Neutrophils are circulating granulocytes that are also known as polymorphonuclear leukocytes (polys or PMNs). They account for 60% to 80% of the total WBC count. Neutrophils normally have two to five nuclear lobes and coarse, clumped chromatin. Neutrophils arise from bone marrow stem cells and undergo several stages of maturation. As illustrated in Figure 9-2, these stages, from least to most mature, are myeloblast, promyelocyte, metamyelocyte, band cell, and mature segmented neutrophil.

Neutrophils stored in the bone marrow outnumber, by about 10-fold, the quantity of circulating neutrophils. An adult produces more than 1 × 10¹¹ neutrophils each day.¹ These stored neutrophils are released into the circulation, where they have a half-life of 4 to 10 hours. Neutrophils that are not recruited into tissues within about 6 hours undergo programmed cell death (apoptosis). Neutrophils are early responders to an acute bacterial infection and arrive in large numbers very quickly. They are phagocytes that engulf and degrade microorganisms. Circulating neutrophils have receptors on their cell surfaces that enable them to bind to endothelial cells in areas of inflammation. These receptors, called L-selectins, allow neutrophils to adhere and roll along the capillary surface.⁵ Other interactions between neutrophil integrin receptors and extracellular matrix then facilitate movement of neutrophils through the capillary wall and into the tissue. Neutrophils are attracted to areas of inflammation and bacterial products by chemotactic factors such as complement fragments and cytokines. This process is discussed in more depth in the section titled Inflammation.

Initially during an acute infection, neutrophilia, or an increase in the number of circulating neutrophils, occurs as the bone marrow releases stored neutrophils. As neutrophils are consumed and demand exceeds production, an increase in the number of immature (band) neutrophils occurs. Bands are identified by their lack of nuclear segmentation. This increase in band cells is referred to as a “shift to the left of normal” (Figure 9-5). Traditionally, the band count has been used to differentiate bacterial from viral infections, and a greater shift to the left is viewed as a more severe infection. The utility of using the band count for these purposes has been called into question because the specificity is poor.⁶

Neutrophils produce potent chemical mediators that enable them to destroy microorganisms. Numerous toxins released by neutrophils have been identified, including oxidizing free radicals, defensins, and proteolytic enzymes, such as elastase.7 Because of the ability to generate free radicals and release enzymes, neutrophils can cause extensive damage to normal tissue during their inflammatory response.

Eosinophils are particularly associated with an increase in number during allergic reactions and infection by intestinal parasites. The role of eosinophils in allergic reactions is less well characterized than that of mast cells. Eosinophils are recruited into areas of inflammation by the chemokine eotaxin, which is produced by epithelial cells.3 Eosinophils release inflammatory chemicals, such as lysosomal enzymes, peroxidase, major basic protein, and cationic protein. The primary function of eosinophils is to kill parasitic helminths (worms). Helminths are too large to be phagocytosed by neutrophils or macrophages, and their exterior is resistant to attack by complement or mast cell products. Eosinophils produce specialized molecules such as major basic protein and eosinophil cationic protein, which may be more effective against helminths.¹ Eosinophils recognize helminths that have been opsonized (coated) with IgE antibody. They bind to the IgE and then release their stored chemicals onto the surface of the opsonized helminth. Parasitic infections are a significant problem in much of the world, with one third of the population being affected.

Mast cell and basophil granules contain histamine, platelet-activating factor, and other vasoactive amines that are important mediators of immediate hypersensitivity responses (Figure 9-6). Degranulation of mast cells and basophils begins the inflammatory response that is characteristically associated with allergic reactions. Mast cells and basophils are also involved in wound healing and chronic inflammatory conditions (see Chapter 10).

Phagocytosis by macrophages is similar to that by neutrophils except that neutrophils are short-lived and die in the process of fighting infection. Macrophages, in contrast, may live for months to years and can migrate in and out of tissue. Macrophages are more efficient phagocytes than neutrophils and can ingest several times as many microorganisms (Figure 9-7). Macrophages are capable of cell division and may proliferate at the site of inflammation.

Macrophages are covered with a variety of receptor proteins on their cell surface (Figure 9-8). Some of these receptors help macrophages locate antigens that have been coated by antibodies. These receptors are called Fc receptors because they bind to the part of an antibody called the constant fragment, or Fc. Macrophages also have receptors for the complement component C3b. Complement, like antibodies, can coat an antigen and make it more recognizable to macrophages. Coating of antigen by antibodies or by complement is called opsonization. Macrophages have receptors that help them recognize bacteria directly. These innate pattern-recognition receptors bind to particular molecules prevalent in the bacterial cell wall. For example, mannose receptors and numerous Toll-like receptors on macrophages allow them to recognize common microbial structures (see Figure 9-8). Other receptors, called selectins and integrins, help macrophages adhere to capillary walls, and enter and move through tissue. Integrin receptors bind to proteins in the extracellular matrix and help macrophages target or “home” to certain areas.

