Ii. Immune System

II. IMMUNE SYSTEM Immune defenses fall into two categories: nonspecific defenses that guard against a wide variety of pathogens; and immunity, composed of mechanisms whereby lymphocytes recognize and destroy specific pathogens.

NONSPECIFIC DEFENSES

Physical Barriers (p. 764) Skin (p. 764) composed mostly of impervious keratin that few pathogens can penetrate. relatively dry and lacks the nutrients to support microbial growth. Mucous membranes (p. 764) The mucous membranes of the digestive, respiratory, urinary, and reproductive tracts protect them from invasion. Mucus traps microbes and contains protective chemicals. Connective Tissue Gel (p. 764) Hyaluronic acid inhibits the spread of pathogens through connective tissues. Many pathogens and some snake venom and bacterial toxins overcome this by producing hyaluronidase. Chemical Barriers (p. 764) Certain bodily secretions inhibit the survival of pathogenic microorganisms. Stomach acid, lactic acid in perspiration, acid in the urethra and vagina, and lysozyme in tears, saliva, and mucus all serve to deter pathogens.

Leukocytes and Macrophages (p. 765)

Leukocytes (p. 765) -Leukocytes fall into five categories. -Neutrophils are highly mobile, and spend their time wandering the connective tissue phagocytizing bacteria. Neutrophils also create a chemical killing zone around themselves, a process that begins with degranulation. This triggers a respiratory burst, and cells form superoxide, which is highly toxic when superoxide radicals and hydrogen ions combine to form hydrogen peroxide. Neutrophils also die in the attack. High counts of neutrophils are indicative of bacterial infections. -Eosinophils phagocytize antigen-antibody complexes, allergens, and inflammatory chemicals. Eosinophils also aggregate around larger parasites and release enzymes that weaken or destroy them. Allergies and parasitic infections are marked by eosinophila. -Basophils secrete the vasodilator histamine and the anticoagulant heparin, both of which allow greater access for other leukocytes into the infected area. -Lymphocytes fall into several functional types. Natural killer (NK) cells are large lymphocytes that attack cells of your own body that are infected by viruses or have turned cancerous. -Monocytes are the circulating precursors of macrophages.

Macrophages (p. 765) -The macrophage system is composed of both wandering macrophages and those that remain fixed in position. -Macrophages include the following cell types: histiocytes, reticular cells, Langerhans cells, microglia, endothelial cells, alveolar macrophages, and Kupffer cells. Inflammation (p. 765, Tables 21.1, 21.2) 1. Inflammation is a response to tissue injury, and is characterized by redness, swelling, heat, pain, and impaired function. 2. The general purposes of inflammation are to limit the spread of the pathogen and destroy it, to remove the debris of damaged tissue, and to initiate tissue repair. 3. Pain and Loss of Function (p. 766) Pain arises from direct injury to nerve endings, their stimulation by inflammatory chemicals, and by tissue swelling. Bradykinin is a potent pain stimulus, which is secreted by basophils and mast cells, and produced from a plasma protein. Prostaglandins and bacterial toxins may also stimulate pain. Pain is an important signal of tissue damage, and signals the body to rest the part while it heals. 4. Hyperemia, Swelling, Redness, and Heat (p. 766) -Bradykinin, histamine, and leukotrienes stimulate vasodilation, which leads to hyperemia that accounts for the heat of the affected area. -Heat speeds metabolic activity, thus promoting cell repair. -Increased blood flow speeds the process of waste removal and tissue repair. -Histamine and leukotrienes increase the permeability of blood capillaries so they release more fluid into tissue, causing swelling. This allows antimicrobial chemicals in the plasma to enter the area, as well as increasing lymphatic drainage to remove dead cells and toxins. -Redness results from capillary permeability and hyperemia. 5. Leukocyte Deployment(p. 767, Fig. 21.13) -Hyperemia and capillary permeability attract leukocytes to the inflamed tissue by three mechanisms: margination, which occurs as cell adhesion molecules within the endothelium make membranes "sticky" and slow the velocity of leukocytes; by diapedisis, in which leukocytes squeeze through endothelial cells; and through chemotaxis, because leukocytes are attracted to bradykinin, leukotrienes, and others. -Neutrophils are the quickest leukocytes to respond. Damaged tissues release leukocytosis-promoting factor, which stimulates a quick release of neutrophils from storage in red bone marrow. -Basophils provide inflammatory chemicals; eosinophils enter when there are allergens or parasites; and monocytes arrive later, differentiating into histiocytes and become the cleanup crew. -The mixture of tissue fluid, cellular debris, dead and dying neutrophils, and microbes is called pus. 6. Tissue Repair (p. 768) a. Endothelial cells and platelets secrete platelet: derived growth factor (PDGF), which stimulates fibroblasts to multiply and synthesize collagen fibers and matrix.

