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I. Overview of Specific Immunity
  1. Specific immune system
    1. Has three major functions
      1. Recognize anything that is nonself
      2. Respond to this foreign material (effector response)-involves the recruitment of various defense molecules and cells to either destroy foreign material or render it harmless
      3. Remember the foreign invader (amnestic response)-a more rapid and intense responses to foreign material that occurs upon later encounters with the material
    2. The characteristics of specificity and memory distinguish the specific immune response from nonspecific resistance
    3. There are two arms of specific immunity
      1. Humoral (antibody-mediated) immunity-based on action of antibodies that bind bacteria, toxins, and extracellular viruses, tagging or marking them for destruction
      2. Cellular (cell-mediated) immunity-based on action of T cells that directly attack cells infected with viruses or parasites, transplanted cells or organs, and cancer cells
  2. Types of acquired immunity-specific immunity that develops after exposure to antigen or after transfer of antibodies or lymphocytes from an immune donor
    1. Naturally acquired immunity
      1. Naturally acquired active immunity-an individual comes in contact with an antigen via a natural process (e.g., infection) and produces sensitized lymphocytes and/or antibodies that inactivate or destroy the antigen
      2. Naturally acquired passive immunity-transfer (e.g., transplacentally or in breast milk) of antibodies from one individual (where they were actively produced) to another (where they are passively received)
    2. Artificially acquired immunity
      1. Artificially acquired active immunity-deliberate exposure of an individual to a vaccine (a solution containing antigen) with subsequent development of an immune response
      2. Artificially acquired passive immunity-deliberate introduction of antibodies from an immune donor into an individual
II. Antigens
  1. Prior to birth, the immune system removes most T cells specific for self-recognition determinants
  2. Antigens are substances, such as proteins, nucleoproteins, polysaccharides, and some glycolipids that elicit an immune response and react with products of that response
    1. Epitopes (antigenic determinant sites) are areas of an antigen that can stimulate production of specific antibodies and that can combine with them
    2. Valence-the number of epitopes on an antigen; determines number of antibody molecules an antigen can combine with at one time
  3. Hapten-a small organic molecule that is not itself antigenic but that may become antigenic when bound to a larger carrier molecule
  4. Superantigens-bacterial proteins that provoke a dramatic immune response by nonspecifically stimulating T cells to proliferate; occurs when superantigen interacts both with class II MHC molecules and T-cell receptors; superantigens cause symptoms by way of release of massive quantities of cytokines; superantigens are associated with various chronic diseases including rheumatic fever, arthritis, and others
  5. Cell-associated differentiation antigens (CDs)-functional cell surface proteins that are used to differentiate between leukocyte subpopulations; concentration of these molecules in serum is usually low and elevated levels are associated with disease (e.g., various cancers, autoimmune diseases, HIV infection); levels in serum can be used in disease management
III. Antibodies
  1. Antibody (immunoglobulin, Ig)-glycoprotein made in response to an antigen; recognizes and binds the antigen that caused its production; five different classes: IgG, IgA, IgM, IgD, and IgE
  2. Immunoglobulin structure
    1. Multiple antigen-combining sites (usually two; some can form multimeric antibodies with up to ten combining sites)
    2. Basic structure is composed of four polypeptide chains
      1. There are two heavy chains and two light chains
      2. Within each chain is a constant region (little amino acid sequence variation within the same class of Ig) and a variable region
    3. The four polypeptides are arranged in the form of a flexible Y
      1. Fc (crystallizable fragment) is stalk of the Y; contains site at which antibody can bind to a cell; composed only of constant region
      2. Fab (antigen binding fragments) are at the top of the Y; they bind compatible epitopes of an antigen; composed of both constant and variable regions
      3. Domains-homologous units, each about 100 amino acids long, observed in heavy chains and in light chains
    4. Light chain exists in two distinct forms kappa (k) and lambda (l)
    5. There are five types of heavy chains: gamma (g), alpha (a), mu (m), delta (d), and epsilon (e); these determine, respectively, the five classes (isotypes) of immunoglobulins: IgG, IgA, IgM, IgD, and IgE
    6. In IgG there are four subclasses, and in IgA there are two subclasses; these subclasses result from variations in the amino acid composition of the heavy chains; the variations are classified as:
      1. Isotypes-variations normally present in all individuals
      2. Allotypes-genetically controlled allelic forms of the immunoglobulin molecules; allelic forms that are not present in all individuals
