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.

·        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.

°        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.

°        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

·        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.

·        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.

à       Any body cell that becomes infected or cancerous can display such peptide antigens by virtue of its class I MHC molecules.

à       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.

°        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.

°        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 lymphocytes allows these cells to directly destroy certain target cells, including “nonself” cancer and transplant cells.

·        The humoral and cell-mediated immune responses are linked by cell-signaling interactions, especially via helper T cells.

 Helper T lymphocytes function in both humoral and cell-mediated immunity.

·        When a helper T cell recognizes a class II MHC molecule-antigen complex on an antigen-presenting cell, the helper T cell proliferates and differentiates into a clone of activated helper T cells and memory helper T cells.

·        A surface protein called CD4 binds the side of the class II MHC molecule.

·        This interaction helps keep the helper T cell and the antigen-presenting cell joined while activation of the helper T cell proceeds.

·        Activated helper T cells secrete several different cytokines that stimulate other lymphocytes, thereby promoting cell-mediated and humoral responses.

·        Dendritic cells are important in triggering a primary immune response.

°        They capture antigens, migrate to the lymphoid tissues, and present antigens, via class II MHC molecules, to helper T cells.

·        Macrophages present antigens to memory helper T cells, while B cells primarily present antigens to helper T cells in the course of the humoral response.

 In the cell-mediated response, cytotoxic T cells counter intracellular pathogens.

·        Antigen-activated cytotoxic T lymphocytes kill cancer cells and cells infected by viruses and other intracellular pathogens.

·        Fragments of nonself proteins synthesized in such target cells associate with class I MHC molecules and are displayed on the cell surface, where they can be recognized by cytotoxic T cells.

°        This interaction is greatly enhanced by the T surface protein CD8 that helps keep the cells together while the cytotoxic T cell is activated.

·        When a cytotoxic T cell is activated by specific contacts with class I MHC-antigen complexes on an infected cell, the activated cytotoxic T cell differentiates into an active killer, which kills its target cell—the antigen-presenting cell—primarily by secreting proteins that act on the bound cell.

°        The death of the infected cell not only deprives the pathogen of a place to reproduce, but also exposes it to circulating antibodies, which mark it for disposal.

°        Once activated, cytotoxic T cells kill other cells infected with the same pathogen.

·        In the same way, cytotoxic T cells defend against malignant tumors.

°        Because tumor cells carry distinctive molecules not found on normal cells, they are identified as foreign by the immune system.

°        Class I MHC molecules on a tumor cell present fragments of tumor antigens to cytotoxic T cells.

°        Interestingly, certain cancers and viruses actively reduce the amount of class I MHC protein on affected cells so that they escape detection by cytotoxic T cells.

°        The body has a backup defense in the form of natural killer cells, part of the nonspecific defenses, which lyse virus-infected and cancer cells.

 In the humoral response, B cells make antibodies against extracellular pathogens.

·        Antigens that elicit a humoral immune response are typically proteins and polysaccharides present on the surface of bacteria or transplanted tissue.

·        The activation of B cells is aided by cytokines secreted by helper T cells activated by the same antigen.

°        These B cells proliferate and differentiate into a clone of antibody-secreting plasma cells and a clone of memory B cells.

·        When antigen first binds to receptors on the surface of a B cell, the cell takes in a few of the foreign molecules by receptor-mediated endocytosis.

·        The B cell then presents antigen fragments to a helper B cell.

·        Many antigens (primarily proteins), called T-dependent antigens, can trigger a humoral immune response by B cells only with the participation of helper T cells.

·        Other antigens, such as polysaccharides and proteins with many identical polypeptides, function as T-independent antigens.

°        These include the polysaccharides of many bacterial capsules and the proteins of the bacterial flagella.

°        These antigens bind simultaneously to a number of membrane antibodies on the B cell surface.

°        This stimulates the B cell to generate antibody-secreting plasma cells without the help of cytokines.

°        While this response is an important defense against many bacteria, it generates a weaker response than T-dependent antigens and generates no memory cells.

·        Any given humoral response stimulates a variety of different B cells, with each giving rise to a clone of thousands of plasma cells.

°        Each plasma cell is estimated to secrete about 2,000 antibody molecules per second over the cell’s 4- to 5-day life span.

°        A secreted antibody has the same general Y-shaped structure as a B cell receptor, but lacks a transmembrane region that would anchor it to a plasma membrane.

·        Antigens that elicit a humoral immune response are typically the protein and polysaccharide surface components of microbes, incompatible transplanted tissues, or incompatible transfused cells.

°        In addition, for some humans, the proteins of foreign substances such as pollen or bee venom act as antigens that induce an allergic, or hypersensitive, humoral response.

·        Antibodies constitute a group of globular serum proteins called immunoglobins (Igs).

