8536d_ch01_001-0238/1/02 4: 25 PM Page 6 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e membranes consist of an outer epithelial layer and an under- tissues are susceptible to bacterial invasion, whereas others lying layer of connective tissue. Although many pathogens are not. enter the body by binding to and penetrating mucous mem- branes, a number of nonspecific defense mechanisms tend to Physiologic Barriers to Infection Include prevent this entry. For example, saliva, tears, and mucous se- General Conditions and Specific molecules antibacterial or antiviral substances. The viscous fluid called The physiologic barriers that contribute to innate immu- mucus,which is secreted by epithelial cells of mucous mem- nity include temperature, PH, and various soluble and cell- branes, entraps foreign microorganisms. In the lower respi- associated molecules. Many species are not susceptible to cer- ratory tract, the mucous membrane is covered by cilia, tain diseases simply because their normal body temperature hairlike protrusions of the epithelial-cell membranes. The inhibits growth of the pathogens. Chickens, for example, synchronous movement of cilia propels mucus-entrapped have innate immunity to anthrax because their high body microorganisms from these tracts. In addition, nonpath- temperature inhibits the growth of the bacteria. Gastric acid genic organisms tend to colonize the epithelial cells of mu- ity is an innate physiologic barrier to infection because very sal surfaces. These normal flora generally outcompete few ingested microorganisms can survive the low pH of the Some organisms have evolved ways of escaping these de- contents are less acid than those of adul re susceptible to pathogens for attachment sites on the epithelial cell surface stomach contents. One reason newborns and for necessary nutrients. some diseases that do not afflict adults is that their stomach ense mechanisms and thus are able to invade the body A variety of soluble factors contribute to innate immu through mucous membranes. For example, influenza virus nity, among them the soluble proteins lysozyme, interferon, ( the agent that causes flu) has a surface molecule that enables and complement. Lysozyme, a hydrolytic enzyme found in it to attach firmly to cells in mucous membranes of the respi- mucous secretions and in tears, is able to cleave the peptide ratory tract, preventing the virus from being swept out by the glycan layer of the bacterial cell wall. Interferon comprises a ciliated epithelial cells. Similarly, the organism that causes group of proteins produced by virus-infected cells. Among gonorrhea has surface projections that allow it to bind to ep- the many functions of the interferons is the ability to bind to thelial cells in the mucous membrane of the urogenital tract. nearby cells and induce a generalized antiviral state Comple Adherence of bacteria to mucous membranes is due to inter- ment, examined in detail in Chapter 13, is a group of serum actions between hairlike protrusions on a bacterium, called proteins that circulate in an inactive state. A variety of spe- fimbriae or pili, and certain glycoproteins or glycolipids that cific and nonspecific immunologic mechanisms can convert are expressed only by epithelial cells of the mucous mem- the inactive forms of complement proteins into an active brane of particular tissues(Figure 1-2). For this reason, some state with the ability to damage the membranes of pathe genic organisms, either destroying the pathogens or facilitat ing their clearance Complement may function as an effector system that is triggered by binding of antibodies to certain cell surfaces, or it may be activated by reactions between complement molecules and certain components of microbial cell walls. Reactions between complement molecules or frag- ments of complement molecules and cellular receptors trig- ger activation of cells of the innate or adaptive immune systems. Recent studies on collectins indicate that these sur factant proteins may kill certain bacteria directly by disrupt- ing their lipid membranes or, alternatively, by aggregating the bacteria to enhance their susceptibility to phagocytosis Many of the molecules involved in innate immunity have the property of pattern recognition, the ability to recognize a given class of molecules. Because there are certain types of mol ecules that are unique to microbes and never found in multi cellular organisms, the ability to immediately recognize and combat invaders displaying such molecules is a strong feature of innate immunity. Molecules with pattern recognition ability may be soluble, like lysozyme and the complement compo FIGURE1-2Electron micrograph of rod-shaped Escherichia coli nents described above, or they may be cell-associated receptors bacteria adhering to surface of epithelial cells of the urinary tract. (TLRS), TLR2 recognizes the lipopolysaccharide(LPS)found Among the class of receptors designated the toll-like receptors [From N. Sharon and H. Lis, 1993, Sci. Am. 268(: 85: photograph courtesy of k. Fujita. J on Gram-negative bacteria. It has long been recognized that
