the first, is stronger, and is often more effective in neutraliz- ing and clearing the pathogen. The major agents of adaptive immunity are lymphocytes and the amibodies and other molecules they produce. Because adaptive immune responses require some time to marshal, innate immunity provides the first Line of defense during the critical period just after the host's exposure to a pathogen. Ia general, most of the microorganisms encoun- tered by a healthy individual are readily cleared within a few days by defense mechanisms of the innate immune system before they activate the adaptive immune system. Innate Immunity Innate immunity can be seen to comprise four types of de- fensive barriers: anatomic, physiologic, phagocytic, and in- flammatory (Table 1-2). The Skin and the Mucosal Surfaces Provide Protective Barriers Against Infection Physical and anatomic barriers that tend to prevent the entry of pathogensarean organism's firs line of defense againstin- fection. The skin and the surface of mucous membranes are included in this category because they are effective barriers to the entry of most miccoorganisms. The skin consists of two. distinct layers: a thinrer outer lsyer—the epidermis—and a thicker layer—the dermis. The epidermis contains several layers of tightly packed epithelial cells, The outer epidermal layer consists of dea¢ cells and :s filled with a waterproofing protein called keratin. The dermis, which is composed of connective tissue, contains blocd vessels, hair follicles, seba- cous glands, and sweat glands. The sebaceous glands are as- sociated with the hair follicles and produce an oily secretion called sebam. Sebum consists of lactic acid and fatty acids, which maintain the pH of the between 3 and 5; this pH inhibits the growth ef most microorganisms. A few bacteria that metabolize sebum live as commensals on the skin and sometimes cause a severe form of acne, One acne drug, isotretinoin (Accutane), is a viamin A derivative that pre= vents the formation of sebum. Breaks in the skin resulting from scratches, wounds, oF abrasion are obvious routes of infection. The skin may also be penetrated by biting insects (c.g., mosquitoes, mites, ticks, fleas, and sand these harbor pathogenic organisms, they can introduce the pathogen into the body as they feed. ‘The protozoan that causes malaria, for example, is deposited in humans by mosquitoes when they take a blood meal. Sim- ilarly, bubonic plague is spread by the bite of fleas, and Lyme Aiscase is spread by the bite of ticks. The conjunctivae and the alimentary, respiratory, and urogenital tracts are lined by mucous membranes, nat by the dry, protective skin that covers the exterior of the bod. These TABLE 1-2 ‘Type Mechanism Anatomic barriers sein Mechanical barrier retards entry of microbes. Acldie environment (pH 3-5) retards growth of microbes. Normal flora compete with mictobes for attachment sites and nutrients. Tolblike receptors recognize microbial molecules, signal cel to secrete mmunostimulatory cytokines. Various cells internalize (endacytose) and breac down foregn macromolecules, Specializee cells (blood monocytes, neutrophil, tissue macrophages) internalize Mucous membranes Mucus ent-aps foreign microorganisms. Cilia prope! microorganisms out of body Physiologic borers Temperature Norrsal body temperature inhibits growth of seme pathogens. Fever response inhibits growth of sore pathogens. tow pH Acidity ofstomach contents kills most ingested microorganisms. Chemica mediators Lysozyme cleaves bacterial eal wall. Ircerferon induces antiviral tate tn uninfected cells Complement yses micoorgarisrrs or faciitates phagocytesis. Collectins dsnupt cell wall of pathogen. Phogocylic/endecytic bariers (phagocytes, kil ard digest whate microorganisms Inflammatary borers Tissue damage and infection induce leakage of vascular flud, containirg serum proteins with antibacterial activity, and influx of phagocytic cells into the affected area Leone ee EEE Erne Scanned with CamScannermembranes consist of an outer epithelial layer and an under- lying layer of connective tissue. Although many pathogens center the body by binding to and penetrating mucous mem- branes, a number of nonspecific defense mechanisms tend to prevent this entry. For example, saliva, tears, and mucous se- ‘retions 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 mem- branes, entraps forcign microorganisms. In the lower respi- ratory 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, nonpatho- genic organisms tend to colonize the epithelial cells of rmu- cosal 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 de- fense mechanisms and thus are able to invade the body through mucous membranes. For example, influenza virus (theagent that causes flu) has asurface molecule that enables it toattach firmly to cells in mucous membranes of the respi Talory tract, preventing the virus from being swept out by the ciliated cpithelial cells. Similarly, the organism that causes gonorrhea has surface projections that allow it to bind to ep- ithelial cellsin the mucous membrane of the urogenital tract. Adherence of bacteria to mucous membranes is due to inter- actions 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 mem- brane of particular tissues (Figure 1-2). For this reason, some Eleczon micrograph of rod-shaped Escherichia col bacteria adhering to surface of epithelial ces of the urinary tae. [From N. Sharon ond 4. Lis, 1993, Sci. Am. 268(1):85; photograph courtesy of K Fujita 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 immu- include temperature, pH, and various soluble and cell- associated molecules. Many speciesare not susceptible to cex- tain 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 acid- ity 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 afilict adults is that their stomach contents are less acid than those of adults. A variety of soluble factors contribute to innate immu- ; among them the soluble proteins lysozyme, interferon, and complement. Lysozyme, 2 hydrolytic enzyme found in mucous secretions and in tears, is able to cleave the peptido- alycan 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 cellsand inducea generalized antiviral tate. Comple- ment, examined in detail in Chapter 13, is a group of serum