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Chapter 43

BIOL 1111 Chapter 43: chapter43 IMMUNE SYSTEM

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Temple University
BIOL 1111
Michael Balsai

1 Chapter 43 The Immune System Lecture Outline Overview: Reconnaissance, Recognition, and Response • An animal must defend itself against unwelcome intruders—the many potentially dangerous viruses, bacteria, and other pathogens it encounters in the air, in food, and in water. • It must also deal with abnormal body cells, which, in some cases, may develop into cancer. • Two major kinds of defense have evolved to counter these threats. • The first kind of defense is innate immunity.  Innate defenses are largely nonspecific, responding to a broad range of microbes.  Innate immunity consists of external barriers formed by the skin and mucous membranes, plus a set of internal cellular and chemical defenses that defend against microbes that breach the external barriers.  The internal defenses include macrophages and other phagocytic cells that ingest and destroy pathogens. • A second kind of defense is acquired immunity.  Acquired immunity develops only after exposure to microbes, abnormal body cells, or other foreign substances.  Acquired defenses are highly specific and can distinguish one inducing agent from another.  This recognition is achieved by white blood cells called lymphocytes, which produce two general types of immune responses. ▪ In the humoral response, cells derived from B-lymphocytes secrete defensive proteins called antibodies that bind to microbes and target them for elimination. ▪ In the cell-mediated response, cytotoxic lymphocytes directly destroy infected body cells, cancer cells, or foreign tissue. Concept 43.1 Innate immunity provides broad defenses against infection • An invading microbe must penetrate the external barrier formed by the skin and mucous membranes, which cover the surface and line the openings of an animal’s body. • If it succeeds, the pathogen encounters the second line of nonspecific defense, innate cellular and chemical mechanisms that defend against the attacking foreign cell. The skin and mucous membrane provide first-line barriers to infection. • Intact skin is a barrier that cannot normally be penetrated by bacteria or viruses, although even minute abrasions may allow their passage. • Likewise, the mucous membranes that line the digestive, respiratory, and genitourinary tracts bar the entry of potentially harmful microbes.  Cells of these mucous membranes produce mucus, a viscous fluid that traps microbes and other particles.  In the trachea, ciliated epithelial cells sweep out mucus with its trapped microbes, preventing them from entering the lungs. 1 2 • Beyond their role as a physical barrier, the skin and mucous membranes counter pathogens with chemical defenses.  In humans, for example, secretions from sebaceous and sweat glands give the skin a pH ranging from 3 to 5, which is acidic enough to prevent colonization by many microbes.  Microbial colonization is also inhibited by the washing action of saliva, tears, and mucous secretions that continually bathe the exposed epithelium. ▪ All these secretions contain antimicrobial proteins. ▪ One of these, the enzyme lysozyme, digests the cell walls of many bacteria, destroying them. • Microbes present in food or water, or those in swallowed mucus, must contend with the highly acidic environment of the stomach.  The acid destroys many microbes before they can enter the intestinal tract.  One exception, the virus hepatitis A, can survive gastric acidity and gain access to the body via the digestive tract. Phagocytic cells and antimicrobial proteins function early in infection. • Microbes that penetrate the first line of defense face the second line of defense, which depends mainly on phagocytosis, the ingestion of invading organisms by certain types of white cells. • Phagocyte function is intimately associated with an effective inflammatory response and also with certain antimicrobial proteins. • Phagocytes attach to their prey via surface receptors found on microbes but not normal body cells. • After attaching to the microbe, a phagocyte engulfs it, forming a vacuole that fuses with a lysosome.  Microbes are destroyed within lysosomes in two ways. ▪ Lysosomes contain nitric oxide and other toxic forms of oxygen, which act as potent antimicrobial agents. ▪ Lysozymes and other enzymes degrade mitochondrial components. • Some microbes have adaptations that allow them to evade destruction by phagocytes.  The outer capsule of some bacterial cells hides their surface polysaccharides and prevents phagocytes from attaching to them.  Other bacteria are engulfed by phagocytes but resist digestion, growing and reproducing within the cells. • Four types of white blood cells are phagocytic. • The phagocytic cells called neutrophils constitute about 60–70% of all white blood cells (leukocytes).  Cells damaged by invading microbes release chemical signals that attract neutrophils from the blood.  The neutrophils enter the infected tissue, engulfing and destroying microbes there.  Neutrophils tend to self-destruct as they destroy foreign invaders, and their average life span is only a few days. • Monocytes, about 5% of leukocytes, provide an even more effective phagocytic defense.  After a few hours in the blood, they migrate into tissues and develop into macrophages, which are large, long-lived phagocytes. 