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Nonspecific Body Defenses and Immunity

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					            Chapter 21

Nonspecific Body Defenses and
           Immunity

      G.R. Pitts, J.R. Schiller, and James F. Thompson, Ph.D.
                 Defense Systems
1. Innate
   (nonspecific)
   defense
   – External body
     membranes
   – Inflammation
      • Antimicrobial
        proteins,
        phagocytes and
        other cells

2. Adaptive (specific)
   defense
   – T cells and B cells
             Innate Defense System
•    Surface Barriers
    – First line of defense
    – Skin and mucosal membranes
    – Mechanical and chemical protection

•    Internal Nonspecific Defenses
    –    Second line of defense
    1.   Phagocytes
    2.   Natural Killer cells (NK lymphocytes)
    3.   Inflammation
    4.   Antimicrobial proteins
    5.   Fever
  Innate Defense: Surface Barriers
• Skin and mucosal membranes
  – Mechanical protection
    • Intact epidermis
    • Mucous membranes
       – line body cavities, mucus prevents drying, traps foreign things
       – nose hairs, respiratory tract cilia
    • Lacrimal apparatus -- tear glands and ducts
       – continually wash the eye to dilute microbial growth
    • Saliva - dilute microbes on the teeth, tongue, and gums
    • Urine - flow dilutes, and acid pH helps kill,
      microorganisms
    • Defecation and vomiting - expel toxic microbes
Innate Defense: Surface Barriers
– Chemical protection: helps prevents bacterial
  growth
  • Skin
     – sebum (unsaturated FA’s) forms oily layer
     – perspiration has fatty acids, salts (NaCl), and mildly acid pH
  • Lysozyme
     – in perspiration, tears, saliva, nasal secretions, other tissue fluids
     – enzyme breaks down bacterial cell walls
  • Hyaluronic acid
     – gel-like matrix in most connective tissues
     – slows the spread of many infectious agents
  • Gastric juice - stomach nearly sterile due to acid pH, ~2
  • Vaginal secretions – mildly acid pH
      Innate Defense: Phagocytes
• Macrophage are the chief phagocytic cell
  – Derived from monocytes
• Free macrophages wander throughout a region in
  search of cellular debris
• Kupffer cells (liver) and microglia (brain) are fixed
  macrophages
• Neutrophils become phagocytic when encountering
  infectious material
• Eosinophils are weakly phagocytic, deploy destructive
  granules against parasitic worms
• Mast cells bind and ingest a wide range of bacteria
       Mechanism of Phagocytosis
•   Chemotaxis
•   Adherence – recognition
    of carbohydrate
    “signature”
    – Aided by opsonization
•   Ingestion
•   Digestion
Innate Defense: Natural Killer Cells
Natural Killer cells (NK lymphocytes)
  – Small, distinct group of large granular
    lymphocytes
  – Nonspecific killers which respond to the lack of
    self-antigens and to the presence of specific
    sugars before the antigen-specific immune system
    is activated
  – Able to kill virus-infected body cells and some
    tumor cells by releasing various defensive
    molecules (perforin) – not by phagocytosis
  – Secrete potent chemicals that enhance the
    inflammatory response
         Innate Defense: Inflammation
1. Inflammation
• Signs:
    1.   Redness
    2.   Heat
    3.   Swelling
    4.   Pain
    5.   Loss of Function

•   Function:
    1. Prevent spread of
       damage
    2. Dispose of pathogens
       and debris
    3. Set stage for tissue
       repair
                          Inflammation
Stage 1: Vasodilation and
increased vessel permeability
 – Macrophages and cells lining the
   gastrointestinal and respiratory tracts bear
   TLRs that recognize specific classes of
   infecting microbes
 – TLR activation causes cytokine release
     • Promotes inflammation
     • chemoattractant
 – Mast cells secrete histamine
 – Other cells secrete various regulatory
   factors
     • Histamine, kinins, prostaglandins,
       leukotrienes, complement
 – Causes local vasodilation, resulting in        http://www.komabiotech.co.kr/technical/review/toll_like_receptor.gif

   hyperemia
 – Increases capillary permeability, resulting
   in edema
          Inflammation: Stage 1
• Edema - A surge of protein-rich fluids into
  tissue spaces