Antimicrobial Proteins (p. 768) 1. Interferons (p. 768) a. Interferons are polypeptides secreted by cells that have been invaded by viruses. They diffuse to neighboring cells and prevent viruses from attaching to them. b. Interferons also activate natural killer cells and macrophages, which destroy infected host cells before they release more viruses. c. Interferons also stimulate the destruction of cancer cells. 2. Complement(p.768, Figs. 21.14,21.15) a. The complement system is a group of 20 or more beta globulins of blood that aid nonspecific resistance and immunity. b. Complement helps destroy pathogens in three ways: by enhanced inflammation, by opsonization (making bacteria easier to phagocytize by coating their surfaces), and through cytolysis (leading to the rupture of target cells).

F. Fever(p.768, Fig. 21.16, Table 21.3) I. Fever (pyrexia) can result from trauma, drug interactions, infection, and other causes. 2. Fever is beneficial in that it promotes interferon activity, elevates metabolic rate and accelerates tissue repair, and it inhibits the reproduction of bacteria and viruses. 3. In bacterial infections, macrophages secrete interleukin-l (Il-l), which may be a pyrogen that stimulates the anterior hypothalamus to secrete prostaglandin E (PGE). PGE, it turn, stimulates the hypothalamic thermostat to rise. 4. The elevated temperature stimulates the liver and spleen to harbor zinc and iron, depriving bacteria of minerals needed for their multiplication. 5. Even though most fevers are beneficial, high temperature can be dangerous because it causes protein denaturation and cellular dysfunction. SPECIFIC IMMUNITY (p. 770)

A. The immune system is an array of widely distributed cells that recognize foreign substances and act to neutralize or destroy them. Two characteristics that distinguish immunity from nonspecific resistance are specificity and memory. Two types of immunity are recognized: humoral (antibody-mediated) immunity is based on the action of antibodies. Circulating antibodies bind to bacteria, toxins, and extracellular viruses, "tagging" them for destruction; and cellular (cell-mediated) immunity is based on the action of lymphocytes that directly attack foreign cells, cells infected with viruses or parasites, and cancer cells. B. Antigens (p. 772, Fig. 21.17) 1. An antigen (Ag) is any molecule that triggers an immune response. Antigens are generally large, complex molecules, such as proteins, polysaccharides, glycoproteins, and glycolipids, with structure unique to each individual. Their uniqueness allows the immune system to distinguish self from non-self. 2. Some molecules are too small to be antigenic alone. These are called haptens, and they can stimulate an immune response by binding to a host macromolecule. a. Cosmetics, detergents, industrial chemicals, poison ivy, and animal dander act as haptens and trigger allergies in some people. C. Antibodies (p. 772, Fig. 21.18, Table 21.4) I. An antibody (Ab), or immunoglobulin, is a gamma globulin. 2. Its basic structure is composed of four polypeptide chains linked by disulfide bonds. Two are heavy chains, and two are light chains, all four of which have a variable region (V region) that give an antibody uniqueness. The rest of each chain is a constant region (C region). 3. The V regions of a heavy and light chain combine to form an antigen- binding site on each arm. 4. There are five classes of antibodies, named for the structures of their C regions. These are 19A, IgD, 19E, IgG, and IgM. D. Passive and Active Immunity (p. 773) 1. When antibodies or lymphocytes are given from one person or source, the recipient acquires passive immunity. Passive immunity lasts only 2-3 weeks. 2. Active immunity refers to the production of one's own antibodies or lymphocytes against an antigen. This can be induced by natural exposure or artificially induced by vaccination, and generally lasts a long time. E. Lymphocytes (p. 773) 1. The major cells of the immune system are lymphocytes and macrophages. Macrophages are active in nonspecific resistance but are also crucial in immunity. Most lymphocytes can be classified as T lymphocytes (T cells) or B lymphocytes (B cells). 2. T Lymphocytes (p. 774) a. During fetal development, the bone marrow releases undifferentiated stem cells into the blood. Some of these colonize the thymus, where they are stimulated to become T (thymus) lymphocytes. Under the influence of thymosin, each cell develops numerous plasma membrane proteins that serve as antigen receptors. The T cell is now immunocompetent. b. An immunocompetent T cell divides rapidly, forming a clone of T cells with identical receptors. All clones yet to encounter an antigen are called the virgin lymphocyte pool. c. Clonal deletion leaves only the T cells capable of responding to foreign antigens, destroying any that are self-reactive. d. T cells account for 70-80% of the lymphocytes in the blood and in lymphatic organs. 3. B Lymphocytes (p. 774) a. Fetal stem cells also settle into other regions of the body where they become B lymphocytes. ("B" stands for the bursa of Fabricus, a lymphatic organ in chickens.) B cells synthesize their antigen receptors, divide rapidly, and produce immunocompetent clones. Each clone can react to only one antigen. b. These clones are evolutionary adaptations to antigens that have afflicted humans throughout their existence. All an antigen does is determine which of the preexisting clones is activated. c. Immunocompetent B cells disperse through the body and colonize the same organs as T cells, accounting for 20-30% of the body's lymphocytes. F. Antigen-Presenting Cells (p. 774) 1. B cells and macrophages also function as antigen presenting cells (APCs). 2. The role of an APC is to phagocytize an antigen, digest it into molecular fragments, and "display" some of these fragments on its surface. Wandering T cells regularly inspect APCs for displayed antigens. G. Interleukins (p. 774, Tables 21.6,21.7) 1. Interleukins are hormonelike messengers between leukocytes or leukocyte derivatives. Those produced by lymphocytes are called lymphokines, and those produced by macrophages are called monokines.

I. Humoral Immunity (p. 775) A. In humoral immunity, the essential stages are recognition, attack, and memory. B. Recognition (p. 775, Figs. 21.19-21.23) 1. The process of recognition involves five steps. a. Since an antigen is a large molecule with numerous copies of each antigenic determinant, it binds to several receptors on a 8 cell and links them together. This capping process activates the cell. b. The capped receptors of the 8 cell become drawn into a cluster, culminating in receptor-mediated endocytosis of the antigen-receptor complex. c. The internalized antigen is digested into segments, linked to MHC proteins, and displayed. This alerts helper T cells to become active. d. A helper factor stimulates the B cell to divide repeatedly into a battalion of identical cells in a process known as clonal selection. e. Most cells of a clone differentiate into plasma cells that can produce antibodies at a rate of2,000 molecules per second. 2. The first time you are exposed to a particular antigen, your plasma cells produce mainly IgM. In later exposures to the same antigen, they produce mainly IgG. 3. Antibody Diversity (p. 776) a. The immune system is thought to be able to produce 2 million different antibodies as a result of somatic recombination that forms new combinations of DNA base sequences in somatic cells. C. Attack (p. 777, Fig. 21.24) 1. Once released by a plasma cell, antibodies use four different mechanisms to render antigens harmless. a. Neutralization occurs as antibodies mask sites that bind to human cells, rendering them harmless. b. Complement fixation occurs when antibodies bind complement, then bind with an antigen and expose its complement binding site. This binds the complement to the antigen, leading to destruction of the pathogen. c. Agglutination occurs as antibody molecules bind to several antigen molecules at once, sticking them together. d. Precipitation occurs as antibodies interact with antigens, binding them in groups, and the complex precipitates out of solution. D. Memory (p. 779, Fig. 21.25) 1. The primary immune response is generated the first time a person is exposed to an antigen. a. During clonal selection, some members of the clone become memory cells that are long-lived. They are more abundant than the original virgin lymphocyte pool, and thus are able to produce a much quicker secondary immune response. b. The quicker, secondary immune response is also called the anamnestic response, since often the antigen has little chance to exert a noticeable effect on the body.