2 3  Some macrophages migrate throughout the body, while others reside permanently in certain tissues, including the lungs, liver, kidneys, connective tissues, brain, and especially in lymph nodes and the spleen. • The fixed macrophages in the spleen, lymph nodes, and other lymphatic tissues are particularly well located to contact infectious agents.  Microbes that enter the blood become trapped in the spleen, while microbes in interstitial fluid flow into lymph and are trapped in lymph nodes.  In either location, microbes soon encounter resident macrophages. • Eosinophils, about 1.5% of all leukocytes, contribute to defense against large parasitic invaders, such as the blood fluke, Schistosoma mansoni.  Eosinophils position themselves against the external wall of a parasite and discharge destructive enzymes from cytoplasmic granules. • Dendritic cells can ingest microbes like macrophages. However, their primary role is to stimulate the development of acquired immunity. • A variety of proteins function in innate defense either by attacking microbes directly or by impeding their reproduction.  In addition to lysozyme, other antimicrobial agents include about 30 serum proteins, known collectively as the complement system. ▪ Substances on the surface of many microbes can trigger a cascade of steps that activate the complement system, leading to lysis of microbes. • Another set of proteins that provide innate defenses are the interferons, which defend against viral infection.  These proteins are secreted by virus-infected body cells and induce uninfected neighboring cells to produce substances that inhibit viral reproduction.  Interferon limits cell-to-cell spread of viruses, helping to control viral infection.  Because they are nonspecific, interferons produced in response to one virus may confer short-term resistance to unrelated viruses.  One type of interferon activates phagocytes.  Interferons can be produced by recombinant DNA technology and are being tested for the treatment of viral infections and cancer. • Damage to tissue by a physical injury or the entry of microbes leads to the release of chemical signals that trigger a localized inflammatory response. • One of the chemical signals of the inflammatory response is histamine, which is stored in mast cells in connective tissues.  When injured, mast cells release their histamine.  Histamine triggers both dilation and increased permeability of nearby capillaries.  Leukocytes and damaged tissue cells also discharge prostaglandins and other substances that promote blood flow to the site of injury.  Increased local blood supply leads to the characteristic swelling, redness, and heat of inflammation.  Blood-engorged leak fluid into neighboring tissue, causing swelling. • Enhanced blood flow and vessel permeability have several effects.  First, they aid in delivering clotting elements to the injured area. ▪ Clotting marks the beginning of the repair process and helps block the spread of microbes elsewhere. 3 4  Second, increased blood flow and vessel permeability increase the migration of phagocytic cells from the blood into the injured tissues. ▪ Phagocyte migration usually begins within an hour after injury. • Chemokines secreted by many cells, including blood vessel endothelial cells and monocytes, attract phagocytes to the area. • The body may also mount a systemic response to severe tissue damage or infection.  Injured cells secrete chemicals that stimulate the release of additional neutrophils from the bone marrow.  In a severe infection, the number of white blood cells may increase significantly within hours of the initial inflammation.  Another systemic response to infection is fever, which may occur when substances released by activated macrophages set the body’s thermostat at a higher temperature. ▪ Moderate fever may facilitate phagocytosis and hasten tissue repair. • Certain bacterial infections can induce an overwhelming systemic inflammatory response leading to a condition known as septic shock.  Characterized by high fever and low blood pressure, septic shock is the most common cause of death in U.S. critical care units.  Clearly, while local inflammation is an essential step toward healing, widespread inflammation can be devastating. • Natural killer (NK) cells do not attack microorganisms directly but destroy virus-infected body cells.  They also attack abnormal body cells that could become cancerous.  NK cells attach to a target cell and release chemicals that bring about apoptosis, or programmed cell death. • To summarize the nonspecific defense systems, the first line of defense, the skin and mucous membranes, prevents most microbes from entering the body. • The second line of defense uses phagocytes, natural killer cells, inflammation, and antimicrobial proteins to defend against microbes that have managed to enter the body. • These two lines of defense are nonspecific in that they do not distinguish among pathogens. Invertebrates also have highly effective innate defenses. • Insect hemolymph contains circulating cells called hemocytes.  Some hemocytes can phagocytose microbes, while others can form a cellular capsule around large parasites.  Other hemocytes secrete antimicrobial peptides that bind to and destroy pathogens. • Current evidence suggests that invertebrates lack cells analogous to lymphocytes, the white blood cells responsible for acquired, specific immunity in vertebrates. • Certain invertebrate defenses do exhibit some features characteristic of acquired immunity.  Sponge cells can distinguish self from nonself cells.  