      3. Idiotypes-individual-specific immunoglobulin molecules that differ in the Fab segments
  3. Immunoglobulin function
    1. Fab region binds to antigen whereas Fc region mediates binding to host tissue, various cells of the immune system, some phagocytic cells, or the first component of the complement system
    2. Binding of antibody to an antigen does not destroy the antigen, but marks (targets) the antigen for immunological attack and activates nonspecific immune responses that destroy the antigen
    3. Opsonization-coating a bacterium with antibodies to stimulate phagocytosis
  4. Immunoglobulin classes
    1. IgG-monomeric protein, 70% to 75% of Ig pool
      1. Antibacterial and antiviral
      2. Enhances opsonization; neutralizes toxins
      3. Only IgG is able to cross placenta (naturally acquired passive immunity for newborn)
      4. Activates the complement system by the classical pathway
      5. Four subclasses with some differences in function
    2. IgM-pentameric protein, 10% of Ig pool
      1. First antibody made during B-cell maturation and first antibody secreted into serum during primary antibody response
      2. Never leaves the bloodstream
      3. Agglutinates bacteria and activates complement by classical pathway; enhances phagocytosis of target cells
      4. Some may be red blood cell agglutinins
      5. Up to 5% may be hexameric; hexameric form is better able to activate the complement system than pentameric IgM; bacterial cell wall antigens may directly stimulate B cells to produce hexameric form
    3. IgA-15% of Ig pool
      1. Some monomeric forms in serum, but most is dimeric and associated with a protein called the secretory component (secretory IgA or sIgA)
      2. sIgA is primary Ig of mucosal-associated lymphoid tissue; also found in saliva, tears, and breast milk (protects nursing newborns); helps rid the body of antigen-antibody complexes by excretion; functions in alternate complement pathway
    4. IgD-monomeric protein, trace amounts in serum
      1. Does not activate the complement system and cannot cross the placenta
      2. Abundant on surface of B cells where it plays a role in signaling B cells to start antibody production
    5. IgE-monomeric protein, less than 1% of Ig pool
      1. Skin-sensitizing and anaphylactic antibodies
      2. When an antigen cross-links two molecules of IgE on the surface of a mast cell or basophil, it triggers release of histamine; stimulates eosinophilia and gut hypermotility, which helps to eliminate helminthic parasites
  5. Diversity of antibodies-three mechanisms contribute to the generation of antibody diversity
    1. Combinatorial joining
      1. Ig genes are interrupted or split genes with many exons; in light chain gene, there are three types of exons (C,V, and J); in heavy chain gene there are four types of exons (C, V, J, and D)
      2. During differentiation of B cells, one C exon, one V exon, and one J exon are joined together to make a functional light chain gene; one C, one V, one J, and one D are joined together to make a functional heavy chain gene; since there are numerous C, V, J, and D exons, many different combinations are possible (2x108)
      3. The number of different antibodies possible is the product of the number of light chains possible and the number of heavy chains possible
    2. Somatic mutations-the V regions of germ-line DNA are susceptible to a high rate of somatic mutation during B-cell development
    3. Alternate joining points-the same exons can be joined at different nucleotides, thus increasing the number of codons and the possible diversity
  6. Specificity of antibodies-clonal selection theory
    1. Because of combinatorial joining and somatic mutation, there are a small number of B cells capable of responding to any given antigen; each group of cells is derived asexually from a parent cell and is referred to as a clone; there is a large, diverse population of B-cell clones that collectively are capable of responding to many possible antigens
    2. Identical antibody molecules, specific to each B cell and a single antigen, are integrated into the plasma membrane of B cell; when these bind the appropriate antigen the B cell is stimulated to divide and differentiate into two populations of cells: plasma cells and memory cells
      1. Plasma cells are protein factories that produce about 2,000 antibodies per second for their brief life span (5-7 days)
      2. Memory cells can initiate antibody-mediated immune response if they are stimulated by being bound to the antigen; they circulate more actively from blood to lymph and have long life spans (years or decades); are responsible for rapid secondary response; are not produced unless B cell has been appropriately signaled by activated T-helper cell
  7. Sources of antibodies
    1. Immunization-purified antigen is injected into host; specific B-cell clone recognizes and responds by proliferating and producing antibodies
      1. To promote antigen stimulation, antigen may be mixed with an adjuvant (a molecule that enhances rate and quantity of antibodies produced)
      2. Blood withdrawn from immunized host is allowed to clot; fluid remaining is called serum
      3. Serum obtained from immunized host is called antiserum
