Innate immunity provides broad defenses against infection cquired immunity

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					                                                43.1 Innate immunity provides broad defenses against infection

Section Vocabulary         Lysozyme - An enzyme in sweat, tears, and saliva that attacks bacterial cell walls.
                           Phagocytosis - A type of endocytosis involving large, particulate substances, accomplished mainly
                           by macrophages, neutrophils, and dendritic cells.
                           Neutrophil - The most abundant type of white blood cell. Neutrophils are phagocytic and tend to
                           self–destruct as they destroy foreign invaders, limiting their life span to a few days.
                           Macrophage - A phagocytic cell present in many tissues that functions in innate immunity by
                           destroying microbes and in acquired immunity as an antigen–presenting cell.
                           Monocyte - A type of white blood cell that migrates into tissues and develops into a macrophage.
                           Eosinophil - A type of white blood cell with low phagocytic activity that is thought to play a role
                           in defense against parasitic worms by releasing enzymes toxic to these invaders.
                           Dendritic Cell - An antigen–presenting cell, located mainly in lymphatic tissues and skin, that is
                           particularly efficient in presenting antigens to naive helper T cells, thereby initiating a primary
                           immune response.
                           Complement System - A group of about 30 blood proteins that may amplify the inflammatory
                           response, enhance phagocytosis, or directly lyse pathogens. The complement system is activated
                           in a cascade initiated by surface antigens on microorganisms or by antigen–antibody complexes.
                           Interferon - A protein that has antiviral or immune regulatory functions. Interferon–β and
                           interferon–γ, secreted by virus–infected cells, help nearby cells resist viral infection; interferon–
                           γ, secreted by T cells, helps activate macrophages.
                           Inflammatory Response - A localized innate immune defense triggered by physical injury or
                           infection of tissue in which changes to nearby small blood vessels enhance the infiltration of
                           white blood cells, antimicrobial proteins, and clotting elements that aid in tissue repair and
                           destruction of invading pathogens; may also involve systemic effects such as fever and increased
                           production of white blood cells.
                           Histamine - A substance released by mast cells that causes blood vessels to dilate and become
                           more permeable during an inflammatory response.
                           Mast Cell - A vertebrate body cell that produces histamine and other molecules that trigger the
                           inflammatory response.
                           Chemokine - Any of about 50 different proteins, secreted by many cell types near a site of injury
                           or infection, that help direct migration of white blood cells to an injury site and induces other
                           changes central to inflammation.
                           Natural Killer (NK) Cell - A type of white blood cell that can kill tumor cells and virus–infected
                           cells; an important component of innate immunity.
                           Apoptosis - The changes that occur within a cell as it undergoes programmed cell death, which is
                           brought about by signals that trigger the activation of a cascade of suicide proteins in the cell
                           destined to die.
Innate immunity provides
broad defenses against
infection                  An invading microbe must penetrate the external barriers formed by an animal’s skin and
                           mucous membranes, which cover the surface and line the openings of the body. A pathogen that
                           successfully breaks through these external defenses soon encounters several innate cellular and
                           chemical mechanisms that impede its attack on the body.

External Defenses          Intact skin is a barrier that cannot normally be penetrated by viruses or bacteria, but even tiny
                           abrasions may allow their passage. Likewise, the mucous membranes lining the digestive,
                           respiratory, and genitourinary tracts bar the entry of potentially harmful microbes. Certain cells
                           of these mucous membranes also produce mucus, a viscous fluid that traps microbes and other
                           particles. In the trachea, for example, ciliated epithelial cells sweep mucus and any entrapped
                           microbes upward, preventing the microbes from entering the lungs (Figure 43.3). Microbial
                           colonization of the body is also inhibited by the washing action of the mucous secretions, saliva,
                           and tears that constantly bathe the surfaces of various exposed epithelia.
                           Beyond their physical role in inhibiting microbe entry, secretions of the skin and mucous
                           membranes provide an environment that is often hostile to microbes. In humans, secretions
                           from sebaceous (oil) glands and sweat glands give the skin a pH ranging from 3 to 5, which is
                           acidic enough to prevent colonization by many microbes. (Bacteria that normally inhabit the skin

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                                             43.1 Innate immunity provides broad defenses against infection