Phagocytic cells of earthworms show immunological memory, responding more quickly to a particular foreign tissue the second time it is encountered. Concept 43.2 In acquired immunity, lymphocytes provide specific defenses against infection 4 5 • While microorganisms are under assault by phagocytic cells, the inflammatory response, and antimicrobial proteins, they inevitably encounter lymphocytes, the key cells of acquired immunity, the body’s second major kind of defense. • As macrophages and dendritic cells phagocytose microbes, they secrete certain cytokines that help activate lymphocytes and other cells of the immune system.  Thus the innate and acquired defenses interact and cooperate with each other. • Any foreign molecule that is recognized by and elicits a response from lymphocytes is called an antigen.  Most antigens are large molecules such as proteins or polysaccharides.  Most are cell-associated molecules that protrude from the surface of pathogens or transplanted cells.  A lymphocyte actually recognizes and binds to a small portion of an antigen called an epitope. Lymphocytes provide the specificity and diversity of the immune system. • The vertebrate body is populated by two main types of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells).  Both types of lymphocytes circulate throughout the blood and lymph and are concentrated in the spleen, lymph nodes, and other lymphatic tissue. • B and T cells recognize antigens by means of antigen-specific receptors embedded in their plasma membranes.  A single B or T cell bears about 100,000 identical antigen receptors. • Because lymphocytes recognize and respond to particular microbes and foreign molecules, they are said to display specificity for a particular epitope on an antigen. • Each B cell receptor for an antigen is a Y-shaped molecule consisting of four polypeptide chains: two identical heavy chains and two identical light chains linked by disulfide bridges.  A region in the tail portion of the molecule, the transmembrane region, anchors the receptor in the cell’s plasma membrane.  A short region at the end of the tail extends into the cytoplasm. • At the two tips of the Y-shaped molecules are the light- and heavy-chain variable (V) regions whose amino acid sequences vary from one B cell to another. • The remainder of the molecule is made up of the constant (C) regions, which do not vary from cell to cell. • Each B cell receptor has two identical antigen-binding sites formed from part of a heavy- chain V region and part of a light-chain V region. • The interaction between an antigen-binding site and its corresponding antigen is stabilized by multiple noncovalent bonds. • Secreted antibodies, or immunoglobulins, are structurally similar to B cell receptors but lack the transmembrane regions that anchor receptors in the cell membrane.  B cell receptors are often called membrane antibodies or membrane immunoglobulins. • Each T cell receptor for an antigen consists of two different polypeptide chains: an alpha chain and a beta chain, linked by a disulfide bridge. • Near the base of the molecule is a transmembrane region that anchors the molecule in the cell’s plasma membrane. 5 6 • At the outer tip of the molecule, the alpha and beta chain variable (V) regions form a single antigen-binding site. • The remainder of the molecule is made up of the constant (C) regions. • T cell receptors recognize and bind with antigens with the same specificity as B cell receptors. • However, while the receptors on B cells recognize intact antigens, the receptors on T cells recognize small fragments of antigens that are bound to normal cell-surface proteins called MHC molecules. • MHC molecules are encoded by a family of genes called the major histocompatibility complex (MHC). • As a newly synthesized MHC molecule is transported toward the plasma membrane, it binds with a fragment of antigen within the cell and brings it to the cell surface, a process called antigen presentation. • There are two ways in which foreign antigens can end up inside cells of the body.  Depending on their source, peptide antigens are handled by a different class of MHC molecule and recognized by a particular subgroup of T cells. ▪ Class I MHC molecules, found on almost all nucleated cells of the body, bind peptides derived from foreign antigens that have been synthesized within the cell.  Any body cell that becomes infected or cancerous can display such peptide antigens by virtue of its class I MHC molecules.  Class I MHC molecules displaying bound peptide antigens are recognized by a subgroup of T cells called cytotoxic T cells.  Class II MHC molecules are made by dendritic cells, macrophages, and B cells. ▪ In these cells, class II MHC molecules bind peptides derived from foreign materials that have been internalized and fragmented by phagocytosis. • For each vertebrate species, there are numerous different alleles for each class I and class II MHC gene, producing the most polymorphic proteins known.  As a result of the large number of different alleles in the human population, most of us are heterozygous for every one of our MHC genes.  Moreover, it is unlikely that any two people, except identical twins, will have exactly the same set of MHC molecules.  The MHC provides a biochemical fingerprint virtually unique to each individual that marks body cells as “self.” Lymphocyte development gives rise to an immune system that distinguishes self from nonself. • Lymphocytes, like all blood cells, originate from pluripotent stem cells in the bone marrow or liver of a developing fetus. • Early lymphocytes are all alike, but they later develop into T cells or B cells, depending on where they continue their maturation. • Lymphocytes that migrate from the bone marrow to the thymus develop into T cells. • Lymphocytes that remain in the bone marrow and continue their maturation there become B cells. • There are three key events in the life of a lymphocyte. 