membranes consist of an outer epithelial layer and an underlying layer of connective tissue. Although many pathogens enter the body by binding to and penetrating mucous membranes, a number of nonspecific defense mechanisms tend to prevent this entry. For example, saliva, tears, and mucous secretions act to wash away potential invaders and also contain antibacterial or antiviral substances. The viscous fluid called mucus, which is secreted by epithelial cells of mucous membranes, entraps foreign microorganisms. In the lower respiratory tract, the mucous membrane is covered by cilia, hairlike protrusions of the epithelial-cell membranes. The synchronous movement of cilia propels mucus-entrapped microorganisms from these tracts. In addition, nonpathogenic organisms tend to colonize the epithelial cells of mucosal surfaces. These normal flora generally outcompete pathogens for attachment sites on the epithelial cell surface and for necessary nutrients. Some organisms have evolved ways of escaping these defense mechanisms and thus are able to invade the body through mucous membranes. For example, influenza virus (the agent that causes flu) has a surface molecule that enables it to attach firmly to cells in mucous membranes of the respiratory tract, preventing the virus from being swept out by the ciliated epithelial cells. Similarly, the organism that causes gonorrhea has surface projections that allow it to bind to epithelial cells in the mucous membrane of the urogenital tract. Adherence of bacteria to mucous membranes is due to interactions between hairlike protrusions on a bacterium, called fimbriae or pili, and certain glycoproteins or glycolipids that are expressed only by epithelial cells of the mucous membrane of particular tissues (Figure 1-2). For this reason, some tissues are susceptible to bacterial invasion, whereas others are not. Physiologic Barriers to Infection Include General Conditions and Specific Molecules The physiologic barriers that contribute to innate immunity include temperature, pH, and various soluble and cellassociated molecules. Many species are not susceptible to certain diseases simply because their normal body temperature inhibits growth of the pathogens. Chickens, for example, have innate immunity to anthrax because their high body temperature inhibits the growth of the bacteria. Gastric acidity is an innate physiologic barrier to infection because very few ingested microorganisms can survive the low pH of the stomach contents. One reason newborns are susceptible to some diseases that do not afflict adults is that their stomach contents are less acid than those of adults. A variety of soluble factors contribute to innate immunity, among them the soluble proteins lysozyme, interferon, and complement. Lysozyme, a hydrolytic enzyme found in mucous secretions and in tears, is able to cleave the peptidoglycan layer of the bacterial cell wall. Interferon comprises a group of proteins produced by virus-infected cells. Among the many functions of the interferons is the ability to bind to nearby cells and induce a generalized antiviral state.Complement, examined in detail in Chapter 13, is a group of serum proteins that circulate in an inactive state. A variety of specific and nonspecific immunologic mechanisms can convert the inactive forms of complement proteins into an active state with the ability to damage the membranes of pathogenic organisms, either destroying the pathogens or facilitating their clearance. Complement may function as an effector system that is triggered by binding of antibodies to certain cell surfaces, or it may be activated by reactions between complement molecules and certain components of microbial cell walls. Reactions between complement molecules or fragments of complement molecules and cellular receptors trigger activation of cells of the innate or adaptive immune systems. Recent studies on collectins indicate that these surfactant proteins may kill certain bacteria directly by disrupting their lipid membranes or, alternatively, by aggregating the bacteria to enhance their susceptibility to phagocytosis. Many of the molecules involved in innate immunity have the property of pattern recognition, the ability to recognize a given class of molecules. Because there are certain types of molecules that are unique to microbes and never found in multicellular organisms, the ability to immediately recognize and combat invaders displaying such molecules is a strong feature of innate immunity. Molecules with pattern recognition ability may be soluble, like lysozyme and the complement components described above, or they may be cell-associated receptors. Among the class of receptors designated the toll-like receptors (TLRs), TLR2 recognizes the lipopolysaccharide (LPS) found on Gram-negative bacteria. It has long been recognized that 6 PART I Introduction FIGURE 1-2 Electron micrograph of rod-shaped Escherichia coli bacteria adhering to surface of epithelial cells of the urinary tract. [From N. Sharon and H. Lis, 1993, Sci. Am. 268(1):85; photograph courtesy of K. Fujita.] 8536d_ch01_001-023 8/1/02 4:25 PM Page 6 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:
