PaRt II Immune Effector Mechanisms TABLE 15-3 Redundant and pleiotropic effects As described earlier, this binding mediates the attachment of IL-1. TNF-c, and IL-6 or tethering of neutrophils to the vascular endothelium. allowing the cells to roll in the direction of the blood flow Effect IL-1 TNF-C IL-6 During this time, chemokines such as IL-8 or other chemoat- tractants act upon the neutrophils, triggering a G-protein ndogenous pyrogen fever mediated activating signal that leads to a conformational Synthesis of acute-phase change in the integrin adhesion molecules, resulting in neu proteins by liver trophil adhesion and subsequent transendothelial migra Increased vascular permeability molecules Once in tissues, the activated neutrophils also express in on vascular endothelin reased levels of receptors for chemoattractants and conse- Fibroblast proliferation quently exhibit chemotaxis, migrating up a gradient of the Platelet production chemoattractant. Among the inflammatory mediators that Chemokine induction(e.g, IL-8) are chemotactic for neutrophils are several che es. com nduction of il-6 plement split products(C3a, C5a, and C5b67), fibrinopep tides, prostaglandins, and leukotrienes. In addition, molecules B-cell activation released by microorganisms, such as formyl methionyl pep- tides, are also chemotactic for neutrophils. Activated neu Increased immunoglobulin synthesis trophils express increased levels of Fc receptors for antibody and receptors for complement, enabling these cells to bind more effectively to antibody- or complement-coated patho- gens, thus increasing phagocytosis The activating signal also stimulates metabolic pathways t The Inflammatory Process a respiratory burst, which produces reactive oxygen interme- diates and reactive nitrogen intermediates(see Chapter 2) Inflammation is a physiologic response to a variety of stimuli Release of some of these reactive intermediates and the release such as infections and tissue injury. In general, an acute of mediators from neutrophil primary and secondary granule inflammatory response has a rapid onset and lasts a short (proteases, phospholipases, elastases, and collagenases) play while. Acute inflammation is generally accompanied by asys- important role in killing various pathogens. These substances temic reaction known as the acute-phase response, which is also contribute to the tissue damage that can result from an characterized by a rapid alteration in the levels of several inflammatory response. The accumulation of dead cells and plasma proteins. In some diseases persistent immune activa- tion can result in chronic inflammation, which often has proteins, makes up what is known as pus. Inflammatory Responses May Be Neutrophils Play an Early and Important Localized or Systemic Role in Inflammation Infection or tissue injury induces a complex cascade of no In the early stages of an inflammatory response, the predom- specific events, known as the inflammatory response, th inant cell type infiltrating the tissue is the neutrophil. Neu- provides early protection by restricting the tissue damage to an inflammatory response, with production of neutrophils response involves both localized and systemic responses. in the bone marrow increasing to meet this need. A normal adult produces more than 101 neutrophils per day, but dur- LOCALIZED INFLAMMATORY RESPONSE ing a period of acute inflammation, neutrophil production The hallmarks of a localized acute inflammatory response, first may increase as much as tenfold. described almost 2000 years ago, are swelling(tumor), redness The neutrophils leave the bone marrow and circulate (rubor), heat(calor), pain(dolor), and loss of function Within within the blood. In response to mediators of acute inflam- minutes after tissue injury, there is an increase in vascular mation, vascular endothelial cells increase their expression of diameter(vasodilation), resulting in an increase in the volume E-and P-selectin Thrombin and histamine induce increased of blood in the area and a reduction in the flow of blood The expression of P-selectin; cytokines such as IL-1 or TNF-a increased blood volume heats the tissue and causes it to redden. induce increased expression of E-selectin. The circulating Vascular permeability also increases, leading to leakage of fluid neutrophils express mucins such as PSGL-1 or the tetrasac- from the blood vessels, particularly at postcapillary venules. charides sialyl Lewis and sialyl Lewis which bind to E-and This results in an accumulation of fluid(edema)in the tissue P-selectin and, in some instances, extravasation of leukocytes, contributThe Inflammatory Process Inflammation is a physiologic response to a variety of stimuli such as infections and tissue injury. In general, an acute inflammatory response has a rapid onset