                        are adapted to its acidic, relatively dry environment.) Similarly, microbes in food or water and
                        those in swallowed mucus must contend with the acidic environment of the stomach, which
                        destroys most pathogens before they can enter the intestines. But some pathogens, such as the
                        hepatitis A virus, can survive gastric acidity and successfully enter the body via the digestive
                        tract.
                        Secretions from the skin and mucous membranes also contain antimicrobial proteins. One such
                        protein is lysozyme, an enzyme that digests the cell walls of many bacteria. Present in saliva,
                        tears, and mucous secretions, lysozyme can destroy susceptible bacteria as they enter the upper
                        respiratory tract or the openings around the eyes.
Internal Cellular and
Chemical Defenses       Microbes that penetrate the body’s external defenses, such as those that enter through a break
                        in the skin, must contend with the body’s internal mechanisms of innate defense. These
                        defenses depend mainly on phagocytosis, the ingestion of invading microorganisms by certain
                        types of white blood cells generically referred to as phagocytes. These cells produce certain
                        antimicrobial proteins and help initiate inflammation, which can limit the spread of microbes in
                        the body. Non–phagocytic white blood cells called natural killer cells also play a key role in innate
                        defenses. The various nonspecific mechanisms help limit the spread of microbes before the body
                        can mount acquired, specific immune responses.

Phagocytic Cells        Phagocytes attach to their prey via surface receptors that bind to structures found on many
                        microorganisms but not on normal body cells. Among the structures bound by these receptors
                        are certain polysaccharides on the surface of bacteria. After attaching to one or more
                        microbes, a phagocyte engulfs the microbes, forming a vacuole that fuses with a lysosome
                        (Figure 43.4). Microbes are destroyed by lysosomes in two ways. First, nitric oxide and other
                        toxic forms of oxygen contained in the lysosomes may poison the engulfed microbes. Second,
                        lysozyme and other enzymes degrade microbial components.
                        Some microorganisms have adaptations that enable them to evade destruction by phagocytic
                        cells. For example, the outer capsule that surrounds some bacterial cells hides their surface
                        polysaccharides and prevents phagocytes from attaching to them. Other bacteria, such as
                        Mycobacterium tuberculosis, which causes tuberculosis, are readily bound and engulfed by
                        phagocytes but are resistant to destruction within lysosomes. Because such microbes can grow
                        and reproduce within their host’s cells, they are effectively hidden from the acquired defenses of
                        the body. Evolution of these and other mechanisms that prevent destruction by the immune
                        system has increased the pathogenic threat of many microbes.
                        Four types of white blood cells (leukocytes) are phagocytic. They differ in their abundance,
                        average life span, and phagocytic ability. By far the most abundant are neutrophils, which
                        constitute about 60–70% of all white blood cells. Neutrophils are attracted to and then enter
                        infected tissue, engulfing and destroying the microbes there. However, neutrophils tend to self–
                        destruct in the process of phagocytosis, and their average life span is only a few days.
                        An even more effective phagocytic defense comes from macrophages (“big eaters”). These large,
                        long–lived cells develop from monocytes, which constitute about 5% of circulating white blood
                        cells. New monocytes circulate in the blood for only a few hours and then migrate into tissues
                        where they are transformed into macrophages. Carrying out phagocytosis sets off internal
                        signaling pathways that activate the macrophages, increasing their defensive abilities in various
                        ways (described later in this chapter). Some macrophages migrate throughout the body, while
                        others reside permanently in various organs and tissues. Macrophages that are permanent
                        residents in the spleen, lymph nodes, and other tissues of the lymphatic system are particularly
                        well positioned to combat infectious agents. Microbes that enter the blood become trapped in
                        the netlike architecture of the spleen, whereas microbes in interstitial fluid flow into lymph and
                        are trapped in lymph nodes. In either location microbes soon encounter resident macrophages.
                        Figure 43.5 shows the components of the lymphatic system and summarizes its role in the body’s
                        defenses.
                        The other two types of phagocytes are less abundant and play a more limited role in innate
                        defense than neutrophils and macrophages. Eosinophils have low phagocytic activity but are
                        critical to defense against multicellular parasitic invaders, such as the blood fluke Schistosoma

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                                              43.1 Innate immunity provides broad defenses against infection

                         mansoni. Rather than engulfing such a parasite, eosinophils position themselves against the
                         parasite’s body and then discharge destructive enzymes that damage the invader. The fourth
                         type of phagocyte, dendritic cells, can ingest microbes like macrophages do. However, as you will
                         learn later in the chapter, their primary role is to stimulate the development of acquired
                         immunity.

