an infection, phagocytes and other cells (such as endothelial cells) release a variety of different cytokines. Some appear early in the infection and are responsible for up-regulation of innate defenses. Others appear late in the infection and help to down-regulate the defense response. Among the earliest-appearing cytokines are granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-3 (IL-3). These cytokines stimulate stem cells to produce monocytes and granulocytes (especially PMNs) and trigger their release from the bone marrow into circulation. Other early-appearing cytokines, such as TNF-α, IL-1, IFN-γ, and interleukin-8 (IL-8), stimulate the monocytes and granulocytes to leave the bloodstream and migrate to the site of infection. The steps in this process for PMNs are illustrated in Figure 3-2.
Normally, PMNs move rapidly through the blood vessels, occasionally colliding with one of the vessel walls. TNF-α, IL-1, and IFN-γ stimulate endothelial cells to produce a set of surface proteins called selectins. These selectins bind to proteins on the surface of PMNs and other phagocytic cells in the blood, causing them to loosely attach to the blood vessel endothelium. This loose attachment slows the movement of the blood cells, causing them to roll along the endothelial surface. As this occurs, other selectins will appear on the endothelial cells, while IL-8 stimulates the PMNs to produce proteins called integrins on their surfaces. The integrins bind another set of cytokine-stimulated proteins on the endothelial cell surface, the intercellular adhesion molecules (ICAMs), to generate a tighter attachment between PMNs and endothelial cells. This tight association stops the movement of the PMNs and causes them to flatten against the blood vessel wall. The slowing and stopping of the PMNs is called margination. The PMNs then force themselves between endothelial cells, a process that is assisted by a PMN protein called platelet-endothelial cell adhesion molecule (PECAM). The proinflammatory complement components C3a and C5a assist in the process of transmigration (diapedesis, or extravasation) from the bloodstream into tissue by causing mast cells to release vasoactive histamine and heparin, which dilate blood vessels and make them leakier. Dilation of blood vessels is also assisted by the cytokine platelet-activating factor (PAF). In addition to histamine and heparin, PAF triggers mast cells to produce a number of other vasoactive compounds from the membrane lipid, arachidonic acid, including various leukotrienes and prostaglandins. Once the PMNs have moved out of the blood vessel and into surrounding tissue, a gradient of soluble complement components, chemokines or bacterial peptides, leads them to the site of infection (through chemotaxis).
As PMNs move through tissue, the proinflammatory cytokines TNF-α, IL-1, IL-8, and PAF also activate the oxidative burst response in PMNs so that the PMNs arrive at the infection site with their full killing capacity in place. Monocytes and the macrophages into which they develop similarly activate as they move into an infected area. IFN-γ further stimulates the killing ability of macrophages, producing activated macrophages. Because the signals that control the activities of PMNs, cytokines, and activated complement components are at their highest concentrations near an infected area, PMNs will exit the blood vessel near the location of infection rather than in other areas of the body. Additionally, the fact that activation of the phagocytes occurs only as they are moving into the infected area minimizes the amount of collateral damage to tissues outside the infected area.
The end result of the signaling pathways just described is that a high number of PMNs and other phagocytic cells will leave the blood vessels near the site of infection. However, there are some underlying conditions that will reduce the effectiveness of this signaling system and reduce PMN transmigration, including steroid use, stress, hypoxia, and alcohol abuse. Their inhibitory effect on transmigration may explain why these underlying health conditions are frequently associated with increased susceptibility to infection.
If the phagocytes are successful in eliminating the invading bacterium, other cytokines begin to predominate. In addition to the inhibitory regulators of the complement cascade mentioned earlier, a number of anti-inflammatory cytokines, such as IL-4, IL-10, and interleukin-13 (IL-13), down-regulate production of TNF-α and reduce the killing activities of phagocytes, thereby countering the proinflammatory response and allowing the phagocyte defense system to return to its normal, relatively inactive level.
Inflammation and Collateral Damage
Inflammation, derived from the Latin word inflammare, which means “to set on fire,” is the immunologic and vascular response of the body to invasion by pathogens. Inflammation is caused by the release of proinflammatory cytokines, including C3a and C5a generated by the complement cascade; tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) released by basophils, mast cells, activated DCs, macrophages, and other phagocytes; and subsequent production of prostaglandins and leukotrienes. Other inflammatory mediators include the vasoactive peptides kallidin and bradykinin, which dilate blood vessels leading to a drop in blood pressure and increase vascular permeability at the site of infection to allow neutrophil and monocyte transmigration (extravasation).
Although inflammation serves to protect and control infections, it can also cause further tissue damage, which is manifested as the disease symptoms of redness, swelling, heat, and pain. The increased blood flow to the area due to vasodilation results in redness and elevated temperature. The increased vascular permeability causes blood fluids to leak out of the vessels as the phagocytes transmigrate, causing edema (swelling) of the surrounding tissue. The source of the pain is still not clearly understood, but it is likely caused by the combined effects of cytokines, prostaglandins, and coagulation cascade components on nerve endings in the inflamed region. Bradykinin also appears to increase sensitivity to pain. To counter the proinflammatory response, there are a number of anti-inflammatory cytokines, including IL-1 receptor antagonist, interleukin-4 (IL-4), and interleukin-10 (IL-10), that serve to regulate the immune response by inhibiting the action of the proinflammatory cytokines.
Although phagocytic cells are effective killers of bacteria and are essential for clearing the invading bacteria from an infected area, the body can pay a high price for this service. During active killing of a bacterium, lysosomal enzymes are released into the surrounding area as well as into the phagolysosome. Released lysosomal enzymes damage adjacent tissues and can be the main cause of tissue damage that results from a bacterial infection. Also, PMNs, NK cells, and macrophages kill themselves as a result of their killing activities, and lysosomal granules released by dying PMNs contribute further to tissue destruction. Pus, a common sign of infection, is composed mainly of dead PMNs and tissue cells. If pus accumulates in an enclosed tissue area, then an abscess can form. Pus is usually whitish or yellowish in color, but sometimes it can have a greenish color due to the abundant presence of myeloperoxidase. Bacteria that cause pus formation are called suppurative, purulent, or pyogenic.
Some of the other roles of the proinflammatory cytokines are listed in Table 3-2 and illustrated in Figure 3-16. These proinflammatory cytokines are responsible for common symptoms of infectious diseases other than those localized at the site of infection: fever, somnolence (drowsiness), malaise, anorexia, chills, decrease in blood iron levels, and weight loss. Cytokines IL-1 and TNF-α interact with the hypothalamus and adrenal gland to produce fever and somnolence, which the patient interprets as a feeling of malaise. Indifference to food, which can also characterize this state, contributes to the anorexia. TNF-α and other cytokines stimulate muscle cells to increase their metabolic rate and catabolize proteins to provide fuel for the mobilization of host defenses. Increased metabolism of muscle cells may be the cause of chills seen in some types of systemic infections. If the infection persists, the combination of anorexia and muscle cell breakdown of protein results in weight loss and visible loss of muscle tissue (wasting syndrome).
Figure 3-16. Overview of nonspecific responses to infection and the effects of cytokines on these responses. Proinflammatory cytokines include TNF-α, IL-1, IL-6, and IL-8,
