocytes and thymocytes (precursors to the lymphocytes). The medulla contains mostly epithelial cells. The thymus is the first organ to become lymphoid in the fetus, as it gets seeded by bloodborne lymphocytes from the yolk sac and the fetal liver. The seeding is aided by thymotaxin, a chemotactic factor secreted by the thymus. Lymphocytes processed in the thymus are called T lymphocytes. During their processing in the thymus, the T lymphocytes develop surface molecules (also called surface markers) called CD4 and CD8, which form