8536dch010079/5/0211:47 AM Page7mac46mac46:385reb: Overview of the Immune System cHAP ph of macrophage(pink) attack gocytized as scribed in part b and breakdown products secreted. The monocyte sle)has been recruited to the vicinity of the encounter by solubl factors secreted by the macrophage. The red sphere is an erythrocyte Schematic diagram of the steps in phagocytosis of a bacterium purified LPS leads to an acute inflammatory response(see be- low). The mechanism for this response is via a TLR on macrophages that recognizes LPS and elicits a variety of mole cules in the inflammatory response upon exposure. When the TLR is exposed to the LpS upon local invasion by a Gram-neg ative bacterium, the contained response results in elimination of the bacterial challenge Cells That Ingest and Destroy Pathogens Make Up a Phagocytic Barrier to Infection Another important innate defense mechanism is the inges- to membrane evaginations tion of extracellular particulate material by phagocytosis. called pseudopodia Phagocytosis is one type of ende the general term for the uptake by a cell of material from its environment. In 31 phagocytosis, a cell,'s plasma membrane expands around the forming phag 20 ate material, which may include whole pathogen microorganisms, to form large vesicles called phagosor (Figure 1-3). Most phagocytosis is conducted by specialized Phagosome fuses with cells, such as blood monocytes, neutrophils, and tissue macrophages(see Chapter 2). Most cell types are capable of 0(83 other forms of endocytosis, such as receptor-mediated endo- ysosomal enzymes digest cytosis, in which extracellular molecules are internalized after captured material binding by specific cellular receptors, and pinocytosis, the process by which cells take up fluid from the surrounding medium along with any molecules contained in it. Digestion products are released from cell Inflammation Represents a Complex Sequence of Events That Stimulates Immune Responses Tissue damage caused by a wound or by an invading genic microorganism induces a complex sequence of events or inflammation"as rubor(redness), tumor(swelling) collectively known as the inflammatory response. As de- calor(heat), and dolor(pain). In the second century AD,an- scribed above, a molecular component of a microbe, such other physician, Galen, added a fifth sign: functio laesa(loss of function). The cardinal signs of inflammation reflect the LPS,may trigger an inflammatory response via interaction three major events of an inflammatory response( Figure 1-4) with cell surface receptors. The end result of inflammation may be the marshalling of a specific immune response to the 1. VasodilationH-an increase in the diameter of blood invasion or clearance of the invader by components of the vessels--of nearby capillaries occurs as the vessels that innate immune system. Many of the classic features of the arry blood away from the affected area constrict, inflammatory response were described as early as 1600 BC, in resulting in engorgement of the capillary network. The Roman physician Celsus described the"four cardinal signs (erythema)and an increase in tissue temperature Egyptian papyrus writings. In the first century AD, the engorged capillaries are responsible for tissue redne
systemic exposure of mammals to relatively small quantities of purified LPS leads to an acute inflammatory response (see below). The mechanism for this response is via a TLR on macrophages that recognizes LPS and elicits a variety of molecules in the inflammatory response upon exposure. When the TLR is exposed to the LPS upon local invasion by a Gram-negative bacterium, the contained response results in elimination of the bacterial challenge. Cells That Ingest and Destroy Pathogens Make Up a Phagocytic Barrier to Infection Another important innate defense mechanism is the ingestion of extracellular particulate material by phagocytosis. Phagocytosis is one type of endocytosis, the general term for the uptake by a cell of material from its environment. In phagocytosis, a cell’s plasma membrane expands around the particulate material, which may include whole pathogenic microorganisms, to form large vesicles called phagosomes (Figure 1-3). Most phagocytosis is conducted by specialized cells, such as blood monocytes, neutrophils, and tissue macrophages (see