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The Body Defenses

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					Chapter 43: The Body’s Defenses
Vertebrates have evolved finely tuned defense mechanisms against microbes, viruses, other pathogens, abnormal
cells, and potentially harmfull substances. These defense mechanisms can be classified as Nonspecific or Specific
defense mechanisms. (Fig 43.1)
Nonspecific defense mechanisms
       We come fully equipped with these mechanisms b/c they are part and parcel of our anatomy. Do not target
        specific pathogens. Effectively reduce the workload of the immune system by preventing entry and spread
        of microorganisms in the body.
       First line of defense
             A. Skin
                       physical barrier
                       chemical secretion of acids by sweat glands.
             B. Mucous membranes (epithelial)
                       line digestive, respiratory, and genitourinary tracts.
                       physical barrier
                       chemical defenses: lysozyme digests cell walls of bacteria.
                       trap particles: swallowed and killed by gastric juices or expelled
                       cilliated cells sweep out microbes and other particles
       Second line of defense
             Depends on a variety of white blood cells (WBC) whose mechanisms of nonspecific defenses is
                  mainly by phagocytosis.
             phagocytosis = ingestion of invading particles by certain types of WBC.
             WBC involved in nonspecific defenses include macrophage and monocytes, neutrophils,
                  eosinophils.
             Neutrophils
                       constitute 60-70% of WBC; attracted to infected area by chemotaxix; phagocytic; short-
                          lived (a few days).
             Macrophage
                       Develop from monocytes. Monocytes mature in blood and then migrate into tissues,
                          enlarge and develop into macrophage.
                       Largest of phagocytic cells, most effective and long-lived.
                       Some macrophage reside permanently in organs and connective tissues and have specific
                          names.
                       Some intercellular bacteria evade phagocytosis. Some prevent fusion with lysosome.
                          Some escape phagosome and replicate in cytoplasm, and still others have cell envelopes
                          resistant to lytic enzymes.
             Eosinophils
                       comprise about 1.5% of WBC
                       have limited phagocytic activity.
                       mainly defend against larger parasitic invaders (nematodes) by discharging degradative
                          enzymes from their granules.
             Natural Killer Cells
                       Destroy body’s own infected cells (especially viral infected)
                       destroy tumor cells
                       mode of destruction is by attack on membrane causing lysis.
             Antimicrobial proteins
                       Complement proteins (complement system)
                                group of over 20 proteins acting together in a cascade of activation steps which
                                    culminate with lysis of invading microbes.
                       Interferon
                                secreted by virus-infected cells and diffuse to uninfected cells, where they
                                    stimulate other proteins that inhibit viral replication in those cells.
                                interferon-gamma activates macrophage, enhancing their ability to kill
                                 microorganisms.
The Inflammatory Response (Fig 43.5)
      Localized response triggered when cells of tissue injured by bacteria or physical damage release chemical
       signals such as histamine, prostaglandins, and cytokines (various interleukins)
      These signals induce increased permeability of capillaries and blood flow to the affected area. Also
       released are certain chemicals (cytokines) that attract phagocytic cells and lymphocytes.
      After their arrival at site of injury, phagocytes consume pathogens and cell debris, and tissue heals.
             Macrophage also clean up remains of tissue cells and neutrophils that are self-destructed.
             Pus = mostly dead cells and fluid that leaked from capillaries during inflammatory response.
             Inflammatory response is localized. However, body can also react systemically to an infection.
                       injured cells release molecules which stimulate the release of more neutrophils from bone
                           marrow (diagnostic of infection).
                       fever: another systemic response. Inhibits growth of some microorganisms.
The Human Lymphatic system (Fig 43.4)
      Returns fluid from interstitial spaces back to the circulatory system. Lymphatic system includes various
       organs that play a crucial role in the body’s defense system.
      lymphatic system divided into 2 semi-independent parts:
            1. meandering one-way networks of lymphatic vessels that start out as lymphatic capillaries
                (extremely permeable) and acts as drainage system.
                      transports fluids that have escaped from the blood vascular system back to the blood.
                      3 L daily.
                      lymph moves through vessels as in veins (1 way valves and muscle action) + rythmic
                          contraction of smooth walls of major lymphatic vessels.
            2. various lymphoid organs and tissues
                      lymph nodes and spleen have high concentrations of macrophages and lymphocytes.
                      provide sites for proliferation of lymphocytes
                      furnishes ideal surveillance vantage point for lymphocytes and macrophage to encounter
                          antigens.
                      lymph nodes:filter lymph returning to blood; 2 basic functions:
                                1. filtration of lymph: phagocytic cells remove and destroy microorganisms and
                                    other debris
                                2. activation of immune cells; contain lymphocytes that monitor for presence of
                                    antigens.
                                sometimes lymphnodes overwhelmed by antigens and become inflammed and
                                    tender to touch.
                      Spleen
                                largest lymphoid organ (size of fist)
                                site of lymphocyte proliferation, immune surveillance and response.
                                has blood cleansing functions: removes old RBCs, platelets, debris, foreign
                                    matter, bacteria, toxins, etc...
                                other function s include: stores breakdown product of hemoglobin and recycles
                                    iron; site of RBC formation in fetus; stores blood platellets.
                      Thymus
                                mainly important during early life.
                                secretes hormones (thymosin and thymopoietin) and causes T-cells to become
                                    immunocompetent.
                                its the only lymphoid organ that does not directly fight antigens.
Specific defense mechanisms (ie the Immune system)
      Immunology = The study of the immune system
      The immune system is the body’s third line of defense, and it develops a specific response against each
       type of foreign microbe, toxin, or transplanted tissue.
     Four key features characterize the immune system: specificity, diversity, memory, self-nonself recognition.
           Specificity
                    Ability to recognize and eliminate particular microorganisms and foreign molecules.
                    Antigen = a foreign substance that elicits an immune response.
                    may be molecules displayed on surface of, produced by, or released from, bacteria, virus,
                        protozoans, parasitic worms, pollen, insect venom, transplanted organs, or worn out cells.
                    each antigen has a unique shape and stimulates the production of antibodies that defend
                        against that particular antigen.
                    Antibodies = An antigen-binding immunoglobulins (protein) produced by B-cells, that
                        functions as the effector in an immune response.
           Diversity
                    Ability to respond to numerous kinds of invaders
                    Based on a wide spectrum of lymphocyte populations.
                    Each population of antibody-producing B-cells is stimulated by a specific antigen.
           Memory
                    Ability to recognize previously encountered antigens.
           Self-nonself recognition
                    Ability of immune system to distinguish between body’s own molecules and foreign
                        molecules (antigens).
                    Failure of this system leads to autoimmune diseases (Rheumatoid arthritis, Lupus, etc...)
Active vs Passive Acquired Immunity
     Active immunity
           Conferred by recovery from infectious disease
           Depends on persons own immune system.
           May be acquired artificially with vaccines.
     Passive immunity
           transferred from person to person through transfer of antibodies.
           Natural instances include antibodies passing across placenta from mother to fetus (provides
               temporary protection) or through the milk.
           Transferred artificially. E.g. antibody injections for rabies, anti rhesus factor, snake venom,
               botulinun toxin.
Cells of the Immune System
     Cells responsible for both humoral and cell-mediated immunity are called Lymphocytes: the different
      responses are mediated by two main classes of lymphocytes, B cells and T cells.
     Immature B and T cells develop from multipotent stem cells in the bone marrow and only differentiate after
      reaching site of maturation.
            B cells form and mature in bone marrow
            T cells form in bone marrow, then migrate to thymus gland to mature.
     Mature B and T cells concentrated in lymph nodes, spleen, and other lymphatic organs (Fig 43.8).
            most likely to contact antigens.
            B and T cells have antigen receptors
            The receptors of B cells are membrane bound antibodies.
            The receptors of T cells are not antibodies, but they also recognize specific antigens.
     Cells which actually defend body during immune response are called Effector cells.Effector cells are
      simply populations of cells resulting from division of lynphocytes which were activated by the binding of
      antigens to their antigen receptors.
            Activated B cells give rise to plasma cells that secrete antibodies.
            Activated T cells produce two types of effector cells: cytotoxic T cells (Tc) which destroy
               infected or cancer cells,; and helper T cells (Th), which secrete cytokines.
            Cytokines = Molecules secreted by one cell as a regulator of neighboring cells.
                     help regulate both B and T cells
Clonal Selection of lymphocytes is cellular basis for immunological specificity
and diversity
      The ability of immune system to respond to virtually an unlimited number of potential antigens is based on
       the enormous diversity of lymphocytes, each able to produce a different antigen receptor (Fig 43.6).
             The different B lymphocytes, each producing only one type of antibody able to recognize one
                antigen, exists in the body even before exposure to any given antigen.
             Diversity of lymphocytes arises by DNA splicing and somatic mutation of
                immunoglobulin/receptor genes.
             When antigen enters body, it binds antigen receptor on a specific lymphocytes. These lymphocytes
                are then activated to divide producing a large number (millions) of identical clones each able to
                recognize the antigen that stimulated the response.
                Clonal selection = Antigenic specific selection of a lymphocyte that activates it to produce clones
                of effector cells dedicated to eliminating the antigen that provoked the initial immune response.
Memory cells function in secondary immune responses
      Primary immune response = proliferation of lymphocytes to form clones of effector cells specific to an
       antigen during the body’s first exposure to the antigen (Fig 43.7).
             there’s lag time (5-10 days) between exposure and maximum production of effector cells. The
                 lymphocytes selected by antigen are differentiating into effector T cells and plasma cells during
                 this lag period.
      Secondary immune response = occurs when body exposed to a previously encountered antigen.
             Response faster and more prolonged than primary response.
             Antibodies are more effective at binding antigen.
      Ability to recognize previously encountered antigens known as Immunologic memory.
             Based on memory cells produced during primary immune response.
             Inactive during primary response. Long lived.
             When a previously encountered antigen enters body, it rapidly activates memory cells to divide
                 and form new clones of effector cells and memory cells. These new effector cells constitute the
                 secondary immune response.
Molecular markers on cell surfaces function in self/nonself recognition
      The surfaces of lymphocytes have antigen receptors responsible for detecting foreign molecules that enter
       the body.
      Why don’t lymphocytes mount immune response to body’s own cells and molecules? Because there are no
       lymphocytes reactive against the body’s own molecules under normal conditions.
       Self-tolerance = the lack of a destructive immune response to the body’s own cells.
             Develops before birth when T and B lymphocytes begin to mature in thymus and bone marrow of
                 embryo.
             Lymphocytes with receptors to self-molecules are either eliminated or suppressed.
      The major histocompatibility complex (MHC or HLA in humans) is a group of glycoproteins embedded
       in the plasma membranes of cells whose main function is antigen presentation. (Fig 43.9).
             Important "self-markers" coded by a family of genes.
             At least 20 MHC genes with at least 100 alleles for each gene.
             Probability of any two individuals having matching MHC sets is virtually zero (except for twins).
             Two main classes of MHC molecules, each of which is recognized by a separate class of T cells.
                     Class I MHC molecules are displayed on all nucleated cells of the body and recognized
                         by receptors of cytotoxic T cells..
                     Class II MHC molecules are found only on specialized cells such as macrophages, B
                         cells, and activated T cells.
                               Class II MHC molecules are important in interactions between cells of the
                                   immune system.
Humoral Immunity and Cell-mediated immunity
      Both types of immunity work in concert and are interdependent (Fig 43.10).
      Humoral immunity
           produces antibodies in response to extracellular pathogens and toxins.
           Depends on antibody-producing B-cells.
     Cell-mediated immunity
           responds to intracellular pathogens, transplanted tissues, and cancer cells.
           Depends on direct action of T-cytotoxic (Tc) cells instead of antibodies.
Helper T lymphocytes function in both humoral and cell-mediated immunity
     Combats pathogens that have already invaded cells (Fig 43.10 and Fig 43.11).
            Key components are helper T cells (Th) and cytotoxic T cells (Tc).
            These T cells mature in thymus and then migrate to lymphoid organs (spleen and lymph nodes).
     T cells respond only to antigenic epitopes displayed on surfaces of body’s own cells.
            Do not detect free antigens in body fluids
            Specific T-cell receptors embedded in the T cell membrane recognize bound antigens.
            The receptor of Th cell recognizes the class II MHC protein-antigen complex.
            The receptor of Tc cells recognizes the class I MHC protein-antigen complex.
            In both cases, antigen is nestled within MHC protein.
            While an MHC molecule can associate with a variety of antigens, each combination is a unique
                complex recognized by specific T cells.
     CD4 is a cell surface molecule displayed by T cells which enhances the interaction between Th cells and
      antigen presenting cells (APC)
            CD4 present on most Th cells and has affinity for a part of class II MHC molecule.
            CD4-class II MHC interaction helps keep Th cell and APC engaged while antigen speficic contact
                is occurring.
            Tc cells carry a surface molecule called CD8 which has affinity for class I MHC molecules.
     The MHC-antigen complex displayed on an infected body cell stimulates T cells with the proper receptor to
      multiply and form clones of activated Th and Tc cells which recognized the pathogen.
            Th cells stimulate B cells to secrete antibodies against T-dependent antigens in a humoral
                response.
            Th cells also activate other types of T cells to mount cell-mediated responses to antigens.
     Helper T cells stimulate other lymphocytes by receiving and sending cytokines.
            When Th cell binds to an antigen presenting macrophage, the macrophage releases interleukin-1 (a
                cytokine).
            Interleukin-1 stimulates Th cell to release interleukin-2.
            By positive feedback, interleukin-2 stimulates the Th cells to grow and divide rapidly resulting in
                the production of more Th cells and an increase in supply of interleukin-2.
            Because interleukin-2 and other cytokines secreted by the increasing numbers of Th cells activate
                B cells, the humoral response is enhanced.
            Increased level of cytokines also increases cell-mediated response by stimulating another class of
                T lymphocytes to differentiate into cytotoxic T cells (effector cells).
Cell-mediated immunity
     How cytotoxic T cells work
     Tc cells destroy infected host cells (Fig 43.12)
           Host cells infected by viruses and other pathogens display antigens complexed with class I MHC
               molecules on their surfaces.
           Tc cells have specific receptors which recognize and bind to antigen-class I MHC markers.
           Since class I MHC is present on all nucleated cells, the Tc receptor can bind to any body cell.
           When Tc cell binds to an infected cell, it releases perforin, a protein that forms lesions in the
               infected cells membrane causing cell lysis..
           Cytotoxic T cells continue to live after destroying infected cell and go on to kill other cells.
     Cytotoxic T cells also function to destroy cancer cells which develop periodically in the body.
           Cancer cells possess distinctive markers not found in normal cells. These markers are recognized
               by Tc cells as non-self.
           Cancer develops primarily in individuals with defective or declining immune systems.
The Humoral response
      Humoral response occurs when an antigen binds to B cell receptors which are specific for the antigen
       epitopes.
             The B cells differentiate into a clone of plasma cells that will secrete antibodies.
             Antibodies are most effective against pathogens circulating in blood or lymph.
             Memory cells are also involved and form basis of secondary immune response.
      Activation of B cells
             Selective activation of B cells to produce plasma cells and memory cells is actually a two-step
                 process:
                 1. Binding of antigen on specific antigen-receptor on surface of B cell.
                 2. Involves macrophages and Th cells. This step results in production of plasma and memory cells.
                 (Fig 43.13)
                       macrophage phagocytose pathogens. Pieces of partially digested antigen are bound to
                          class II MHC molecules which are then moved to and presented on the surface of
                          macrophage (antigen processing). Macrophage now functioning as antigen-presenting
                          cell.
                       A Th cell with receptor specific for the presented antigen binds to class II MHC protein-
                          antigen complex.
                       T cell is now activated and proliferates to produce a clone of activated Th cells specific
                          for for the presented antigen.
                       These activated Th cells secrete cytokines which stimulate B cells that have encountered
                          same antigen; recognition of these B cells also involves a Class II MHC protein-antigen
                          complex to which the receptor on the Th cell binds.
                       The T cell contact activates these B cells to form clone of plasma cells.
                       each plasma cells (effector) then secretes antibodies for the specific antigen. Each effectr
                          cells can produce a many as 2,000 antibodies per second during its 4-5 day life span.