6 7  The first two events take place as a lymphocyte matures, before it has contact with any antigen.  The third event occurs when a mature lymphocyte encounters and binds a specific antigen, leading to its activation, proliferation, and differentiation—a process called clonal selection. • The variable regions at the tip of each antigen receptor chain, which form the antigen- binding site, account for the diversity of lymphocytes.  The variability of these regions is enormous.  Each person has as many as a million different B cells and 10 million different T cells, each with a specific antigen-binding ability. • At the core of lymphocyte diversity are the unique genes that encode the antigen receptor chains.  These genes consist of numerous coding gene segments that undergo random, permanent rearrangement, forming functional genes that can be expressed as receptor chains.  Genes for the light chain of the B cell receptor and for the alpha and beta chains of the T cell receptor undergo similar rearrangements, but we will consider only the gene coding for the light chain of the B cell receptor.  The immunoglobulin light-chain gene contains a series of 40 variable (V) gene segments separated by a long stretch of DNA from 5 joining (J) gene segments.  Beyond the J gene segments is an intron, followed by a single exon that codes for the constant region of the light chain.  In this state, the light-chain gene is not functional.  However, early in B cell development, a set of enzymes called recombinase link one V gene segment to one J gene segment, forming a single exon that is part V and part J. ▪ Recombinase acts randomly and can link any one of 40 V gene segments to any one of 5 J gene segments. ▪ For the light-chain gene, there are 200 possible gene products (20 V × 5 J). ▪ Once V-J rearrangement has occurred, the gene is transcribed and translated into a light chain with a variable and constant region. The light chains combine randomly with the heavy chains that are similarly produced.  The random rearrangements of antigen receptor genes may produce antigen receptors that are specific for the body’s own molecules.  As B and T cells mature, their antigen receptors are tested for potential self-reactivity.  Lymphocytes bearing receptors specific for molecules present in the body are either destroyed by apoptosis or rendered nonfunctional. ▪ Failure to do this can lead to autoimmune diseases such as multiple sclerosis. Antigens interact with specific lymphocytes, inducing immune responses and immunological memory. • Although it encounters a large repertoire of B cells and T cells, a microorganism interacts only with lymphocytes bearing receptors specific for its various antigenic molecules. • A lymphocyte is “selected” when it encounters a microbe with epitopes matching its receptors.  Selection activates the lymphocyte, stimulating it to divide and differentiate, and eventually to produce two clones of cells.  One clone consists of a large number of effector cells, short-lived cells that combat the same antigen. 7 8  The other clone consists of memory cells, long-lived cells bearing receptors for the same antigen. • This antigen-driven cloning of lymphocytes is called clonal selection and is fundamental to acquired immunity.  Each antigen, by binding selectively to specific receptors, activates a tiny fraction of cells from the body’s diverse pool of lymphocytes.  This relatively small number of selected cells gives rise to clones of thousands of cells, all specific for and dedicated to eliminating that antigen. • The selective proliferation and differentiation of lymphocytes that occur the first time the body is exposed to an antigen is the primary immune response.  About 10 to 17 days are required from the initial exposure for the maximum effector cell response.  During this period, selected B cells and T cells generate antibody-producing effector B cells called plasma cells, and effector T cells, respectively.  While this response is developing, a stricken individual may become ill, but symptoms of the illness diminish and disappear as antibodies and effector T cells clear the antigen from the body. • A second exposure to the same antigen at some later time elicits the secondary immune response.  This response is faster (only 2 to 7 days), of greater magnitude, and more prolonged.  In addition, the antibodies produced in the secondary response tend to have greater affinity for the antigen than those secreted in the primary response. • Measures of antibody concentrations in the blood serum over time show the difference between primary and secondary immune responses.  The immune system’s capacity to generate secondary immune responses is called immunological memory, based not only on effector cells, but also on clones of long-lived T and B memory cells. ▪ These memory cells proliferate and differentiate rapidly when they later contact the same antigen. Concept 43.3 Humoral and cell-mediated immunity defend against different types of threats • The immune system can mount two types of responses to antigens: a humoral response and a cell-mediated response.  Humoral immunity involves B cell activation and clonal selection and results in the production of antibodies that circulate in the blood plasma and lymph. ▪ Circulating antibodies defend mainly against free bacteria, toxins, and viruses in the body fluids.  In cell-mediated immunity, activation and clonal selection of cytotoxic T
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