Chapter 2). Most cell types are capable of other forms of endocytosis, such as receptor-mediated endocytosis, in which extracellular molecules are internalized after binding by specific cellular receptors, and pinocytosis, the process by which cells take up fluid from the surrounding medium along with any molecules contained in it. Inflammation Represents a Complex Sequence of Events That Stimulates Immune Responses Tissue damage caused by a wound or by an invading pathogenic microorganism induces a complex sequence of events collectively known as the inflammatory response. As described above, a molecular component of a microbe, such as LPS, may trigger an inflammatory response via interaction with cell surface receptors. The end result of inflammation may be the marshalling of a specific immune response to the invasion or clearance of the invader by components of the innate immune system. Many of the classic features of the inflammatory response were described as early as 1600 BC, in Egyptian papyrus writings. In the first century AD, the Roman physician Celsus described the “four cardinal signs Overview of the Immune System CHAPTER 1 7 FIGURE 1-3 (a) Electronmicrograph of macrophage (pink) attacking Escherichia coli (green). The bacteria are phagocytized as described in part b and breakdown products secreted. The monocyte (purple) has been recruited to the vicinity of the encounter by soluble factors secreted by the macrophage. The red sphere is an erythrocyte. (b) Schematic diagram of the steps in phagocytosis of a bacterium. [Part a, Dennis Kunkel Microscopy, Inc./Dennis Kunkel.] Bacterium becomes attached to membrane evaginations called pseudopodia Bacterium is ingested, forming phagosome Phagosome fuses with lysosome Lysosomal enzymes digest captured material Digestion products are released from cell 3 2 4 5 1 (a) (b) of inflammation” as rubor (redness), tumor (swelling), calor (heat), and dolor (pain). In the second century AD, another physician, Galen, added a fifth sign: functio laesa (loss of function). The cardinal signs of inflammation reflect the three major events of an inflammatory response (Figure 1-4): 1. Vasodilation—an increase in the diameter of blood vessels—of nearby capillaries occurs as the vessels that carry blood away from the affected area constrict, resulting in engorgement of the capillary network. The engorged capillaries are responsible for tissue redness (erythema) and an increase in tissue temperature. 8536d_ch01_007 9/5/02 11:47 AM Page 7 mac46 mac46:385_reb:
8536d_ch01_001-0238/1/02 4: 25 PM Page 8 mac79 Mac 79: 45_BW: Goldsby et al./ Immunology 5e Bacteria MMU MMf 4/A Tissue damage causes release of Phagocytes and antibacterial I vasoactive and chemotactic factors exudate destroy bacteria that trigger a local increase in blood flow and capillary permeability (complement, antibody, grate to site of Permeable capillaries allow Creactive protein) amation(chemotaxis) influx of fluid (exudate) an Extravasation Capillary FIGURE 1-4 Major events in the inflammatory response. A bacte. blood cells, including phagocytes and lymphocytes, from the blood rial infection causes tissue damage with release of various vasoactive into the tissues. The serum proteins contained in the exudate have and chemotactic factors. These factors induce increased blood flow antibacterial properties, and the phagocytes begin to engulf the bac- to the area, increased capillary permeability, and an influx of white teria, as illustrated in Figure 1-3 2. An increase in capillary permeability facilitates an influx isms, some are released from damaged cells in response to tis- of fluid and cells from the engorged capillaries into the sue injury, some are generated by several plasma enzyme sys- tissue. The fluid that accumulates (exudate)has a mue tems,and some are products of various white blood cells higher protein content than fluid normally released from participating in the inflammatory response the vasculature. Accumulation of exudate contributes to Among the chemical mediators released in response to tis tissue swelling(edema). sue damage are various serum proteins called acute-phase 3. Influx of phagocytes from the capillaries into the tissues is proteins. The concentrations of these proteins increase dra- facilitated by the increased permeability of the capil matically in tissue-damaging infections. C-reactive protein is laries. The emigration of phagocytes is a multistep a major acute-phase protein produced by the liver in re- process that includes adherence of the cells to the sponse to tissue damage. Its name derives from its pattern endothelial wall of the blood vessels(margination) recognition activity: C-reactive protein binds to the followed by their emigration between the capillary C-polysaccharide cell-wall component found on a variety of endothelial cells into the tissue( diapedesis or