IMMUNE SYSTEM

• Organization of the Immune System

• Two major categories of immune mechanisms.
  • Nonspecific immunity
  • Specific immunity
• Nonspecific immunity includes mechanisms that resist a variety of threatening agents or conditions.
  • The term nonspecific immunity means that these immune mechanisms do not act on one or two specific invaders, but rather provide a more general defense by simply acting against any thing recognized as not self.

• Specific immunity involves mechanisms that recognize specific threatening agents and respond by targeting their activity against these agents--and these agents only.
  • These mechanisms often take some time to recognize their targets and react with sufficient force to overcome the threat.
• As in any body system, the work of the immune system is done by cells or substances made by cells.
• Primary types of cells involved in nonspecific immunity.
  • Neutrophils
  • Monocytes
  • Macrophages
  • Natural-Killer (NK) cells
• The primary types of cells involved in specific immunity are:
• T-cells
• B-cells

• Nonspecific Immunity

• Specific resistance
  • Refers to a phenomenon in which genetic characteristics common to a particular kind of organism, or species, provide defense against certain pathogens.
    • For example, humans do not have to worry about getting Dutch Elm Disease or canine viral distemper.
  • Usually, species resistance in humans results from the fact that our internal environment is not suitable for certain pathogens.
• Mechanical and Chemical Barriers OH- T-136 Nonspecific Defenses
  • Internal environment of the human body is protected by a continuous mechanical barrier formed by the cutaneous membrane (skin) and mucous membranes.
    • Often called the first line of defense
  • Besides forming a protective wall, the skin and mucous membranes operate various additional immune mechanisms.
    • Sebum--contains pathogen-inhibiting agents.
    • Mucus--pathogens may stick and be swept away.
    • Enzymes--may hydrolyze pathogens.
    • Hydrochloric acid--may destroy pathogens.
• Inflammation OH-T-138 The Inflammation Process
  • The inflammatory response
    • Recall from first semester that tissue damage elicits many responses that counteract the injury and promote a return to normal.
      • Bacteria cause tissue damages that, in turn, triggers the release of mediators from cells such as mast cells found in connective tissue.
      • These inflammation mediators include:
    • Histamine
    • Kinins
    • Prostaglandins
    • Many of these mediators are substances that attract white blood cells to the area by a process called chemotaxis.

• (3) Many also cause increased blood flow and increased vascular permeability.
• Phagocytosis OH-Phagocytosis
  • Is the ingestion and destruction of microorganisms or other small particles by phagocytes.
• The most numerous types of phagocytes are the neutrophils and the macrophages.
  • Macrophages are phagocytocytic monocytes that have grown to several times their normal size after migrating out of the blood stream.
  • Natural Killer Cells OH-T-135 Derivation and Distribution of Lymphocytes
    • Are a group of lymphocytes that kill many types of tumor cells and cells infected by different kinds of viruses.
      • Generally kill cells by releasing enzymes that lyse the pathogen's cell membrane or protein coat.
  • Interferon
    • Several types of cells, if invaded by viruses, respond rapidly by synthesizing the protein interferon and releasing some of it into circulation.
      • Interferon proteins interfere with the ability of viruses to cause disease by preventing the viruses from multiplying in the cell.
    • Three (3) major types of interferon:
      • Leucocyte interferon
      • Fibroblast interferon
      • Immune interferon
  • Complement
    • Is the name given to each of a group of about twenty (20) inactive enzymes in the plasma.
    • Are activated in a cascade of chemical reactions triggered by either specific or nonspecific mechanisms.
    • The complement cascade causes lysis of the foreign cell that triggered it.

• Overview of Specific Immunity 20870

• The various types of specific immune mechanisms attack specific agents that the body recognizes as "not self".
• Specific immunity is orchestrated by two different classes of lymphocytes.
• Lymphocytes are formed in red bone marrow and are derived from primitive cells called stem cells. OH T-135 Derivation and Distribution of Lymphocytes
  • Stem cells destined to become lymphocytes follow two (2) developmental paths and differentiate into two (2) major classes of lymphocytes.
    • B-lymphocytes or B-cells
    • T-lymphocytes or T-cells
• B-cells do not attack pathogens themselves but, instead produce antibodies that attack the pathogens or direct other cells, such as phagocytes, to attack them.
  • B-cell mechanisms are often classified as antibody-mediated-immunity. 20875