Antimicrobial Proteins   Numerous proteins function in innate defense by attacking microbes directly or by impeding
                         their reproduction. You have already learned about the antimicrobial action of lysozyme. Other
                         antimicrobial proteins include about 30 serum proteins that make up the complement system. In
                         the absence of infection, these proteins are inactive. Substances on the surface of many
                         microbes, however, can trigger a cascade of steps that activate the complement system, leading
                         to lysis (bursting) of invading cells. Certain complement proteins also help trigger inflammation
                         or play a role in acquired defense.
                         Two types of interferon (α and β) provide innate defense against viral infections. These proteins
                         are secreted by virus–infected body cells and induce neighboring uninfected cells to produce
                         other substances that inhibit viral reproduction. In this way, interferons limit the cell–to–cell
                         spread of viruses in the body, helping control viral infections such as colds and influenza. This
                         innate defense mechanism is not virus–specific; interferons produced in response to one virus
                         may also confer short–term resistance to unrelated viruses. Certain lymphocytes secrete a third
                         type of interferon (γ) that helps activate macrophages, enhancing their phagocytic ability.
                         Interferons can now be mass–produced by recombinant DNA technology and are being tested for
                         the treatment of viral infections and cancer.
                         Yet another group of antimicrobial proteins, fittingly named defensins, are secreted by activated
                         macrophages. These small proteins damage broad groups of pathogens by various mechanisms
                         without harming body cells.

Inflammatory Response    Damage to tissue by physical injury or the entry of pathogens leads to release of numerous
                         chemical signals that trigger a localized inflammatory response. One of the most active
                         chemicals is histamine, which is stored in mast cells found in connective tissues. When injured,
                         mast cells release their histamine, triggering dilation and increased permeability of nearby
                         capillaries. Activated macrophages and other cells discharge additional signals, such as
                         prostaglandins, that further promote blood flow to the injured site. The resulting increased
                         local blood supply causes the redness and heat typical of inflammation (from the Latin
                         inflammare, to set on fire). The blood–engorged capillaries leak fluid into neighboring tissues,
                         causing swelling, another sign of local inflammation.
                         Although heat and swelling are uncomfortable sensations, the enhanced blood flow and vessel
                         permeability that cause them are critical to innate defense. These vascular changes help deliver
                         antimicrobial proteins and clotting elements to the injured area. Several activated complement
                         proteins, for example, promote the release of histamine or attract phagocytes to the site. Blood
                         clotting begins the repair process and helps block the spread of microbes to other parts of the
                         body. In addition, increased local blood flow and vessel permeability allow more neutrophils and
                         monocyte–macrophages to move from the blood into injured tissues. Small proteins called
                         chemokines direct the migration of these phagocytes and signal them to increase production of
                         microbe–killing compounds. Chemokines are secreted by many cell types, including blood vessel
                         endothelial cells, near a site of injury or infection. Figure 43.6, on the next page, summarizes the
                         major events in local inflammation resulting from an infected pinprick.
                         A minor injury causes local inflammation, but the body may also mount a systemic (widespread)
                         response to severe tissue damage or infection. Injured cells often put out a call for
                         reinforcements, secreting chemicals that stimulate the release of additional neutrophils from the
                         bone marrow. In a severe infection, such as meningitis or appendicitis, the number of white
                         blood cells in the blood may increase several fold within a few hours of the initial inflammatory
                         events. Another systemic response to infection is fever. Fever may occur when certain toxins
                         produced by pathogens and substances released by activated macrophages set the body’s
                         thermostat at a higher temperature. A very high fever is dangerous, but moderate fever may
                         facilitate phagocytosis and, by speeding up body reactions, hasten the repair of tissues.

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                                                        43.1 Innate immunity provides broad defenses against infection

                                   Certain bacterial infections can induce an overwhelming systemic inflammatory response,
                                   leading to a condition known as septic shock. Characterized by very high fever and low blood
                                   pressure, septic shock is a common cause of death in hospital critical care units. Clearly, local
                                   inflammation is essential for healing, but systemic inflammation can be devastating.