  – Helps to dilute harmful substances

  – Brings in large quantities of oxygen and nutrients
    needed for repair

  – Allows entry of clotting proteins, which prevents the
    spread of bacteria
                        Inflammation
Stage 2. Phagocyte
moblization
 1. Leukocytosis-inducing
    factors: increase
    neutrophil production
 2. Margination
    (pavementing)
 3. Diapedesis (amoeboid
    movement)
 4. Chemotaxis of WBCs
     • neutrophils – rapid arrival
     • monocytes – slower arrival
                     Inflammation
Stage 3. Tissue
repair
 – Tissue regrowth and
   repair of damage or
   scar formation

 – Pus
    • dead phagocytes and
      other WBCs, damaged
      tissue, and perhaps
      microbes
    • if too numerous for
      effective removal by
      phagocytes, an abscess
      may develop
          Effects of Inflammation
• Increased blood
  flow which results
  in increased local
  temperature and
  local cellular
  metabolism

• Increased capillary
  permeability and
  phagocytic
  migration to the
  injured tissue
     Innate Defense: Antimicrobial
               Proteins
•   Enhance the innate defenses by:
     1. Attacking microorganisms directly
     2. Hindering microorganisms’ ability to reproduce

•   The most important antimicrobial proteins
    are:
     1. Interferon
     2. Complement proteins
     3. Transferrins bind Fe2+ in plasma, inhibiting
        bacterial growth
 Interferon (IFN)
• Produced by cells in response
  to viral infections
• Diffuses to uninfected cells
  and binds to surface receptors
   – stimulates production of antiviral
     proteins like PKR.
       • PKR blocks viral replication
   – enhances macrophages and
     natural killer lymphocytes
   – inhibits growth of virally infected
     cells
   – suppresses growth of tumor cells
• FDA-approved alpha IFN is
  used:
   – As an antiviral drug against
     hepatitis C virus
   – To treat genital warts caused by
     the herpes virus
    Innate Defense: Antimicrobial
              Proteins
• Complement
  – 20 plasma and cell membrane proteins that exist in inactive
    forms
  – When activated, the complement system functions to
    “complement” or enhance certain immune, allergic, and
    inflammatory responses
  – Amplifies all aspects of the inflammatory response
  – Kills bacteria and certain other cell types (our cells are
    immune to complement)
  – Enhances the effectiveness of both nonspecific and specific
    defenses
          Complement Pathways
Classical pathway is linked to the immune
  system
  – Requires binding of antibodies to antigens of
    invading organisms
  – Subsequently, C1 binds to the antigen-antibody
    complexes (complement fixation)


Alternative pathway is triggered by interaction
  among factors B, D, and P, and polysaccharide
  molecules present on microorganisms (direct
  recognition of microbial antigens)
Complement
Pathways
• Each pathway involves a
  cascade
• Both pathways converge on
  C3, which cleaves into C3a
  and C3b
• C3b initiates formation of a
  membrane attack complex
  (MAC)
• MAC causes cell lysis by
  interfering with a cell’s ability
  to control intracellular [Ca2+]
• C3b also causes opsonization
• C3a causes inflammation
          Innate Defense: Fever
• Pyrogens reset the temperature set-point in the
  hypothalamus
• Inhibits some microbes from growing
• Increases metabolic rate, which speeds up tissue
  repair
• The liver and spleen to sequester iron and zinc
  (needed by microorganisms)
• Increases effects of antimicrobial substances
  produced by the immune system

• High fevers are dangerous
    Innate Defense System: Review
•    Surface Barriers
    – First line of defense
    – Skin and mucosal membranes
    – Mechanical and chemical protection

•    Internal Nonspecific Defenses
    –    Second line of defense
    1.   Phagocytes
    2.   Natural Killer cells (NK lymphocytes)
    3.   Inflammation
    4.   Antimicrobial proteins
    5.   Fever
               Adaptive Defense
• The adaptive immune system is a functional
  system that:
  – Acts to immobilize, neutralize, or destroy foreign
    substances
  – Amplifies the inflammatory response and activates
    complement
  – Is antigen-specific, systemic, and has memory
     • Recognizes specific foreign substances

  – Has two separate but overlapping arms
     • Humoral, or antibody-mediated immunity
     • Cellular, or cell-mediated immunity
              Adaptive Defense

• Definitions:
  – Immunity: the ability of the body to defend itself
    against specific foreign invaders (molecules or cells)

  – Immunogenicity: the ability to stimulate
    proliferation of specific lymphocytes and antibody
    production

  – Reactivity: the ability to react with the products of
    the activated lymphocytes and the antibodies
    released in response to them
              Adaptive Defense
• Definitions:

  – Specificity: the antigen triggers immune defenses
    (from lymphocytes) that respond only to the
    antigens of this foreign substance/cell

  – Memory: the immune system produces clones of
    specific memory lymphocytes (T & B) which react
    rapidly when the particular foreign substance/cell is
    encountered again

  – Specificity and memory differentiate this system
    from the non-specific system’s defenses
               Adaptive Defense
• Antigen – any
  substance which
  provokes specific
  immune responses
• Antigenic determinants
  – Parts of antigens that
    trigger the specific
    immune response
  – An antigen may be an         Most “antigens” are
    entire microorganism or     complex and express
    only small structures or      multiple types of
    subregions of large        antigenic determinants.
    molecules
                 Adaptive Defense
• Chemical nature of antigens
  – “Complete”: large, complex
    molecules - usually proteins (nucleo-
    , lipo-, glyco-) -- sometimes
    carbohydrates or lipids

  – Are immunogenic & reactive

  – “Incomplete”: smaller molecules
    (haptens)
     • react with antibodies but cannot cause
       an immune response without aid
       (protein carrier)
     • e.g., poison ivy allergen
                    Adaptive Defense
• Antigen receptor diversity
   – >1 billion different antigenic
     determinants are recognized by the
     body
   – Genetic recombination shuffles and
     reorganizes different Ab genes

• Major histocompatibility complex
  antigens (MHC)
   – unique to each individual’s cells;
     help in identifying what is self
     versus foreign
   – 2 classes of MHC antigens
       • class I MHC – found on all body
         cells except RBC's
       • class II MHC - only on antigen
         presenting cells (APC’s), thymus
         cells, and activated T cells
 Cells of the Adaptive Immune System:
               Lymphocytes
• Immature lymphocytes
  released from bone marrow
  are essentially identical
• Whether a lymphocyte
  matures into a B cell or a T
  cell depends on where it
  becomes able to recognize a
  specific antigen
  (immunocompetent)
  – B cells mature in the bone
    marrow & oversee humoral
    immunity
  – T cells mature in the thymus &
    oversee cell-mediated
    immunity
     Immunocompetent B or T cells
• Display a unique type of receptor for a specific
  antigen
  – Occurs before cells encounter antigens they may later
    attack
  – It is genes, not antigens, that determine which foreign
    substances our immune system will recognize and resist

• Naive cells are exported to secondary lymphoid
  tissue where cells may encounter antigens
  – Mature into fully functional antigen-activated cells upon
    binding with their recognized antigen
                               T Cells
• T cells mature in the thymus
  under positive and negative
  selection pressures                              Survive




  – Positive selection – thymic cortex
     • Selects T cells with a weak response to
       self-antigens (MHC molecules)
                                                  Apoptosis




     • These cells become both
       immunocompetent and self-tolerant
     • Non-selected cells die via apoptosis
                                                 Apoptosis


  – Negative selection – inner portion of
    thymic cortex
     • Eliminates T cells that strongly react
       with self-antigens (other than the MHC)
                        B Cells
• B cells become immunocompetent and self-
  tolerant in bone marrow
  – Some self-reactive B cells are killed by apoptosis
    (clonal deletion)
  – Some self-reactive B cells modify the self-reactive
    antigen (receptor editing)

• Some self-reactive B cells are released from the
  bone and are inactivated (anergy)
      Cells of the Adaptive Immune
               System: APCs
• Antigen-presenting cells (APCs):
  – Engulf, process, and present parts of antigens
  – Do not respond to specific antigens
  – Play essential auxiliary roles in immunity
  – Dendritic (Langerhans) cells: connective tissue and
    epidermis
  – Macrophage
  – B lymphocytes

The major initiators of adaptive immunity are DCs,
  which actively migrate to the lymph nodes and
  secondary lymphoid organs and present antigens to T
  and B cells
      Humoral Immune Response
• Antigen challenge – first encounter between an
  antigen and a naive lymphocyte
   – Usually in the spleen or lymph node, but can
     occur in other lymphoid organs

• If the lymphocyte is a B cell, a humoral
  immune response is provoked
   1. Binding of the antigen to the receptor activates
      the lymphocyte
   2. Clonal selection occurs
   3. Antibodies are produced against the challenger
               Clonal Selection
• Activated B cell
  grows & mitotically
  divides, forming
  clones bearing the
  same antigen-
  specific receptors
               Fate of the Clones
• Most clone cells become plasma cells that secrete
  specific antibodies
• Clones that do
  not become
  plasma cells
  become memory
  cells that can
  respond to
  subsequent
  exposures of
  the same antigen
          Immunological Memory
• Primary immune response – cellular
  differentiation and proliferation, which occurs
  on the first exposure to a specific antigen

  – Lag period: 3 to 6 days after antigen challenge

  – Peak levels of plasma antibody are achieved in 10
    days

  – Antibody levels then decline
          Immunological Memory
• Secondary immune response – re-exposure to
  the same antigen

  – Sensitized memory cells respond within hours

  – Antibody levels peak in 2 to 3 days at much higher
    levels than in the primary response

  – Antibodies bind with greater affinity, and their
    levels in the blood can remain high for weeks to
    months
Primary and Secondary Humoral Responses
Soluble antibodies are the simplest ammunition of the
immune response and interact in extracellular
environments
       Types of Humoral Immunity
• Active immunity: B cells encounter antigens and
  produce antibodies against them
  – Naturally acquired – response to a bacterial or viral infection
  – Artificially acquired – response to a vaccine of dead or
    attenuated (weakened) pathogens

• Passive immunity: B cells are not challenged by
  antigens
  – Immunological memory does not occur
  – Protection ends when antigens naturally degrade in the body
  – Naturally acquired – from the mother to her fetus via the
    placenta or colostrum
  – Artificially acquired – from the injection of serum, such as
    gamma globulin
                     Antibodies
• Also called immunoglobulins
  – Constitute the gamma globulin portion of blood
    proteins
  – Are soluble proteins secreted by activated B cells
    and plasma cells in response to an antigen
  – Are capable of binding specifically with that antigen
           Basic Antibody Structure
• Four polypeptide chains
  linked together with disulfide
  bonds
• The four chains bound
  together form an antibody
  monomer
• Each chain has a variable (V)
  region at one end and a
  constant (C) region at the
  other
• Variable regions of the heavy
  and light chains combine to
  form the antigen-binding site
             Antibody Structure
• Antibodies responding to different antigens
  have different V regions but the C region is the
  same for all antibodies in a given class

• C regions form the stem of the Y-shaped
  antibody and:
  – Serve common functions in all antibodies
  – Dictate the cells and chemicals that the antibody
    can bind to
  – Determine the class of the antibody
  – Determine how the antibody class will function in
    elimination of antigens
            Classes of Antibodies
• IgD: monomer attached to the surface of B cells,
  important in B cell activation
• IgM: pentamer released by plasma cells during the
  primary immune response
• IgG: monomer that is the most abundant and diverse
  antibody in primary and secondary response; crosses
  the placenta and confers passive immunity
• IgA: dimer that helps prevent attachment of
  pathogens to epithelial cell surfaces
• IgE: monomer that binds to mast cells and basophils,
  causing histamine release when activated
              Antibody Targets
• Antibodies themselves do not destroy antigen;
  they inactivate and tag it for destruction

• All antibodies form an antigen-antibody
  (immune) complex

• Defensive mechanisms used by antibodies are
  neutralization, agglutination, precipitation, and
  complement fixation
      Antibody Mechanisms of Action
1. Neutralization: Antibodies bind to and block specific
   sites on viruses or exotoxins, thus preventing these
   antigens from binding to receptors on tissue cells
2. Agglutination: Antibodies bind the same determinant
   on more than one antigen
  –   Makes antigen-antibody complexes that are cross-linked
      into large lattices
  –   Cell-bound antigens are cross-linked, causing clumping
      (agglutination)

3. Precipitation – soluble molecules are cross-linked
   into large insoluble complexes
        Antibody Mechanisms of Action
4. Complement fixation is the main mechanism
   used against cellular antigens
  – Antibodies bound to cells change shape and
    expose complement binding sites
  – This triggers complement fixation and cell lysis
  – Complement activation:
    •   Enhances the inflammatory response
    •   Uses a positive feedback cycle to promote phagocytosis

  – Enlists more and more defensive elements
Mechanisms of Antibody Action




                           Figure 21.13
           Monoclonal Antibodies
• Commercially prepared antibodies are used:
  – To provide passive immunity
  – In research, clinical testing, and treatment of
    certain cancers


• Monoclonal antibodies are pure antibody
  preparations
  – Specific for a single antigenic determinant
  – Produced from descendents of a single cell
           Cell-Mediated Immunity
• Since antibodies are useless against
  intracellular antigens, cell-mediated immunity is
  needed
• Two major populations of T cells mediate
  cellular immunity
  – CD4 cells (T4 cells) are primarily helper T cells (TH)
  – CD8 cells (T8 cells) are cytotoxic T cells (TC) that destroy
    cells harboring foreign antigens

• Other types of T cells are:
  – Suppressor T cells (TS)
  – Memory T cells
      Importance of Cell-Mediated
              Immunity
• T cells recognize and respond only to processed
  fragments of antigen displayed on the surface
  of body cells

• T cells are best suited for cell-to-cell
  interactions, and target:
  – Cells infected with viruses, bacteria, or intracellular
    parasites
  – Abnormal or cancerous cells
  – Cells of infused or transplanted foreign tissue
        Cell -Mediated Immunity

Basic steps
  1. Recognition of antigen presented by an antigen-
     presenting cell by T cell receptors (TCR’s)

  2. Proliferation and differentiation of T cells once
     activated

  3. Production of a clone of identical effector T cells
     capable of recognizing initial activator (antigen)

  4. Elimination of the foreign intruder
      Antigen Recognition and MHC
               Restriction
• Allows the immune system to recognize the
  presence of intracellular microorganisms
• Immunocompetent T cells are activated when
  the variable regions of their surface receptors
  bind to a recognized antigen and the T cells
  simultaneously recognize a self-antigen (an
  MHC protein)
• MHC proteins are ignored by T cells if they are
  loaded with self protein fragments
             Antigen Recognition
• If MHC proteins are complexed with
  endogenous or exogenous antigenic peptides,
  they:
  – Indicate the presence of intracellular infectious
    microorganisms
  – Act as antigen holders
  – Form the self part of the self-antiself complexes
    recognized by T cells

• There are 2 classes of MHC proteins
              Class I MHC Proteins
• Found on all cells, except RBCs
• Always recognized by cytotoxic TC cells (CD8)
• Display peptides from endogenous antigens
  – Endogenous antigens are:
     • Degraded by proteases and enter the endoplasmic
       reticulum
     • Transported via TAP (Transporter associated with
       Antigen Processing)
     • Loaded onto class I MHC molecules
     • Displayed on the cell surface in association with a class I
       MHC molecule
Class I MHC Proteins
            Class II MHC Proteins
1. Found only on mature B cells, some T cells, and
   antigen-presenting cells
2. A phagosome containing pathogens (with exogenous
   antigens) merges with a lysosome
3. Class II MHC proteins are synthesized in the ER
  – Invariant protein prevents class II MHC proteins from
    binding to peptides in the endoplasmic reticulum
4. Class II MHC proteins migrate into the phagosomes
   where the antigen is degraded and the invariant
   chain is removed for peptide loading
5. Loaded class II MHC molecules then migrate to the
   cell membrane and display antigenic peptide for
   recognition by CD4 TH cells
Class II MHC Proteins
  T Cell Activation- Step 1: Antigen Binding
• T cell antigen receptors (TCRs):
  – Activated by binding to an antigen-MHC protein complex
  – Have variable and constant regions consisting of two chains
    (alpha and beta)
  – Linked to multiple intracellular signaling pathways

• MHC restriction
  – Tc binds to antigens complexed with class I MHC
  – TH binds to antigens complexed with class II MHC

• Mobile APCs (Langerhans/dendritic cells) quickly alert
  the body to the presence of antigen by migrating to
  the lymph nodes and presenting antigen
  – May display exogenous antigens from dying virus-infected
    cells or tumor cells on class I and II MHC proteins
T Cell
Activation-
Step 1:
Antigen
Binding
   T Cell Activation- Step 2: Co-stimulation

• T cells must bind to other surface receptors on
  an APC
  – Macrophage & dendritic cells produce surface B7
    proteins when nonspecific defenses are mobilized
  – B7 binding with the CD28 receptor on the surface of
    T cells is a crucial co-stimulatory signal

• After co-stimulation, other cytokines such as
  interleukin 1 and 2 stimulate proliferation and
  differentiation of T cells
    T Cell Activation- Step 2: Co-stimulation
• Without co-stimulation, T
  cells:
   – Become tolerant to that
     antigen (anergy)
   – Are unable to divide
   – Do not secrete cytokines