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  • Because T-cells attack pathogens more directly, T-cell immune mechanisms are classified as cell-mediated-immunity. 20871
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  • The densest populations of phagocytes occur in the bone marrow, thymus gland, lymph nodes, and spleen.
    • From these structures, lymphocytes enter the blood and distribute themselves throughout the tissues of the body.
    • After wandering throughout the tissue spaces, they eventually make their way into lymphatic tissues.
    • Lymph flow transports the lymphocytes through a succession of lymph nodes and lymph vessels and empties them by way of the thoracic and right lymphatic ducts into the subclavian veins.
  • Vocabulary
    • Antigens--macromolecules that induce the immune system to make certain responses.
      • Most antigens are foreign proteins.
      • Some may be polysaccharides and some are nucleic acids--i.e. found in cell walls or outer membranes of microorganisms or the outer coats of viruses.
      • Some tumor cells produce antigens that are called non-self antigens.
    • Antigenic determinants--variously shaped small regions on the surface of an antigen molecules; called epitopes.
      • An epitope consists of a sequence of only about ten (10) amino acids that are part of a much longer, folded chain of amino acids.
      • The sequence of the amino acids in an epitope determines its shape.
      • Each kind of antigen usually has a specific and uniquely shaped epitope.
    • Antibodies--plasma proteins of the class called immunoglobulins.
    • Combining sites--two small concave regions on the surface of an antibody molecule.
      • An antibody's combining sites are so shaped that an antigen's epitope that has a complementary shape can fit into the combining site and thereby bind the antigen to the antibody to form an antigen-antibody complex.
    • Clone--family of cells, all of which descended from one cell.
    • Complement--a group of proteins that, when activated, work together to destroy foreign cells.

B-CELLS AND ANTIBODY-MEDIATED IMMUNITY

• First Stages in the Development and Activation of B-Cells OH-T-105

• B-cells start their development in the embryonic yolk sac, then the red marrow or fetal liver.
  • By the time a human infant is a few months old, its pre-B-cells have completed the first stage of development.
    • Are then known as inactive B-cells.
• Inactive B-cells synthesize antibody molecules but secrete few if any of them.
  • Instead, they insert on the surface of their plasma membranes perhaps 100,000 antibody molecules.
    • The combining sites of these surface antibody molecules are now ready to serve as receptors for a specific antigen if it comes by.
• After being released from the bone marrow, inactive B-cells circulate to the lymph nodes, spleen, and other lymphoid structures.

• Second Stage of B-Cell Development OH T-105

• Occurs when the inactive B-cells become activated.
• Activation of a B-cell must be initiated by an encounter between an inactive B-cell and its specific antigen.
• The antigen binds to these antibodies on the B-cell's surface.
  • Antigen-antibody binding activates the B-cell triggering a rapid series of mitotic divisions.
  • By dividing rapidly, a single B-cell produces a clone.
    • Some of them become differentiated to form plasma cells.
    • Others do not differentiate completely and remain in lymphatic tissue as memory B-cells.
• Plasma cells synthesize and secrete large amounts of antibody.
• Memory B-cells do not themselves secrete antibodies, but if they are later exposed to the antigen that triggered their formation, memory B-cells become plasma cells and the plasma cells secrete antibodies that can combine with the initiating antigen.
  • The ultimate function of B-cells is to serve as ancestors of antibody-secreting plasma cells.

• Structure of Antibody Molecules OH-Chemical Structure of Immunoglobin G

• Antibodies are proteins of the family called immunoglobulins.
• Each immunoglobulin molecule consists of four (4) polypeptide chains joined together by disulfide bonds (S-S)

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  • Two (2) heavy chains.
  • Two (2) light chains.
  • Each polypeptide chain is folded to form globular regions that are joined together in such a way that the whole molecule is Y-shaped.
  • Each chain has a V (variable) region, which has a markedly different amino acid sequence in different antibodies, and a C (constant) region, which is essentially identical in different antibodies of the same class.
  • The variable regions are the antigen-binding sites of the antibody; hence each antibody monomer has two binding sites.
  • OH (b) Enlargement of an antigenic determinant bound to an antigen-binding site.
  • OH (c) Computer generated image of antibody structure.
    • Each tiny colored dot (sphere) represents an individual amino acid of the polypeptide chain.
  • Each of us is thought normally to have millions of different kinds of antibody molecules in our bodies.
    • Each of these has its own uniquely shaped combining sites.
    • It is this structural feature that enables antibodies to recognize and combine with specific antigens, both of which are crucial first steps in the body's defense against microbes and other foreign cells.