      4. Limitations 1) This method results in polyclonal antibodies, which have different epitope specificities; thus sensitivity is lower, and the antibodies often cross-react with closely related antigens 2) Repeated injections with antiserum from one species into another can cause serious allergic reactions 3) Antiserum contains a mixture of antibodies, not all of which are of interest
    2. Primary antibody response-with immunization and natural acquired immunity, levels (titer) of antibody change over time
      1. Initial lag phase of several days
      2. Log phase-antibody titer rises logarithmically
      3. Plateau phase-antibody titer stabilizes
      4. Decline phase-antibody titer decreases because the antibodies are metabolized or cleared from the circulation
      5. Mostly IgM (low-affinity antibodies)
    3. Secondary antibody response (amnestic response)-has shorter lag phase, higher antibody titer, and more IgG, which have high affinity for antigens (affinity maturation)
    4. Hybridomas-overcome some of the limitations of antisera by producing a monoclonal antibody with a single specificity
      1. Made by injecting animals with antigen; when they begin to produce antibodies, spleen is removed and plasma cells are isolated
      2. Plasma cells are fused with myeloma cells (easily cultured tumor cells of the immune system that produce large quantities of antibodies); the resulting fused cells are hybridomas
      3. Hybridomas are cultured so that each grows into a separate colony; these are screened to identify those producing desired antibody
      4. Monoclonal antibodies have a variety of uses: tissue typing for transplants, identification and epidemiological study of infectious microorganisms, identification of tumor and other surface antigens, classification of leukemias and identification of T-cell populations
IV. T-Cell Biology
  1. T-cell antigen receptors-bind to antigens only when antigen is presented by an antigen-presenting cell
  2. Major histocompatibility complex (MHC)-proteins encoded by a group of genes called the major histocompatibility complex (MHC) genes; comprise three classes; only class I and class II are involved in antigen presentation
    1. Both class I and class II MHC molecules consist of two protein chains and are attached to cytoplasmic membrane
    2. Both class I and class II MHC molecules fold into similar shapes, each having a deep groove into which a short peptide or other antigen fragment can bind; the presence of a foreign peptide in this groove alerts immune system and activates T cells or macrophages
    3. Class I MHC molecules bind to peptides that originate in the cytoplasm (endogenous antigens, such as those from replicating viruses); class II MHC molecules bind to fragments that arise from exogenous antigen
      1. Endogenous proteins-pumped by specific transporter proteins from cytoplasm to endoplasmic reticulum, where they become associated with newly synthesized class I MHC molecules; the peptide-class I MHC complex is then carried to and incorporated within the plasma membrane; detected by cytotoxic T cells
      2. Exogenous proteins arise from bacteria and viruses taken in endocytotically; digestion of bacterium or virus in phagolysosome creates peptides; these peptides combine with class II MHC and are delivered to cell surface; detected by T-helper cells
    4. Class I MHC-made by all cells except red blood cells; function to identify cells as Aself@; primary basis of HLA typing for organ transplant
    5. Class II MHC-produced only by activated macrophages, mature B cells, some T cells, and certain cells of other tissues; function in T-cell communication with macrophages and B cells
    6. Class III-involved in the classical and alternate complement pathways
  3. Types of T cells
    1. Effector cells (cytotoxic T cells-TC)-attach by their T-cell receptor to virus-infected cells that display class I MHC proteins and viral antigens; are then stimulated by T-helper cells; activated cytotoxic T cells produce cytokines that limit viral reproduction and activate macrophages and other phagocytic cells; ultimately cytotoxic T cell destroys target cell; two mechanisms are:
      1. CD95 pathway-transmembrane signal transduction leads to initiation of apoptosis
      2. Perforin pathway-release of perforins that damage the target cell membrane, resulting in cytolysis of target cell
    2. Regulator T cells
      1. T-helper cells (TH) 1) Three subsets: TH1, TH2, and TH0; each produces and secretes a specific mixture of cytokines 2) TH1-requires two signals for activation (presentation of antigen by an antigen-presenting cell and binding of a TH1 receptor to a macrophage surface protein); activated TH1 secretes cytokines that activate cytotoxic T cells and macrophages 3) TH2-requires two signals for activation (antigen presentation and interleukin-1); activated TH2 releases cytokines that stimulate B-cell proliferation and differentiation
      2. T-suppressor cells (TS)-suppress B-cell and T-cell responses; activated by interleukin-2, which is produced by activated T-helper cells; proliferation of TS occurs slowly and provides negative feedback control for acquired immune tolerance
V. B-Cell Biology
  1. Have surface molecules important to their function
    1. Surface molecules include B-cell antigen receptors (BCRs-IgM and IgD on surface of B cell), Fc receptors, and complement receptors