In addition to their phagocytic function, macrophages have important secretory function. Some of the substances secreted by macrophages are cytokines, which help to coordinate the activities of other immune cells (Figure 9-9). Macrophage cytokines include IL-1, IL-6, IL-12, and tumor necrosis factor-α (TNF-α). These cytokines promote inflammation, as well as the activity of other WBCs, including neutrophils and lymphocytes (see the section titled Cytokines and Chemokines).

Dendritic cells are derived in the bone marrow from the same progenitor cells that produce monocytes and macrophages (Figure 9-10) and are structurally and functionally similar to macrophages (Figure 9-11). Dendritic cells derive their name from an unusual shape that has extensive projections from the surface. Dendritic cells are located throughout the body as part of the mononuclear phagocyte system. They function primarily as antigen-presenting cells, capturing antigen in tissues and then migrating to lymphoid areas to present antigen to T cells. Some types of dendritic cells produce chemical messengers called type I interferon (IFN-α and IFN-β) in response to viral infections. Type I interferons suppress the viral replication machinery in nearby cells and help stop the local spread of the virus.

The complement system consists of about 20 plasma proteins that interact to enhance inflammation, chemotaxis, and lysis of target cells. Complement proteins are synthesized in the liver and by macrophages and neutrophils. They circulate in the blood in an inactive form. Activation of the complement cascade occurs via three different pathways: classical, alternative, and lectin. In all three pathways, the inactive complement proteins are converted to their active form in a sequence of reactions. Major actions of complement proteins include cell lysis, facilitation of phagocytosis by opsonization, inflammation, and chemotaxis (Figure 9-16).

The classical pathway is usually triggered by IgG or IgM antibody-antigen complexes. The alternative pathway can be initiated on first exposure to an antigen. Lipopolysaccharide, in bacterial cell walls, and bacterial endotoxin are effective triggers of the alternative pathway. In the classical pathway, an antibody hooked onto an antigen combines with C1, the first of the complement proteins. This step sets in motion a domino effect called the complement cascade (Figure 9-17). The alternative pathway begins with the activation of C3. The alternative pathway can be activated on first exposure and is part of the innate immune response.¹⁰ The lectin pathway also can be triggered on first exposure. Lectin is a circulating biomolecule that binds mannose on bacterial cell walls and triggers complement activation at C2 and C4. C3 spontaneously degrades into active C3b fragments in plasma. If microbial cell surfaces are present, the C3b fragment can bind directly to the microbe. Two other complement proteins, factors B and D, combine with C3b to initiate the alternative pathway. C3 is the most important and plentiful of the complement proteins. C3 divides into two fragments called C3a and C3b. C3a is a proinflammatory protein that causes histamine release from mast cells, contraction of smooth muscle, and increased endothelial cell permeability. C3b initiates the next step in the cascade by cleaving C5 into its active fragments C5a and C5b. Complement protein fragment C5a is both a powerful inflammatory chemical and a potent chemotactic agent. C5a chemotaxis stimulates neutrophils and monocytes to migrate to the inflamed tissue. C5a also activates neutrophils by triggering their oxidative activity and increasing their glucose uptake.

The C5b fragment combines with C6, C7, C8, and multiple units of C9 to form a large porelike structure (C5b6789) called the membrane attack complex. The membrane attack complex has a direct cytotoxic effect by attacking cell membranes and disrupting the lipid bilayer. This action allows free movement of sodium and water into the target cell, which causes it to rupture (see Figure 9-17). The complement system is a potent inflammatory and cytotoxic system that is carefully regulated by eight known inhibitory factors.³ Normal host cells produce membrane and inhibitory plasma proteins that prevent complement binding to their surface (e.g., C1 inhibitor, protein S).

Bradykinin and kallidin are two of the many kinins present in the body. Kinins are small polypeptides that cause powerful vasodilation. They are especially active in the inflammatory process. The kinin system is linked to the clotting system via the Hageman factor (XII) and is activated with the activation of clotting.1 The first step in this process is the conversion of factor XII to factor XIIa (Figure 9-18). Factor XIIa converts a substance known as prekallikrein to kallikrein. Kallikrein converts precursor substances known as kininogens to kinins. The most prevalent is kallidin, which is then converted to bradykinin. Activated kinins cause increased vascular permeability, vasodilation, and smooth muscle contraction. Kinins are also responsible for pain, which is one of the classic signs of inflammation.

The blood coagulation cascade’s major purpose is to stop bleeding. It is also intimately involved in inflammation and triggering of the kinin system. The key linkage between the inflammatory response and clotting system is activated factor XII (Hageman factor) (see Figure 9-18). (The blood coagulation cascade is discussed in detail in Chapter 14.) Activation of the coagulation cascade results in the formation of insoluble fibrin strands, which provide an effective barrier to the spread of infection. Clot formation also activates the fibrinolytic cascade, which splits fibrin proteins. Some of the fibrin degradation products are chemotactic signals for neutrophils.

