Nadph

NADPH oxidase

NADP"

A complex set of biochemical events unfolds after phagocytosis to activate the neutrophil NADPH oxidase, which is dormant in resting cells. The oxidase is activated by its interaction with an activated G protein and cy-tosolic molecules that are generated during phagocytosis. The NADPH oxidase is activated in a manner that allows the enzyme to secrete the toxic free radical, superoxide, into the phagocytic vacuole while oxidizing NADPH in the cell's cytoplasm. This explosion of metabolic activity, collectively termed the respiratory burst, leads to the generation of potent, reactive agents not otherwise generated in biological systems. These agents are so reactive that they actually generate light (biological chemiluminescence) when they oxidize components in the bacterial cell wall.

Other bactericidal agents and processes operate in neu-trophils to ensure efficient bacterial killing. Phagocytized bacteria encounter intracellular defensins, cationic proteins that bind to and inhibit the replication of bacteria. De-fensins and other antibacterial agents pour into the phago-cytic vacuole after phagocytosis. Agents stored in neutrophil granules include lysozyme, a bacteriolytic enzyme, and myeloperoxidase, which reacts with hydrogen peroxide to generate potent, bacteria-killing oxidants. One of the oxidants generated by the myeloperoxidase reaction is hypochlorous acid (HOCl), the killing agent found in household bleach. Granules also contain collagenase and other proteases.

Eosinophils. Eosinophils are rare in the circulation but are easily identified on stained blood films. As the name implies, the eosinophil takes on a deep eosin color during polychromatic staining; the large, refractile cytoplasmic granules of these cells stain orange-red to bright yellow. Like neutrophils, eosinophils migrate to sites where they are needed and exhibit a metabolic burst when activated. Eosinophils participate in defense against certain parasites, and they are involved in allergic reactions. The exposure of allergic individuals to an allergen often results in a transient increase in eosinophil count known as eosinophilia. Infection with parasites often results in a sustained overproduction of eosinophils.

Basophils. Basophils are polymorphonuclear leukocytes with multiple pleomorphic, coarse, deep-staining metachromatic granules throughout their cytoplasm. These granules contain heparin and histamine, which have anticoagulant and vasodilating properties, respectively. The release of these and other mediators by basophils increases regional blood flow, facilitating the transport of other leukocytes to areas of infection and allergic reactivity or other forms of hypersensitivity.

Monocytes and Lymphocytes. In contrast to granulocytes, monocytes and lymphocytes are mononuclear cells. Monocytes are phagocytic cells but lymphocytes are not; both participate in multiple aspects of immunity. Mono-cytes were originally differentiated from lymphocytes based on morphological characteristics. The cytoplasm of monocytes appears pale blue or blue-gray with Wright's stain. The cytoplasm contains multiple fine reddish-blue granules. The monocyte nucleus may be shaped like a kidney bean, indented, or shaped like a horseshoe. Frequently, however, it is rounded or ovoid. Upon activation, mono-cytes transform into macrophages—large, active mononuclear phagocytes.

Morphologically, circulating lymphocytes have been assigned to two broad categories: large and small lymphocytes. In blood, small lymphocytes are more numerous than larger ones; the latter closely resemble mono-cytes. Small lymphocytes possess a deeply stained, coarse nucleus that is large in relation to the remainder of the cell, so that often only a small rim of cytoplasm appears around parts of the nucleus. In contrast, a broad band of cytoplasm surrounds the nucleus of large lymphocytes; the nucleus of these cells is similar in size and appearance to that of small lymphocytes.

The morphological homogeneity of lymphocytes obscures their functional heterogeneity. As is discussed below, lymphocytes participate in multiple aspects of the immune response. Lymphocyte subtypes in blood (see Fig. 11.2) are often identified based on their reaction with fluorescent monoclonal antibodies. The majority of circulating lymphocytes are T cells or T lymphocytes (for "thymus-dependent lymphocytes"). These cells participate in certain types of immune responses that do not depend on antibody. T cells comprise 40 to 60% of the total circulating pool of lymphocytes.

Subtypes of T cells have been identified using fluorescent monoclonal antibodies to specific cell-surface antigens, known as CD antigens. All T cells possess the common CD3 antigen. So-called helper T cells possess the CD4 antigen cluster, while suppressor T cells lack CD4 but possess CD8. Patients with AIDS show decreased circulating levels of CD4-positive cells. Natural killer (NK) cells are T lymphocytes that possess the ability to kill tumor cells without prior exposure or priming.