·        There are five major types of heavy-chain constant regions, determining the five major classes of antibodies.

°        Two classes exist primarily as polymers of the basic antibody molecule: IgM as a pentamer and IgA as a dimmer.

°        The other three classes—IgG, IgE, and IgD—exist exclusively as monomers,

·        The power of antibody specificity and antigen-antibody binding has been applied in laboratory research, clinical diagnosis, and disease treatment.

°        Some antibody tools are polyclonal, the products of many different clones of B cells, each specific for a different epitope.

°        Others are monoclonal, prepared from a single clone of B cells grown in culture.

§        These cells produce monoclonal antibodies, specific for the same epitope on an antigen.

§        These have been used to tag specific molecules.

§        For example, toxin-linked antibodies search and destroy tumor cells.

·        The binding of antibodies to antigens is also the basis of several antigen disposal mechanisms.

°        In viral neutralization, antibodies bind to proteins on the surface of a virus, blocking the virus’s ability to infect a host cell.

°        In opsonization, the bound antibodies enhance macrophage attachment to and phagocytosis of the microbes. Neither the B cell receptor for an antigen nor the secreted antibody actually binds to an entire antigen molecule.

·        Antibody-mediated agglutination of bacteria or viruses effectively neutralizes and opsonizes the microbes.

°        Agglutination is possible because each antibody molecule has at least two antigen-binding sites.

°        IgM can link together five or more viruses or bacteria.

°        These large complexes are readily phagocytosed by macrophages.

·        In precipitation, the cross-linking of soluble antigen molecules—molecules dissolved in body fluids—forms immobile precipitates that are disposed of by phagocytosis.

·        The complement system participates in the antibody-mediated disposal of microbes and transplanted body cells.

·        The pathway begins when IgM or IgG antibodies bind to a pathogen, such as a bacterium.

°        The first complement component links two bound antibodies and is activated, initiating the cascade.

§        Ultimately, complement proteins generate a membrane attack complex (MAC), which forms a pore in the bacterial membrane, resulting in cell lysis.

°        Whether activated as part of innate or acquired defenses, the complement cascade results in the lysis of microbes and produces activated complement proteins that promote inflammation or stimulate phagocytosis.

 Immunity can be achieved naturally or artificially.

·        Immunity conferred by recovering from an infectious disease such as chicken pox is called active immunity because it depends on the response of the infected person’s own immune system.

°        Active immunity can be acquired naturally or artificially, by immunization, also known as vaccination.

°        Vaccines include inactivated bacterial toxins, killed microbes, parts of microbes, viable but weakened microbes, and even genes encoding microbial proteins.

°        These agents can act as antigens, stimulating an immune response and, more important, producing immunological memory.

·        A vaccinated person who encounters the actual pathogen will have the same quick secondary response based on memory cells as a person who has had the disease.

°        Routine immunization of infants and children has dramatically reduced the incidence of infectious diseases such as measles and whooping cough, and has led to the eradication of smallpox, a viral disease.

°        Unfortunately, not all infectious agents are easily managed by vaccination.

§        For example, the emergence of new strains of pathogens with slightly altered surface antigens complicates development of vaccines against some microbes, such as the parasite that causes malaria.

·        Antibodies can be transferred from one individual to another, providing passive immunity.

°        This occurs naturally when IgG antibodies of a pregnant woman cross the placenta to her fetus.

°        In addition, IgA antibodies are passed from mother to nursing infant in breast milk.

°        Passive immunity persists as long as these antibodies last, a few weeks to a few months.

§        This protects the infant from infections until the baby’s own immune system has matured.

·        Passive immunity can be transferred artificially by injecting antibodies from an animal that is already immune to a disease into another animal.

°        This confers short-term, but immediate, protection against that disease.

°        For example, a person bitten by a rabid animal may be injected with antibodies against rabies virus because rabies may progress rapidly, and the response to an active immunization could take too long to save the life of the victim.

§        Most people infected with rabies virus are given both passive immunizations (the immediate defense) and active immunizations (a longer-term defense).

 

Concept 43.4 The immune system’s ability to distinguish self from nonself limits tissue transplantation

·        In addition to attacking pathogens, the immune system will also attack cells from other individuals.

°        For example, a skin graft from one person to a nonidentical individual will look healthy for a day or two, but it will then be destroyed by immune responses.

°        Interestingly, a pregnant woman does not reject the fetus as a foreign body. Apparently, the structure of the placenta is the key to this acceptance.

·        One source of potential problems with blood transfusions is an immune reaction from individuals with incompatible blood types.

°        In the ABO blood groups, an individual with type A blood has A antigens on the surface of red blood cells.

§        This is not recognized as an antigen by the “owner,” but it can be identified as foreign if placed in the body of another individual.

°        B antigens are found on type B red blood cells.

°        Both A and B antigens are found on type AB red blood cells.