and lasts a short while. Acute inflammation is generally accompanied by a sys￾temic reaction known as the acute-phase response, which is characterized by a rapid alteration in the levels of several plasma proteins. In some diseases persistent immune activa￾tion can result in chronic inflammation, which often has pathologic consequences. Neutrophils Play an Early and Important Role in Inflammation In the early stages of an inflammatory response, the predom￾inant cell type infiltrating the tissue is the neutrophil. Neu￾trophil infiltration into the tissue peaks within the first 6 h of an inflammatory response, with production of neutrophils in the bone marrow increasing to meet this need. A normal adult produces more than 1010 neutrophils per day, but dur￾ing a period of acute inflammation, neutrophil production may increase as much as tenfold. The neutrophils leave the bone marrow and circulate within the blood. In response to mediators of acute inflam￾mation, vascular endothelial cells increase their expression of E- and P-selectin. Thrombin and histamine induce increased expression of P-selectin; cytokines such as IL-1 or TNF- induce increased expression of E-selectin. The circulating neutrophils express mucins such as PSGL-1 or the tetrasac￾charides sialyl Lewisa and sialyl Lewisx , which bind to E- and P-selectin. As described earlier, this binding mediates the attachment or tethering of neutrophils to the vascular endothelium, allowing the cells to roll in the direction of the blood flow. During this time, chemokines such as IL-8 or other chemoat￾tractants act upon the neutrophils, triggering a G-protein– mediated activating signal that leads to a conformational change in the integrin adhesion molecules, resulting in neu￾trophil adhesion and subsequent transendothelial migration (see Figure 15-3). Once in tissues, the activated neutrophils also express in￾creased levels of receptors for chemoattractants and conse￾quently exhibit chemotaxis, migrating up a gradient of the chemoattractant. Among the inflammatory mediators that are chemotactic for neutrophils are several chemokines, com￾plement split products (C3a, C5a, and C5b67), fibrinopep￾tides, prostaglandins, and leukotrienes. In addition, molecules released by microorganisms, such as formyl methionyl pep￾tides, are also chemotactic for neutrophils. Activated neu￾trophils express increased levels of Fc receptors for antibody and receptors for complement, enabling these cells to bind more effectively to antibody- or complement-coated patho￾gens, thus increasing phagocytosis. The activating signal also stimulates metabolic pathways to a respiratory burst, which produces reactive oxygen interme￾diates and reactive nitrogen intermediates (see Chapter 2). Release of some of these reactive intermediates and the release of mediators from neutrophil primary and secondary granules (proteases, phospholipases, elastases, and collagenases) play an important role in killing various pathogens. These substances also contribute to the tissue damage that can result from an inflammatory response. The accumulation of dead cells and microorganisms, together with accumulated fluid and various proteins, makes up what is known as pus. Inflammatory Responses May Be Localized or Systemic Infection or tissue injury induces a complex cascade of non￾specific events, known as the inflammatory response, that provides early protection by restricting the tissue damage to the site of infection or tissue injury. The acute inflammatory response involves both localized and systemic responses. LOCALIZED INFLAMMATORY RESPONSE The hallmarks of a localized acute inflammatory response, first described almost 2000 years ago, are swelling (tumor), redness (rubor), heat (calor), pain (dolor), and loss of function. Within minutes after tissue injury, there is an increase in vascular diameter (vasodilation), resulting in an increase in the volume of blood in the area and a reduction in the flow of blood. The increased blood volume heats the tissue and causes it to redden. Vascular permeability also increases, leading to leakage of fluid from the blood vessels, particularly at postcapillary venules. This results in an accumulation of fluid (edema) in the tissue and, in some instances, extravasation of leukocytes, contribut- 350 PART III Immune Effector Mechanisms TABLE 15-3 Redundant and pleiotropic effects of IL-1, TNF-, and IL-6 Effect IL-1 TNF- IL-6 Endogenous pyrogen fever + + + Synthesis of acute-phase proteins by liver + + + Increased vascular permeability + + + Increased adhesion molecules on vascular endothelium + + – Fibroblast proliferation + + – Platelet production + – + Chemokine induction (e.g., IL-8) + + – Induction of IL-6 + +– T-cell activation + + + B-cell activation + + + Increased immunoglobulin synthesis – – +