    2. Binding of receptors to target molecules is involved in activation of B cell and in phagocytosis, processing, and presentation of antigens
  2. Antigen-antibody binding-occurs within the pocket formed by folding the VH and VL regions of Fab; binding is due to weak, noncovalent bonds and in most cases shapes of epitope and binding site must be highly complementary (i.e., lock and key) for efficient binding; in at least one case, it is known that the antigen induces a shape change of the antigen-binding site (induced fit mechanism); high complementarity of epitope and binding site provides for the high specificity associated with antigen-antibody binding
  3. B-cell activation
    1. T-dependent antigen triggering
      1. Macrophage ingests the antigen or antigen-bearing organism, processes the antigen, and displays a fragment of the antigen and with its Class II MHC to a T-helper cell; macrophage also secretes interleukins (IL-1 and IL-6) b IL-1 and IL-6 stimulate the T-helper cell to divide and secrete interleukins (IL- 2, IL-4, IL-5, and IL-6); IL-1 also induces fever
      2. IL-2, IL-4, IL-5 and IL-6 stimulate proliferation of the T-helper cell
      3. The resulting T-helper clones bind to B cells presenting the appropriate antigen on their surface; they also secrete B-cell growth factor (BCGF), which causes B cells to divide, and B-cell differentiation factor (BCDF), which causes the B cells to differentiate into plasma cells and produce antibodies
      4. Note that this pathway for B-cell activation also requires an interaction between the B cell and the antigen; B cell recognizes antigen through its BCRs
    2. T-independent antigen triggering-causes production of IgM; occurs with polymeric antigens, which have a large number of identical epitopes; antibodies produced, which have low affinity for antigen, never switch to high-affinity IgG or other isotypes; no memory cells are produced
VI. Action of Antibodies
  1. Toxin neutralization-antibody (antitoxin) binding to toxin renders the toxin incapable of attachment or entry into target cells
  2. Viral neutralization-binding prevents viral attachment to target cells
  3. Adherence inhibition-sIgA prevents bacterial adherence to mucosal surfaces
  4. IgE and parasitic infection-in the presence of elevated IgE levels, eosinophils bind parasites and release lysosomal enzymes that lead to destruction of parasite
  5. Opsonization-enhancement of phagocytosis; results form coating of microorganisms or other material by antibodies or complement; this prepares the microorganism for phagocytosis
  6. Immune complex formation-two or more antigen-binding sites per antibody molecule lead to cross-linking, forming molecular aggregates called immune complexes; these complexes are more easily phagocytized
    1. Precipitation (precipitin) reaction-soluble particles are cross-linked, causing them to precipitate from solution; the antibody involved is called a precipitin antibody
    2. Agglutination reaction-particles or cells are cross-linked, forming an aggregate; the antibody involved is called an agglutinin
    3. Hemagglutination-agglutination of red blood cells; antibody is called a hemagglutinin
VII. The Classical Complement Pathway
  1. Activation of this pathway requires interaction of antibody with an antigen that is usually cell bound
  2. Following antigen-antibody binding, a complement component (C1) attaches to Fc; this leads to a cascade of enzymatic reactions that culminate in the production of a complex of proteins (C5b67)
  3. This complex binds membrane of the target cell; two other complement components then bind, forming the membrane attack complex; this creates a pore in the membrane of the target cell, causing it to lyse
VIII. Acquired immune tolerance
  1. Nonresponse to self; three mechanisms have been proposed: negative selection by clonal deletion, induction of anergy, and inhibition of immune response by T-suppressor cells
  2. Negative selection by clonal deletion-T cells with ability to interact with self-antigens are destroyed in the thymus
  3. Induction of anergy-an example of peripheral tolerance (tolerance that develops in areas other than thymus); lymphocytes that can interact with self-antigens are given incomplete activation signals, causing them to enter into an unresponsive state known as anergy
IX. Summary: The Role of Antibodies and Lymphocytes in Resistance
  1. Response of a host to any particular pathogen may involve a complex interaction between host and pathogen, as well as the components of both nonspecific and specific immunity
  2. Immunity to viral infection
    1. Antibodies neutralize viruses
    2. Antibodies enhance phagocytosis
    3. Interferons shut down protein synthesis in virus-infected cells; interferons stimulate the activity of T cells and NK cells
    4. Activated macrophages and cytotoxic T cells destroy virus-infected cells
  3. Immunity to bacterial infections
    1. Antibodies trigger complement attack by the classical pathway, leading to the formation of the membrane attack complex
    2. Complement activation attracts neutrophils and macrophages to site of infection
    3. Toxin neutralization
    4. Activated macrophages and cytotoxic T cells destroy cells infected with intracellular pathogenic bacteria

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