• Classes of Antibodies

• There are five (5) classes of antibodies identified by letter names as immunoglobulins M, G, A, E, and D.
• Ig M (Immunoglobulin M)
  • Is the antibody that immature B cells synthesize and insert into their plasma membranes.
  • Is the predominate class of antibody produced after initial contact with an antigen in the blood.
• Ig G (Immunoglobulin G)
  • Most abundant circulating antibody.
  • Normally makes up about 75% of the antibodies in the blood.
• Ig A (Immunoglobulin A)
  • Major class of antibody present in the mucous membranes of the body, in saliva, and in tears.
• Ig E (Immunoglobulin E)
  • Minor in amount.
  • Can produce harmful effects such as those associated with allergies.
• Ig D (Immunoglobulin D)
  • Present in the blood in very small amounts and its precise function is unknown.

• Functions of Antibodies

• The function of antibody molecules is to produce antibody-mediated immunity.
  • This type of immunity is also called humoral immunity because it occurs within the plasma. OH T-140 Humoral Immunity
• Antigen-Antibody Reactions
  • Antibodies fight disease by distinguishing non-self antigens from self antigens.
  • Recognition occurs when an antigen's epitopes fit into and bind to an antibody molecule's antigen-binding sites.
  • The binding forms an antibody-antigen complex that may produce one or more effects.
    • It transforms antigens that are toxins into harmless substances.
    • It agglutinates antigens that are molecules on the surface of microorganisms which makes them stick together so phagocytes can engulf them.
• Complement OH-T-137 Complement Activation
  • Is a component of blood plasma that consists of about twenty (20) protein compounds.
  • Are inactive enzymes that become activated by the binding of an antibody to an antigen located on the surface of a cell.
  • By binding to these sites, complement protein becomes activated and touches off a cascade reaction that causes cytolysis of the cell.
• Clonal Selection Theory
  • Proposed in 1959 by Sir Macfarlane Burnet
  • Has two (2) basic tenets.
    • The body contains an enormous number of diverse clones of cells, each committed by certain of its genes to synthesize a different antibody.
    • When an antigen enters the body, it selects the clone whose cells are committed to synthesizing its specific antibody and stimulated these cells to proliferate and to produce more antibody.
  • We now know that the clones selected by the antigens consist of lymphocytes.
  • We also know how antigens select lymphocytes--by the shape of the antigen receptors on the lymphocyte's plasma membrane.
  • By selecting the precise clone committed to making its specific antibody, each antigen provides its own destruction.

T-CELLS AND CELL-MEDIATED IMMUNITY

• Development of T-Cells OH T-106 Stimulation and Effects of T Cells

• By definition, T-cells are lymphocytes that have made a detour through the thymus gland before migrating to the lymph nodes and spleen.
• During their residence in the thymus, pre-T-cells develop into thymocytes.
  • Thymocytes divide up to three (3) times/day and their numbers increase enormously in a relatively short period of time.
  • They leave the thymus and move into the blood and take up residence in areas of the lymph nodes and spleen called t-dependent zones.
    • From this time on they are known as T-cells.
• Activation and Function of T-Cells
• Each T-cell, like each B-cell, displays antigen receptors in its surface membrane.
• When an antigen (preprocessed and presented by macrophages) encounters a T-cell whose surface receptors fit the antigen's epitopes, the antigen binds to the T-cell's receptors.
  • This activated or sensitizes the T-cell, causing it to divide repeatedly to form a clone of sensitized T-cells.
• The sensitized T-cells then travel to the site where the antigen originally entered the body.
  • There in inflamed tissue, the sensitized T-cells bind to antigens of the same kind that led to their formation.
    • T-cells will bind to their specific antigen only if the antigen is presented by a macrophage.
• The antigen-bound sensitized T-cells then release chemical messengers into the inflamed tissues called cytokines.
  • Names of some cytokines and their function.
    • Chemotactic factors--attracts macrophages causing hundreds of then to migrate into the vicinity of the antigen bound, sensitized T-cells.
    • Macrophage activating factor--causes the macrophages to destroy antigens by phagocytosing them at a rapid rate.
    • Lymphotoxin--powerful poison that acts more directly, quickly killing any cell it attacks.
• Sensitized T-cells that release lymphotoxin are called killer T-cells or cytotoxic T-cells.

• Types of Specific Immunity

• Inherited immunity--immunity to certain diseases develops before birth--also called inborn immunity.
  • Example--inborn resistance to diseases that affect animals--viral canine distemper.
• Acquired immunity
  • Natural immunity--Exposure to the causative agent is not deliberate.
    • Active (exposure)--A child develops measles and acquires an immunity to subsequent infection.
    • Passive (exposure)--A fetus receives protection from the mother through the placenta, or an infant receives protection by way of the mother's milk.
  • Artificial immunity--exposure is deliberate.
    • Active--injection of the causative agent, such as vaccination against polio, confers immunity.
    • Passive--injection of protective material (antibodies) that was developed by another individual's immune system.

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