°        Neither antigen is found on type O red blood cells.

·        A person with type A blood already has antibodies to the B antigen, even if the person has never been exposed to type B blood.

°        These antibodies arise in response to bacteria (normal flora) that have epitopes very similar to blood group antigens.

°        Thus, an individual with type A blood does not make antibodies to A-like bacterial epitopes—these are considered self—but that person does make antibodies to B-like bacterial epitopes.

°        If a person with type A blood receives a transfusion of type B blood, the preexisting anti-B antibodies will induce an immediate and devastating transfusion reaction.

·        Because blood group antigens are polysaccharides, they induce T-independent responses, which elicit no memory cells.

°        Each response is like a primary response, and it generates IgM anti-blood-group antibodies, not IgG.

°        This is fortunate, because IgM antibodies do not cross the placenta, where they may harm a developing fetus with a blood type different from its mother’s.

·        However, another blood group antigen, the Rh factor, can cause mother-fetus problems because antibodies produced for it are IgG.

°        This situation arises when a mother that is Rh-negative (lacks the Rh factor) has a fetus that is Rh-positive, having inherited the factor from the father.

°        If small amounts of fetal blood cross the placenta late in pregnancy or during delivery, the mother mounts a humoral response against the Rh factor.

°        The danger occurs in subsequent Rh-positive pregnancies, when the mother’s Rh-specific memory B cells produce IgG antibodies that can cross the placenta and destroy the red blood cells of the fetus.

·        To prevent this, the mother is injected with anti-Rh antibodies after delivering her first Rh-positive baby.

°        She is, in effect, passively immunized (artificially) to eliminate the Rh antigen before her own immune system responds and generates immunological memory against the Rh factor, endangering her future Rh-positive babies.

·        Major histocompatibility complex (MHC) molecules are responsible for stimulating rejection of tissue grafts and organ transplants.

°        Because MHC creates a unique protein fingerprint for each individual, foreign MHC molecules are antigenic, inducing immune responses against the donated tissue or organ.

°        To minimize rejection, attempts are made to match MHC of tissue donor and recipient as closely as possible.

§        In the absence of identical twins, siblings usually provide the closest tissue-type match.

·        In addition to MHC matching, various medicines are used to suppress the immune response to the transplant.

°        However, this strategy leaves the recipient more susceptible to infection and cancer during the course of treatment.

°        More selective drugs, which suppress helper T cell activation without crippling nonspecific defense or T-independent humoral responses, have greatly improved the success of organ transplants.

·        In bone marrow transplants, it is the graft itself, rather than the recipient, which is the source of potential immune rejection.

°        Bone marrow transplants are used to treat leukemia and other cancers as well as various hematological diseases.

°        Prior to the transplant, the recipient is typically treated with irradiation to eliminate the recipient’s immune system, eliminating all abnormal cells and leaving little chance of graft rejection.

°        However, the donated marrow, containing lymphocytes, may react against the recipient, producing graft versus host reaction, unless well matched.

 

Concept 43.5 Exaggerated, self-directed, or diminished immune responses can cause disease

·        Malfunctions of the immune system can produce effects ranging from the minor inconvenience of some allergies to the serious and often fatal consequences of certain autoimmune and immunodeficiency diseases.

·        Allergies are hypersensitive (exaggerated) responses to certain environmental antigens, called allergens.

°        One hypothesis to explain the origin of allergies is that they are evolutionary remnants of the immune system’s response to parasitic worms.

°        The humoral mechanism that combats worms is similar to the allergic response that causes such disorders as hay fever and allergic asthma.

·        The most common allergies involve antibodies of the IgE class.

°        Hay fever, for example, occurs when plasma cells secrete IgE specific for pollen allergens.

°        Some IgE antibodies attach by their tails to mast cells present in connective tissue, without binding to the pollen.

°        Later, when pollen grains enter the body, they attach to the antigen-binding sites of mast cell-associated IgE, cross-linking adjacent antibody molecules.

·        This event triggers the mast cell to degranulate—that is, to release histamines and other inflammatory agents from vesicles called granules.

·        High levels of histamines cause dilation and increased permeability of small blood vessels.

°        These inflammatory events lead to typical allergy symptoms: sneezing, runny nose, tearing eyes, and smooth muscle contractions that can result in breathing difficulty.

°        Antihistamines diminish allergy symptoms by blocking receptors for histamine.

·        Sometimes, an acute allergic response can result in anaphylactic shock, a life-threatening reaction to injected or ingested allergens.

°        Anaphylactic shock results when widespread mast cell degranulation triggers abrupt dilation of peripheral blood vessels, causing a precipitous drop in blood pressure.

§        Death may occur within minutes.

°        Triggers of anaphylactic shock in susceptible individuals include bee venom, penicillin, or foods such as peanuts or fish.