Cytokines are polypeptide signaling molecules that affect the function of other cells by stimulating surface receptors. Cytokines function in a complex intercellular communication network. WBC cytokines have previously had many names, including monokines, lymphokines, and interleukins, depending on their cell of origin. The number of known cytokines is large and growing; they can be grouped according to their source and function (Table 9-2).

TABLE 9-2

SELECTED IMMUNE CYTOKINES AND THEIR FUNCTIONS

CYTOKINE	ORIGIN	FUNCTION
IFN-α	Macrophages and induced by RNA or DNA viruses and by single- or double-stranded polyribonucleotides	Inhibits virus replication, toxic to cancer cells, stimulates leukocytes, facilitates NK cell activity, produces fever, increases B- and T-cell activity
IFN-β	Fibroblasts and induced by RNA or DNA viruses and by single- or double-stranded polyribonucleotides	Inhibits virus replication, toxic to cancer cells, facilitates NK cell activity, produces fever
IFN-γ	T cells (TH1 and CD8+) and NK cells	Inhibits virus replication, promotes antigen expression, activates macrophages, inhibits cell growth, induces myeloid cell lines, promotes B cell switch to IgG
IL-1	Mononuclear phagocyte	Stimulates T cells and macrophages, induces acute phase reaction of inflammation, produces fever; similar to TNF and endogenous pyrogen
IL-2	T helper cells (TH1)	Promotes growth of T cells, enhances function of NK cells, assists T-cell maturation in thymus and B-cell proliferation
IL-3	T cells, endothelial cells, fibroblasts, other cells	Induces proliferation and differentiation of other lymphocytes, pluripotent stem cells, mast cells, and granulocytes
IL-4	T helper cells (TH2)	Promotes T-cell/B-cell interactions, promotes synthesis of IgE by B-cell and TH2 cell growth, promotes mast cell and hematopoietic cell growth
IL-5	T helper cells (TH2)	Promotes growth and differentiation of B cells to secrete IgA, induces differentiation of eosinophils
IL-6	Mononuclear phagocytes, T helper cells (TH2), tumors, and nonlymphoid cells (e.g., endothelium)	Promotes immunoglobulin secretion by B cells, induces fever, promotes release of inflammation factors from liver cells, promotes differentiation of hematopoietic stem cells and nerve cells
IL-7	Stromal cells in bone marrow	Stimulates immature lymphocytes to divide to produce B and T cells
IL-8	Macrophages	Enhances inflammation and chemotaxis (CXCL chemokine)
IL-9	TH2 cells	Enhances growth of T helper cells
IL-10	T cells and macrophages	Inhibits activation of macrophages and dendritic cells, inhibits IL-12 production
IL-11	Stromal cells in bone marrow	Stimulates platelet production
IL-12	Macrophages, dendritic cells	Enhances TH1 cell activities and release of IFN-γ by T cells and NK cells
IL-13	TH2 cells	Stimulates B-cell growth and IgE production, suppresses macrophages
IL-14	T cells	Induces B-cell proliferation
IL-15	Macrophages (esp. viral infection)	Similar actions to IL-2, enhances proliferation of T cells (CD8) and NK cells
IL-16	CD8+ T cells	CD4+ cell chemotaxis, suppresses viral replication of HIV
IL-17	CD4+ T cells	Stimulates production of colony-stimulating factors and chemokines
IL-18	Macrophages in response to microbes	Increases NK cell proliferation and secretion of IFN-γ by TH1
IL-19	Macrophages	Stimulates macrophage IL-1 secretion
IL-20	Monocytes	Stimulates hematopoietic stem cells
IL-21	TH2 and TH17 cells	Activates B cells, stimulates production of NK cells
IL-22	TH17 cells	Epithelial cells, increased barrier function, defensin production
IL-23	Macrophages and dendritic cells	Similar to IL-12, stimulates cell-mediated immunity
IL-24	Monocytes, T cells	Monocyte inflammatory cytokine production
IL-25	TH2 cells	Stimulates production of cytokines by TH2 cells
IL-26	T cells, monocytes	Uncertain
IL-27	Macrophages and dendritic cells	Inhibits TH1 cells
TNF-α	Macrophages	Induces leukocytosis, fever, weight loss, inflammation, necrosis of some tumors; stimulates lymphokine synthesis; activates macrophages; toxic to viruses and tumor cells
TNF-β	T cells	Inhibits B-cell and T-cell proliferation
G-CSF, M-CSF, GM-CSF	Macrophages, T cells, fibroblasts	Stimulates granulocyte and monocyte production in bone marrow
TGF-β	T cells, macrophages	Inhibits T cells, B cells, and macrophages
Chemokines
CXCL 1-16	Macrophages and various cells in tissues	Recruitment of neutrophils, macrophages, lymphocytes
CCL 1-28	Macrophages and various cells in tissues	Recruitment of neutrophils, macrophages, lymphocytes

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