Some 20 to 30% of circulating lymphocytes are B cells, which have immunoglobulin or antibody on their surface. B cells are bone marrow-derived lymphocytes; when im-munologically activated, they transform into plasma cells that secrete immunoglobulin. Lymphocytes not characteristic of either T cells or B cells are called null cells. The entire scope of the function of null cells, which comprise only 1 to 5% of circulating lymphocytes, is unknown, but it has been established that null cells are capable of destroying tumor cells and virus-infected cells.

While B cells mediate immune responses by releasing antibody, T cells often exert their effects by synthesizing and releasing cytokines, hormone-like proteins that act by binding specific receptors on their target cells. Recent research has led to the discovery of many cytokines, with activities ranging from tumor destruction, a function of tumor necrosis factor, to the promotion of blood cell production. Cytokines that limit viral replication in cells, known as interferons, suppress or potentiate the function of T cells, stimulate macrophages, and activate neutrophils.

In some cases, cytokines, like other hormones, can exert potent effects when supplied exogenously. For example, colony-stimulating factors injected into cancer patients can prevent decreases in the production of leukocytes that result from the administration of chemotherapeutic drugs or radiation therapy. The technology of molecular biology is used to produce cytokines for therapy. In this process, sections of lymphocyte DNA containing the gene that codes for the specified cytokine are isolated and then transfected into a bacterial cell, fungus, or rapidly growing mammalian cell. These cells then produce the cytokine and release it into their culture supernatant, from which it can be purified, concentrated, and sterilized for injection. The biological diversity and potency of the cytokines has opened the door to the development of a variety of new pharmacological agents that have proved useful in the treatment of cancer, immune disorders, and other diseases.

Blood Cells Are Born in the Bone Marrow

Mature cells are transient residents of blood. Erythrocytes survive in the circulation for about 120 days, after which they are broken down and their components recycled, as discussed above. Platelets have an average lifespan of 15 to 45 days in the circulation; many, if not most, of these cells are consumed as they continuously participate in day-today hemostasis. The rate of platelet consumption accelerates rapidly during the repair of bleeding caused by trauma. Leukocytes have a variable lifespan. Some lymphocytes circulate for 1 year or longer after production. Neutrophils, constantly guarding body fluids and tissues against infection, have a circulating half-life of only a few hours. Neu-trophils and other blood cells must, therefore, be continuously replenished.

As mentioned earlier, the process of blood cell generation, hematopoiesis, occurs in healthy adults only in the bone marrow. Extramedullary hematopoiesis (e.g., the generation of blood cells in the spleen) is observed only in some disease states, such as leukemia. Hematopoietic cells are found in high levels in the liver, spleen, and blood of the developing fetus. Shortly before birth, blood cell production gradually begins to shift to the marrow. In newborns, the hematopoietic cell content of the circulating blood is relatively high; hematopoietic cells are also found in the blood of adults, but in extremely low numbers. Large numbers of hematopoietic cells can be recovered from aspirates of the iliac crest, sternum, pelvic bones, long bones, and ribs of adults. Within the bones, hematopoietic cells germinate in extravascular sinuses, called marrow stroma. Circulating factors and factors released from capillary en-dothelial cells, stromal fibroblasts, and mature blood cells regulate the generation of immature blood cells from hematopoietic cells and the subsequent differentiation of newly formed immature cells.

Blood cell production begins with the proliferation of pluripotent (uncommitted) stem cells. Depending on the stimulating factors, the progeny of pluripotent stem cells may be other uncommitted stem cells or stem cells committed to development along a certain lineage. The committed stem cells include myeloblasts, which form cells of the myeloid series (neutrophils, basophils, and eosinophils); ery-throblasts; lymphoblasts; and monoblasts (Fig. 11.7; see also Fig. 11.2). Promoted by hematopoietins and other cy-tokines, each of these blast cells differentiates further, a process that ultimately results in the formation of mature blood cells. This is a dynamic process; the hematopoietic cells of the bone marrow are among the most actively reproducing cells of the body. Interruption of hematopoiesis (e.g., by cancer treatment) results in the eventual disappearance of granulocytes from the blood, a condition known as granulo-cytopenia, or, when specific to neutrophils, neutropenia, in a matter of hours. Platelets disappear next—thrombocytopenia—followed by erythrocytes, a sequence that reflects

Pluripotent (uncommitted) stem cell

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