°        Some hypersensitive individuals carry syringes with epinephrine, which counteracts this allergic response.

·        Sometimes the immune system loses tolerance for self and turns against certain molecules of the body, causing one of many autoimmune diseases.

°        In systemic lupus erythematosus (lupus), the immune system generates antibodies against various self-molecules, including histones and DNA released by the normal breakdown of body cells.

§        Lupus is characterized by skin rashes, fever, arthritis, and kidney dysfunction.

°        Rheumatoid arthritis leads to damage and painful inflammation of the cartilage and bone of joints.

°        In insulin-dependent diabetes mellitus, the insulin-producing beta cells of the pancreas are the targets of autoimmune cytotoxic T cells.

·        Multiple sclerosis (MS) is the most common chronic neurological disease in developed countries.

°        In MS, T cells reactive against myelin infiltrate the central nervous system and destroy the myelin sheath that surrounds some neurons.

°        People with MS experience a number of serious neurological abnormalities.

·        The mechanisms that lead to autoimmunity are not fully understood.

°        It was thought that people with autoimmune diseases had self-reactive lymphocytes that escaped elimination during their development.

°        We now know that healthy people also have lymphocytes with the capacity to react against self, but these cells are inhibited from inducing an autoimmune reaction by several regulatory mechanisms.

°        Autoimmune disease likely arises from some failure in immune regulation, perhaps linked with particular MHC alleles.

·        In immunodeficiency diseases, the function of either the humoral or cell-mediated immune defense is compromised.

·        An immunodeficiency disease caused by a genetic or developmental defect in the immune system is called an inborn or primary immunodeficiency.

·        An immunodeficiency defect in the immune system that develops later in life, following exposure to a chemical or biological agent, is called an acquired or secondary immunodeficiency.

·        In severe combined immunodeficiency (SCID), both branches of the immune system fail to function.

°        For individuals with this disease, long-term survival requires a bone marrow transplant that will continue to supply functional lymphocytes.

°        Several gene therapy approaches are in clinical trials to attempt to reverse SCID.

°        Recent successes include a child with SCID who received gene therapy in 2002 when she was 2 years old. In 2004, her T cells and B cells were still functioning normally.

·        Immunodeficiency may also develop later in life.

°        For example, certain cancers suppress the immune system. An example is Hodgkin’s disease, which damages the lymphatic system.

·        AIDS is another acquired immune deficiency.

·        Healthy immune system function appears to depend on both the endocrine system and the nervous system.

°        For example, hormones secreted by the adrenal glands during stress affect the number of white blood cells and may suppress the immune system in other ways.

°        Similarly, some neurotransmitters secreted when we are relaxed and happy may enhance immunity.

°        Physiological evidence also points to an immune system–nervous system link based on the presence of neurotransmitter receptors on the surfaces of lymphocytes and a network of nerve fibers that penetrates deep into the thymus.

 AIDS is an immunodeficiency disease caused by a virus.

·        In 1981, increased rates of two rare diseases, Kaposi’s sarcoma, a cancer of the skin and blood vessels, and pneumonia caused by the protozoan Pneumocystis carinii, were the first signals to the medical community of a new threat to humans, later known as acquired immunodeficiency syndrome, or AIDS.

°        Both conditions were previously known to occur mainly in severely immunosuppressed individuals.

°        People with AIDS are susceptible to opportunistic diseases.

°        Because AIDS arises from the loss of helper T cells, both humoral and cell-mediated immune responses are impaired.

·        In 1983, a retrovirus, now called human immunodeficiency virus (HIV), was identified as the causative agent of AIDS.

·        HIV gains entry into cells by making use of proteins that participate in normal immune responses.

°        The main receptor for HIV on helper T cells is the cell’s CD4 molecule.

°        In addition to CD4, HIV requires a second cell-surface protein, a coreceptor.

·        Once inside the cell, the HIV RNA is reverse-transcribed, and the product DNA is integrated into the host cell’s genome.

·        In this form, the viral genome can direct the production of new viral particles.

·        The death of helper T cells in HIV infection is due to the damaging effects of viral reproduction, coupled with inappropriately timed apoptosis triggered by the virus.

·        HIV infection cannot yet be cured, although certain drugs slow HIV reproduction and the progression to AIDS.

°        However, these drugs are very expensive and not available to all infected people, especially in developing countries.

°        In addition, the mutational changes that occur with each round of virus reproduction can generate drug-resistant strains of HIV.

°        Transmission of HIV requires the transfer of body fluids containing infected cells, such as semen or blood, from person to person.

°        In December 2003, the Joint UN Program on AIDS estimated that 40 million people worldwide are living with HIV/AIDS. The best approach for slowing the spread of HIV is to educate people about the practices that lead to transmission, such as using dirty needles or having unprotected intercourse.