proteins that circulate in an inactive state. A variety of spe- cific and nonspecific immunologic mechanisms can convert the inactive forms of complement proteins into an active state with the ability to damage the membranes of patho- genic organisms, either destroying the pathogens or facilitat- ing their clearance. Complement may function asan 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- get 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- cccules that arc 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 ofinnate immunity. Molecules with pattern recognition ability may be soluble, ike lysozyme and the complement compo- nentsdescribed above, or they may be cell-associated receptors. Among the class of receptors designated the toll-like receptors (TLRs), TLR? recognizes the lipopolysaccharide (LPS) found on Gram-negative bacteria. It has long been recognized that Scanned with CamScannerGETTIN (a1 Electronmiciograph of macrophage {pink) attack ing Eicherichio coli (green). The bactevia are phagecytized as de scribed in part b ard breakdown products secreted. The monocyte {purple) has been recruited to the vicinity of the encounter by solible factors secreted by the macrophage. The red spheve Is anerytheoeyte (6) Schernatic diagram of the steps in phagocytosis of a bactenum_ [Part o, Denris Kunkel Microscopy, Inc /Dennis Kuckel] systemic exposure of mammals to relatively small quantities of purified LPS leeds to an acute inflammatory response (sce be- low). The mechanism for this response is via a TLR on ‘macrophages that recognizes LPS and clicis a variety of mole- cals in the inflarumatory response upon exposure. When the “TLRis 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- tion 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 indude whole pathogenic mictoorganisms, 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 reveptor-mediated enddo~ cytosis, in which extracellular molecules are internalized after binding by specific cellular receptors, and pinocytosis, the process by which cells take up uid 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 patho- {genic microorganism induces a compler sequence of events Collectively known as the inflammatory response. As de- scribed above, a molecular component of a microbe, such as LPS, may trigger an inflammatory response via interaction with cell surface receptors. The end resul 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 flammatory response were described as early as 1600 wc in Egyptian papyrus writings. In the first century ap, the Romen physician Celsus described the “four cardinal signs ® oy 02S pae to membrane evaginations called pseudopodia —— P Racierium is ingested, eaiag phage o———____-& ‘phagosome fuses with tysosome o—_____ @) rosomal enzymes digest captured material ——_——_, ‘Digestion products are released from cell of inflammation” as rubor (redness), tumor (swelling), calor (heat), and dolor (pain). In the second century Ap, an- other physician, Galen, added a fifth sign: functio Tnesa (loss of function). The cardinal signs of inflammation reflect the three major events ofan inflammatory response (Figure 1): 1. Vasodilation—an increase in the diameter of blood vessels—af nearby capillaries occurs as the vessels that carry blood away from the affected arca constrict, resulting in engorgement of the capillary network. The engorged capillaries are responsible for tissue redness (erythema) and an increase in tissue temperature. Scanned with CamScannerTissue damape causes release of vasoactive and chemotactic factors a that trigger a local increase in blood flow and capillary permeability <= Or maneconscratowan —) mpm andy. = ++---| influx of fluid (exudate) and cells Keseeecte Pecea DP rragocytes migatc to ste ot | inflammation (chemotaxis) I J Major events in the inflammatory response. Abacte- rial infection causes tissue damage with release of various vasoactive and chemotactic factors. These factors induce increased blood llow to the area, increased capillary permeability, and an influx of white 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 capil- laries. The emigration of phagocytes isa multistep process that includes adherence of the cells to the ‘endothelial wall of the blood vessels (margination), followed by their emigration between the capillary endothelial cells into the tissue (diapedesis or extrava- sation), 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 cels, digested material, and fluid forms a substance called pus. ‘The events in the inflammatory response are initiated by a complex series of events involving variety of chemical me- distors whose interactions are only partly understood. Some of these mediators are derived from invading microorgan- blood cells including phagocytes and lymphoeytes, from the blood into the tissues. The serum proteins eontained in the exsdate have antibacterial properties, and the phagocytes begin to engulf the bac- teria, as illustrated in Figure 1-3 isms,some are released from damaged cells in response totis- sue injury, some are generated by several plasma enzyme sys- tems, and some are products of various white blood cells participating in the inflammatory response. ‘Among the chemical mediators released in response to tis- sue damage are various serum proteins called acute-phase proteins, The concentrations of these proteins increase dra- matically in tissue-damaging infections, C-reactive protein is ‘a major acute-phase protein produced by the liver in re- sponse to tissue damage. Its name derives (rom its paitern- recognition activity: C-reactive protein binds to the C-polysaccharide ccll-wall component found on a variety of bacteria and fungi. This binding activates the complement system, resulting in increased clearance of the pathogen ci- ther by complement-mediated lysis or by a complement- mediated increase in phagocytosis. One of the principal mediators of the inflammatory re- sponse 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 in excased permeability, Another important group of inflam- matory mediators, small peptides called kinins, are normally presentin blood plasma in an inactive form. Tissue injury ac- tivates these peptides, which then cause vasodilation and in- Scanned with CamScanner