extrava- bacteria and fungi. This binding activates the complement sation), and, finally, their migration through the tissue to system, resulting in increased clearance of the pathogen ei- the site of the invasion(chemotaxis ). As phagocytic cells ther by complement-mediated lysis or by a complement- accumulate at the site and begin to phagocytose bacteria mediated increase in phagocytosis. One of the principal mediators of the inflammatory re- healthy cells. The accumulation of dead cells, digested sponse is histamine, a chemical released by a variety of cells material, and fluid forms a substance called pus in response to tissue injury. Histamine binds to receptors on nearby capillaries and venules, causing vasodilation and in The events in the inflammatory response are initiated by a creased permeability. Another important group of inflam complex series of events involving a variety of chemical me- matory mediators, small peptides called kinins, are normally diators whose interactions are only partly understood. Some present in blood plasma in an inactive form. Tissue injury ac of these mediators are derived from invading microorgan- tivates these peptides, which then cause vasodilation and in
2. An increase in capillary permeability facilitates an influx of fluid and cells from the engorged capillaries into the tissue. The fluid that accumulates (exudate) has a much higher protein content than fluid normally released from the vasculature. Accumulation of exudate contributes to tissue swelling (edema). 3. Influx of phagocytes from the capillaries into the tissues is facilitated by the increased permeability of the capillaries. The emigration of phagocytes is a multistep process that includes adherence of the cells to the endothelial wall of the blood vessels (margination), followed by their emigration between the capillaryendothelial cells into the tissue (diapedesis or extravasation), and, finally, their migration through the tissue to the site of the invasion (chemotaxis). As phagocytic cells accumulate at the site and begin to phagocytose bacteria, they release lytic enzymes, which can damage nearby healthy cells. The accumulation of dead cells, digested material, and fluid forms a substance called pus. The events in the inflammatory response are initiated by a complex series of events involving a variety of chemical mediators whose interactions are only partly understood. Some of these mediators are derived from invading microorganisms, some are released from damaged cells in response to tissue injury, some are generated by several plasma enzyme systems, and some are products of various white blood cells participating in the inflammatory response. Among the chemical mediators released in response to tissue damage are various serum proteins called acute-phase proteins. The concentrations of these proteins increase dramatically in tissue-damaging infections. C-reactive protein is a major acute-phase protein produced by the liver in response to tissue damage. Its name derives from its patternrecognition activity: C-reactive protein binds to the C-polysaccharide cell-wall component found on a variety of bacteria and fungi. This binding activates the complement system, resulting in increased clearance of the pathogen either by complement-mediated lysis or by a complementmediated increase in phagocytosis. One of the principal mediators of the inflammatory response is histamine, a chemical released by a variety of cells in response to tissue injury. Histamine binds to receptors on nearby capillaries and venules, causing vasodilation and increased permeability. Another important group of inflammatory mediators, small peptides called kinins, are normally present in blood plasma in an inactive form. Tissue injury activates these peptides, which then cause vasodilation and in- 8 PART I Introduction Tissue damage causes release of vasoactive and chemotactic factors that trigger a local increase in blood flow and capillary permeability Permeable capillaries allow an influx of fluid (exudate) and cells Phagocytes and antibacterial exudate destroy bacteria Phagocytes migrate to site of inflammation (chemotaxis) 2 1 3 4 Exudate (complement, antibody, C-reactive protein) Capillary Margination Extravasation Tissue damage Bacteria FIGURE 1-4 Major events in the inflammatory response. A bacterial infection causes tissue damage with release of various vasoactive and chemotactic factors. These factors induce increased blood flow to the area, increased capillary permeability, and an influx of white blood cells, including phagocytes and lymphocytes, from the blood into the tissues. The serum proteins contained in the exudate have antibacterial properties, and the phagocytes begin to engulf the bacteria, as illustrated in Figure 1-3. 8536d_ch01_001-023 8/1/02 4:25 PM Page 8 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: