SECTION A: IMMUNOLOGY: DEFENSES AGAINST FOREIGN MATTER

1. CELLS MEDIATING IMMUNE DEFENSES
   1. Immune defenses may be nonspecific, in which the identity of the target is not recognized, or specific, in which it is.
   2. The cells of the immune system are leukocytes (neutrophils, eosinophils, basophils, monocytes, and Iymphocytes), plasma cells, macrophages, macrophage-like cells, and mast cells. The leukocytes use the blood for transportation but function mainly in the tissues.
   3. Cells of the immune system (as well as some other cells) secrete protein messengers that regulate immune responses and are collectively termed cytokines.

2. NONSPECIFIC IMMUNE DEFENSES
   1. External barriers to infection are the skin, the linings of the respiratory, gastrointestinal, and genitourinary tracts, the cilia of these linings, and antimicrobial chemicals in glandular secretions.
   2. Inflammation, the local response to injury or infection, includes vasodilation, increased vascular permeability to protein, phagocyte chemotaxis, destruction of the invader via phagocytosis or extracellular killing, and tissue repair.
      1. The mediators controlling these processes are either released from cells in the area or generated extracellularly from plasma proteins. Mediators of local inflammatory response include kinins, complement, blood clotting products, histamine, eicosanoids, platelet-activating factor, interleukins 1 and 6, tumor necrosis factor, lysosomal enzymes, nitric oxide, and other oxygen-derived substances.
      2. The main cells that function as phagocytes are the neutrophils, monocytes, macrophages, and macrophage-like cells. They also secrete many inflammatory mediators.
      3. One group of inflammatory mediators (the complement family of plasma proteins activated during nonspecific inflammation by the alternate pathway) not only stimulates many of the steps of inflammation but mediates extracellular killing via their membrane attack complex.
      4. The end result of infection or tissue damage is tissue repair.

   3. Interferon stimulates the production of intracellular proteins that nonspecifically inhibit viral replication.

3. SPECIFIC IMMUNE DEFENSES
   1. Lymphocytes mediate specific immune responses.
   2. Specific immune responses occur in three stages.
      1. A Iymphocyte programmed to recognize a specific antigen encounters it and binds to it via plasma-membrane receptors specific for the antigen.
      2. The Iymphocyte undergoes activation which is a cycle of cell divisions and differentiation.
      3. The multiple active Iymphocytes produced in this manner launch an attack against antigens of that kind all over the body.

   3. The Iymphoid organs are categorized as primary (bone marrow and thymus) or secondary (Iymph nodes, spleen, tonsils, and Iymphocyte collections in the linings of the body's tracts).
      1. The primary lymphoid organs are the sites of maturation of lymphocytes that will then be carried to the secondary lymphoid organs, which are the major sites of lymphocyte cell division and specific immune responses.
      2. Lymphocytes undergo a continuous recirculation among the secondary lymphoid organs, lymph, blood, and all the body's organs and tissues.

   4. The three broad populations of lymphocytes are B, T, and NK cells.
      1. B cells mature in the bone marrow and are carried to the secondary lymphoid organs, where additional B cells arise by cell division.
      2. T cells leave the bone marrow in an immature state, are carried to the thymus and undergo maturation there. These cells then travel to the secondary lymphoid organs and new T cells arise from them by cell division.
      3. The origin of NK cells is in the bone marrow.

   5. B cells and T cells have different functions.
      1. B cells, upon activation, differentiate into plasma cells, which secrete antibodies. Antibody-mediated responses constitute the major defense against bacteria, viruses, and toxins in the extracellular fluid.
      2. Cytotoxic T cells directly attack and kill virus-infected cells and cancer cells, without the participation of antibodies.
      3. Helper T cells stimulate B cells and cytotoxic T cells via cytokines they secrete. With few exceptions, this help is essential for activation of the B cells and cytotoxic T cells.

   6. Bcell surface plasma-membrane receptors are copies of the specific antibody (immunoglobulin) the cell is capable of producing.
      1. Any given B cell or clone of B cells produces antibodies that have a unique antigen binding site.
      2. Antibodies are composed of four interlocking polypeptide chains; the variable regions of the antibodies are the sites that bind antigen.

   7. Tcell surface plasma-membrane receptors are not immunoglobulins, but they do have specific antigen binding sites that differ from one T cell clone to another.
      1. The Tcell receptor binds antigen only when the antigen is complexed to one of the body's own plasma-membrane MHC proteins.
      2. Class I MHC proteins are found on all nucleated cells of the body, whereas class II MHC proteins are found only on macrophages, B cells, and macrophage-like cells. Cytotoxic T cells require antigen to be complexed to class I proteins, whereas helper T cells require class II proteins.

   8. Antigen presentation is required for Tcell activation.
      1. Only macrophages, B cells, and macrophage-like cells function as antigen-presenting cells (APCs) for helper T cells. The antigen is internalized by the APC and hydrolyzed to peptide fragments, which are complexed with Class II MHC proteins. This complex is then shuttled to the plasma membrane of the APC, which also delivers a nonspecific costimulus to the T cell and secretes interleukin 1.
      2. A virus-infected cell or cancer cell can function as an APC for cytotoxic T cells. The viral antigen or cancer-associated antigen is synthesized by the cell itself and hydrolyzed to peptide fragments, which are complexed to class I MHC proteins. The complex is then shuttled to the plasma membrane of the cell.

   9. NK cells have the same targets as cytotoxic T cells, but they are not antigen-specific; their mechanism of target identification is not understood.
   10. Immune tolerance is the result of clonal deletion and clonal activation.
   11. In antibody-mediated responses, the membrane receptors of a B cell bind antigen, and at the same time a helper T cell also binds antigen in association with a class II MHC protein on a macrophage or other APC.
       1. The helper T cell, activated both by the antigen and by IL-1 secreted by the APC, secretes IL-2, which then causes the helper T cell to proliferate into a clone of cells that secretes additional cytokines.
       2. These cytokines then stimulate the antigen-bound B cell to proliferate and differentiate into plasma cells, which secrete antibodies. Some of the activated B cells become memory cells, which are responsible for active immunity.
       3. There are five major classes of secreted antibodies: IgG, IgM, IgA, IgD, and IgE. The first two are the major antibodies utilized against bacterial and viral infection.
       4. The secreted antibodies are carried throughout the body by the blood and combine with antigen. The antigen-antibody complex enhances the inflammatory response mainly by activating the complement system. Complement proteins mediate many steps of inflammation, act as opsonins, and directly kill antibody-bound cells via the membrane attack complex.
       5. Antibodies of the IgG class act directly as opsonins and also link target cells to NK cells, which directly kill the target cells.
       6. Antibodies also neutralize toxins and extracellular viruses.

   12. Virus-infected cells and cancer cells are killed by cytotoxic T cells, NK cells, and activated macrophages.
       1. A cytotoxic Tcell binds, via its membrane receptor, to cells bearing a viral antigen or cancer-associated antigen in association with a class I MHC protein.
       2. Activation of the cytotoxic T cell also requires cytokines secreted by helper T cells, themselves activated by antigen presented by a macrophage. The cytotoxic T cell then releases perforin, which kills the attached target cell by making it leaky.
       3. NK cells and macrophages are also stimulated by helper T cell cytokines, particularly IL-2 and interferon-gamma to attack and kill virus-infected or cancer cells.

4. SYSTEMIC MANIFESTATIONS OF INFECTION
   1. The acute phase response is summarized in Figure 20-18.
   2. The major mediators of this response are IL-1, TNF, and IL-6.

5. FACTORS THAT ALTER THE BODY'S RESISTANCE TO INFECTION
   1. The body's capacity to resist infection is influenced by nutritional status, the presence of other diseases, psychological factors, and the intactness of the immune system.
   2. AIDS is caused by a retrovirus that destroys helper T cells and therefore reduces the ability to resist infection and cancer.
   3. Antibiotics interfere with the synthesis of macromolecules by bacteria.

6. HARMFUL IMMUNE RESPONSES
   1. Rejection of tissue transplants is initiated by MHC proteins on the transplanted cells and is mediated mainly by cytotoxic T cells.
   2. Transfusion reactions are mediated by antibodies.
      1. Transfused erythrocytes will be destroyed if the recipient has natural antibodies against antigens (type A or type B) on the cells.
      2. Antibodies against Rh positive erythrocytes can be produced following exposure of an Rh negative person to such cells.

   3. Allergy (hypersensitivity reactions), caused by allergens, are of several types.
      1. In delayed hypersensitivity, the inflammation is due to the interplay of helper T cell cytokines and macrophages. Immune complex hypersensitivity is due to complement activation by antigen-antibody complexes.
      2. In immediate hypersensitivity, antigen binds to IgE antibodies themselves bound to mast cells. The mast cells then release inflammatory mediators such as histamine that produce the symptoms of the allergy. The late phase of immediate hypersensitivity is mediated by eosinophils.

   4. Autoimmune attacks are directed against the body's own proteins, acting as antigens. Reasons for the failure of immune tolerance are summarized in Table 20-10.
   5. Normal tissues can be damaged by excessive inflammatory responses to microbes.

SECTION B: NONIMMUNE METABOLISM OF FOREIGN CHEMICALS

1. TOXICOLOGY: METABOLISM OF FOREIGN CHEMICALS
   1. The concentration of a foreign chemical in the body depends upon degree of exposure to the chemical, its rate of absorption across the GI tract, lung, skin, or placenta, and its rates of storage, biotransformation, and excretion.
   2. Biotransformation occurs in the liver and other tissues and is mediated by multiple enzymes, notably the microsomal enzyme system (MES). Its major function is to make lipid-soluble substances more polar (less lipid-soluble), thereby decreasing renal tubular reabsorption and increasing excretion.
      1. The MES can be induced or inhibited by the chemicals it processes and by other chemicals.
      2. It detoxifies some chemicals but toxifies others, notably carcinogens.

SECTION C: RESISTANCE TO STRESS

1. RESISTANCE TO STRESS
   1. Classical responses to stress, whether physical or psychological, are increased secretion of cortisol from the adrenal cortex and activation of the sympathetic nervous system, including release of epinephrine by the adrenal medulla.
   2. The functions of these responses, summarized in Tables 20-12 and 20-13, can be viewed both as a preparation for fight or flight and for coping with new situations.
   3. Other hormones released during stress include aldosterone, vasopressin, glucagon, growth hormone, and prolactin. Insulin secretion is usually decreased.