             Thus, both macrophages and B cells act as antigen-presentig cells in their interaction with Th
                 cells. The difference is that each macrophage can present more than one antigen at a time, whereas
                 B cells can only present one antigen.
                       Macrophages, which are nonspecific, enhance specific defence by selectively activating
                          Th cells which in turn activate B cells specific for the antigen.
                       Th cells are also antigen-specific and are activated only by macrophages presenting the
                          ptoper class II MHC protein-antigen complex.
             NOTE: Some antigens trigger humoral response without macrophage or Th cells involvement.
                 This response is weaker and no memory is generated. These antigens are usually polymeric and
                 bind many receptors on B cell, and apparently are enough to activate them.
The molecular basis of antigen-antibody specificity
      Antigens = usually proteins or large polysaccharides which make up a portion of the outer covering of
       pathogens or transplanted cells.
            May be components fo viral coats, cell wall and capsules of bacteria or surface molecules of other
               cell types.
            Antibodies recognize only a small region on surface of antigen (the epitope or antigenic
               determinant). (Fig 43.14).
               o Several antibodies generated form different B cells may be produced to many epitopes on a
               single antigen.
      Antibodies = specific type of proteins clalled immunoglobulins (Igs) (Fig 43.15)
            Structure associated with function.
            Y-shaped molecules comprised of 4 polypeptide chains: 2 identical light chains and 2 identical
               heavy chains.
            All four chains have constant (C) regions: vary little in amino acid sequence among antibodies of
               a given type.
            All four chains have variable (V) regions: amino acid sequence varies considerably from
               antibody to antibody. Act as antigen binding regions.
                Antigen-binding site responsible for antibody’s ability to identify its specific antigen epitope.
                 Stem region (constant) responsible for mechanism of inactivation of antigen.
Five types of constant regions give rise to five classes of immunoglobulins
(Table 43.1 for summary)
     IgM: composed of 5 monomers (pentamer). Circulating antibodies which appear in response to an initial
        exposure to an antigen.
     IgG: Monomer; most abundant circulating antibody; readily crosses blood vessels and enters tissue fluids;
        protects against bacteria, viruses, and toxins circulating in blood and lymph; triggers complement system.
     IgA: Dimer; produced predominantly by cells abundant in mucous membranes; prevents attachment of
        bacteria and viruses to epithelial surface; found in saliva, tears, perspiration, colostrum.
     IgD: Monomer; found primarily on external surfaces of B cells. probably functions as receptor which
        initiates differentiation f B cells.
     IgE: Monomer; Stem region attaches to surface of mast cells and basophils; stimulates these cells to release
        histamine and other chmicals that cause allergic reactions when triggered by antigen.
How antibodies work
       Do not destroy antigenic pathogen directly. Binds to antigen to form complex that tags invader for
        destruction by one of several effector mechanisms (Fig 43.16).
       1. Neutralization
              simplest mechanism
              blocks attachment sites or coats toxin making them ineffective. Complex eventually destroyed by
                 phagocytes.
       2. Agglutination
              cross-linking of bacteria forms clumps which facilitates phagocytosis
       3. Precipitation
              Same as agglutination, except that antigens not bacteria are involved. Form immobile precipitates
                 that are easily engulfed.
       4. Activation of complement system
              Antibodies combine with complement proteins to form leasions in foreign cell’s membrane that
                 result in lysis.
Complement proteins participate in humoral and cell-mediated immunity
       Over 20 complement proteins circulate in blood in inactive form. These become activated in a cascade with
        each activating the next in the series. (Fig 43.17)
       The classical pathway describes the complement’s activation in the immune response.
             Initiated when antibodies bind to a specific pathogen which targets the cell for destruction.
             A complement proteins attaches to, and bridges the gap between, two adjacent antibody
                 molecules.
             The antibody-complement association triggers complement proteins to form, step-by-step, a
                 membrane attack complex causing lesions and lysis of pathogen.
       The alternative pathway is activated in nonspecific defense mechanisms.
             Antibodies not involved.
             activated by substance found in many pathogens.
       Complement proteins can also function in inflamation response by attracting phagocytic cells and by
        binding to histamine containing cells making them release histamine.

				
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