Natural Killer Cells               We wrap up our discussion of vertebrate innate defenses with natural killer (NK) cells. NK cells
                                   patrol the body and attack virus–infected body cells and cancer cells. Surface receptors on an NK
                                   cell recognize general features on the surface of its targets. Once it is attached to a virus–
                                   infected cell or cancer cell, the NK cell releases chemicals that lead to the death of the stricken
                                   cell by apoptosis, or programmed cell death (see Figure 21.18). Although the defense provided
                                   by NK cells is not 100% effective, viral infections and cancer would occur much more often
                                   without these innate sentinels of the body.
Invertebrate Immune
Mechanisms                         Before we move on to examine acquired immunity in vertebrates, we should note that
                                   invertebrates also have highly effective innate defenses. For example, sea stars possess
                                   amoeboid cells that ingest foreign matter by phagocytosis and secrete molecules that enhance
                                   the animal’s defensive response. Recent studies of the fruit fly Drosophila melanogaster also
                                   have revealed striking parallels between insect defenses and vertebrate innate defenses. The
                                   exoskeleton of insects, like the skin and mucous membranes of vertebrates, provides an
                                   external barrier that can prevent entry of intruders. If an insect’s exoskeleton is damaged,
                                   pathogens that enter the insect’s body must face several internal innate defenses.
                                   The insect equivalent to blood, the hemolymph, contains circulating cells called hemocytes.
                                   Some hemocytes ingest bacteria and other foreign substances by phagocytosis, while other
                                   hemocytes form a cellular capsule around large parasites. The presence of pathogens signals
                                   still other hemocytes to make and secrete various antimicrobial peptides that bind to their
                                   pathogen targets, leading to death of the pathogens. The internal signaling pathways that
                                   trigger hemocytes to produce antimicrobial peptides are comparable to those that activate
                                   vertebrate macrophages. In addition, certain hemocytes contain the enzyme phenoloxidase.
                                   Once activated, this enzyme converts phenols to reactive compounds that link together into
                                   large aggregates. These are deposited around parasites and wounded tissue, helping to prevent
                                   the spread of parasites beyond the affected area. Activation of phenoloxidase in insects occurs
                                   by a cascade of steps similar to those that activate vertebrate complement proteins.
                                   Recent research indicates that invertebrates lack cells analogous to lymphocytes, the white blood
                                   cells responsible for acquired, specific immunity in vertebrates (see Figure 43.2). But even though
                                   they depend on innate, nonspecific mechanisms, certain invertebrate defenses do exhibit some
                                   features characteristic of acquired immunity. For instance, acquired immunity usually is directed
                                   against nonself cells, not normal body (self) cells. The ability to distinguish self from nonself is
                                   seen in the most ancient invertebrate lineage, the sponges. If cells from two sponges of the same
                                   species are mixed, the cells from each sponge sort themselves and reaggregate, excluding cells
                                   from the other individual.
                                   Another hallmark of acquired immunity is immunological memory—the ability to respond more
                                   quickly to a particular invader or foreign tissue the second time it is encountered. Earthworms
                                   exhibit something like this: Phagocytic cells in a worm attack a second graft from the same donor
                                   worm much more rapidly than the first graft. Most invertebrates, however, exhibit no such
                                   immunological memory.
                                   Following this glimpse at invertebrate host defenses, we begin in the next section to examine the
                                   highly developed mechanisms of acquired immunity found in vertebrates.


    1.   Innate defenses are nonspecific. How, then, do macrophages recognize an infectious agent, such as a bacterium?
             a. Macrophages have receptors that bind to polysaccharides present on the surface of bacterial cells but not on body
                 cells.




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                                                     43.1 Innate immunity provides broad defenses against infection

2.   What causes the common signs of inflammation—redness, swelling, and heat—and how do these changes help protect the
     body against infection?
        a. Vessel dilation, which allows enhanced blood flow, and increased vessel permeability result in the common signs of
             inflammation. These vascular changes aid in delivering clotting factors, antimicrobial proteins, and phagocytic cells
             to the tissue of the affected region; all of these help in repairing tissue damage and stopping the spread of
             infection.

3.   State two ways in which the innate defenses of insects (invertebrates) and vertebrates are similar.
         a. The exoskeleton of insects provides an external barrier similar to the skin and mucous membranes of vertebrates.
             Phagocytic cells and antimicrobial proteins also contribute to innate defenses in both insects and vertebrates.




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