II. Cellular Immunity (p. 779) A. In cellular immunity, lymphocytes directly attack and destroy foreign cells and diseased host cells. This involves cytotoxic T cells that carry out the attack, helper T cells that promote defense mechanisms, suppressor T cells that regulate the attack, and memory T cells that lie in wait for the next time the antigen in encountered. I. Helper T cells have a CD4 glycoprotein on their surface. Cytotoxic T cells bear a CD8 glycoprotein. B. Recognition (p. 780) 1. Antigen Presentation (p. 780, Table 21.5) a. Recognition involves antigen presentation and T cell activation. b. T cells respond only to antigen fragments displayed by APCs, not to free antigens. c. Both helper and cytotoxic T cells are involved in surveillance and examine the MHC proteins of all cells. d. MHC-I {class I) proteins occur on all body cells; MHC-II {class 11) proteins occur only on the surfaces on APCs, including B cells, macrophages, and some T cells. A MHC-II protein displaying an antigen stimulates helper T cells. e. Cytotoxic T cells respond only to MHC-I proteins, and helper T cells respond only to MHC-II proteins. 2. T Cell Activation (p. 780) a. CD4 and CD8 proteins are cell adhesion molecules that bind a T cell to a target cell during antigen presentation. They are also linked to a second-messenger system that triggers clonal selection in the T cell. b. Clonal selection requires costimulation, whereby an A PC and a T cell communicate through interleukins. C. Attack (p. 780) 1. Helper T Cells (p. 781, Fig. 21.26) a. When a helper T recognizes a MHC-antigen complex, it secretes a variety of, lymphokines that attract neutrophils and promote inflammation. b. One of the lymphokines, macrophage-activating factor (MAP), enhances the phagocytic activity of macrophages. 2. Cytotoxic T Cells (p. 781, Figs. 21.27,21.28) a. Cytotoxic (killer) T cells are the only T lymphocytes that directly attack and kill other cells. b. When a cytotoxic T cell recognizes a complex of antigen and MHC-I protein, it "docks" on that cell and delivers a lethal hit. c. Cytotoxic T cells degranulate and release perforin that is inserted into the enemy plasma protein. The perforin gradually polymerizes and creates holes in the energy cell. d. Other ways that cytotoxic T cells kill include release of lymphotoxin that destroys the target cell's DNA, and tumor necrosis factor that kills cancer cells. 3. Suppressor T Cells (p. 783) a. Suppressor T cells release lymphokines that inhibit T cell and B cell activity. D. Memory(p.783,Tables21.6,21.7) 1. On first exposure to a pathogen, this constitutes the primary response. Following clonal selection, some T cells become memory cells. 2. Upon second exposure to a pathogen, memory cells mount a quick attack called the T cell recall response.

III. Immune System Disorders (p. 784) A. Hypersensitivity (p. 784) 1. Hypersensitive people produce antibodies to substances that most people tolerate, such as pollen or bee stings. Such substances are called allergens. 2. Type I (acute) hypersensitivity is the most common form and begins within seconds of exposure, and subsides within 30 minutes. a. Anaphylaxis is a variant of type I in which the allergen contacts an 19E molecule associated with mast cells and basophils. The cells release inflammatory chemicals that cause edema, mucus production, and congestion, as well as cramps, vomiting and diarrhea. b. Asthma is a local anaphylactic reaction to inhaled allergens. Allergen exposure can cause massive release of histamine, which triggers spasmodic contraction of the bronchioles, and wheezing. Asthma can be deadly in severe cases. c. Anaphylactic shock is a systemic response from injection of an allergen into the bloodstream (bee sting or penicillin). Bronchiolar constriction, circulatory shock, and sometimes death, result. 3. Type II (antibody-dependent cytotoxic) hypersensitivity occurs when IgG or IgM binds to antigens on cells and lyses them, as is the case in a transfusion reaction. 4. Type III (immune complex) hypersensitivity, also mediated by IgG or IgM, stems from the formation of large amounts of antigen-antibody complex throughout the body. These complexes can be trapped under the endothelium of blood vessels and trigger intense inflammation. 5. Type IV (delayed) hypersensitivity occurs 12 to 72 hours after exposure. It occurs when APCs display antigens to helper T cells in the lymph nodes. Cosmetics and poison ivy haptens are common culprits. B. Autoimmune Diseases (p. 785) 1. Autoimmune diseases are failures of the immune system to distinguish self from foreign antigens. 2. The immune system produces autoantibodies that attack the body's own tissues as a result of cross-reactivity (some foreign antigens are similar to those of the body, causing antibodies to direct their attack against the body), to abnormal exposure of self-antigens to the blood, or to changes in the structure of self-antigens. C. Immunodeficiency Diseases (p. 786, Fig. 21.29) 1. In immunodeficiency diseases, the immune system fails to respond vigorously enough. 2. Severe combined immunodeficiency disease (SCID) is a congenital deficiency of both T and B cells. Children with SCID are highly vulnerable to opportunistic infections and must live in protective enclosures. 3. Acquired immunodeficiency diseases are contracted after birth, such as acquired, immunodeficiency syndrome, or AIDS (p. 787, Figs. E.I , E.2). i. The human immunodeficiency virus (HIV) was first isolated in 983. It invades helper T (CD4) cells, along with macrophages, neutrophils, and brain cells. ii. Since HIV targets CD4 cells, nonspecific defenses, humoral immunity, and cellular immunity are hampered. At first, antibodies against HIV are produced, helping the CD4 count to return to near normal. Eventually, as the virus replicates, more CD4 cells are destroyed. iii. Most people with AIDS die of opportunistic infections. iv. Transmission of my can be prevented by not sharing intravenous needles, and protected sexual intercourse. v. Treatment involves a variety of new drugs, each with adverse side effects.