• T cells that are activated:
   – Enlarge, proliferate, and
     form clones
   – Differentiate and perform
     functions according to their
     T cell class
   T Cell Activation- Step 2: Co-stimulation
• Primary T cell response peaks within a week
  after signal exposure
• T cells then undergo apoptosis between days 7
  and 30
• Effector activity wanes as the amount of
  antigen declines
• The disposal of activated effector cells is a
  protective mechanism for the body
• Memory T cells remain and mediate secondary
  responses to the same antigen
                Helper T Cells (TH)
• Regulatory cells that play a
  central role in the immune
  response
• Once primed by APC
  presentation of antigen,
  they:
  – Chemically or directly
    stimulate proliferation of other
    T cells
  – Stimulate B cells that have
    already become bound to
    antigen
• There is NO immune
  response without TH
                    Helper T Cell
• TH cells interact directly with B cells that have antigen
  fragments on their surfaces bound to MHC II
  receptors
• TH cells stimulate B cells to divide more rapidly and
  begin antibody formation
• B cells may be activated without TH cells by binding to
  T cell–independent antigens
• Most antigens, however, require TH co-stimulation to
  activate B cells
• Cytokines released by TH amplify nonspecific defenses
                 Cytotoxic T Cell (Tc)
• TC cells, or killer T cells, are the only T cells that can
  directly attack and kill other cells

• They circulate throughout the body in search of body
  cells that display the antigen to which they have been
  sensitized

• Their targets include:
   –   Virus-infected cells
   –   Cells with intracellular bacteria or parasites
   –   Cancer cells
   –   Foreign cells from blood transfusions or transplants
               Cytotoxic T Cells
• Bind to self-antiself complexes on all body cells
• Infected or abnormal cells can be destroyed as
  long as appropriate antigen and co-stimulatory
  stimuli (e.g., IL-2) are present
• In contrast, natural killer cells activate their
  killing machinery when they bind to MICA
  receptor
  – MICA receptor – MHC-related cell surface protein in
    cancer cells, virus-infected cells, and cells of
    transplanted organs
          Mechanisms of Tc Action
• In some cases, TC cells:
  – Bind to the target cell and release perforin into its
    membrane
     • In the presence of Ca2+ perforin causes cell lysis by
       creating transmembrane pores
           Other Tc and Ts Cells
• Other TC cells induce cell death by:
  – Secreting lymphotoxin, which fragments the target
    cell’s DNA
  – Secreting gamma interferon, which stimulates
    phagocytosis by macrophages

• Suppressor T cells (TS) – regulatory cells that
  release cytokines, which suppress the activity
  of both T cells and B cells
Summary of
the Primary
Immune
Response
     Adaptive Immunity: Summary
• Two-fisted defensive system that uses
  lymphocytes, APCs, and specific molecules to
  identify and destroy nonself particles

• Its response depends upon the ability of its
  cells to:
  – Recognize foreign substances (antigens) by binding
    to them
  – Communicate with one another so that the whole
    system mounts a response specific to those
    antigens
    Adaptive Immunity: Summary
To start an immune response, B and T cells must
 recognize foreign antigen

B cells can recognize and bind to certain
  antigens in the blood or the extracellular fluid
  (ECF)

More often, B and T cells only recognize antigen
 (protein fragments) when Ag is presented by
 the phagocytes in combination with MHC Class
 II surface markers
              Organ Transplants
• The four major types of grafts are:

  – Autografts – graft transplanted from one site on the
    body to another in the same person

  – Isografts – grafts between identical twins

  – Allografts – transplants between individuals that are
    not identical twins, but belong to same species

  – Xenografts – grafts taken from another animal
    species
         Prevention of Rejection
• Prevention of tissue rejection is accomplished
  by using immunosuppressive drugs

• However, these drugs depress patient’s
  immune system so it cannot fight off foreign
  agents
     Pathologies: Immunodeficiencies
• Human Immunodeficiency Virus
  – HIV enters certain cell types by receptor
    mediated endocytosis
      • infects primarily helper T cells
      • attaches to the CD4 protein on cell surface
  – A retrovirus
      • carries its genetic material as RNA
      • inserts its genetic material into host cell DNA
        with the enzyme reverse transcriptase
      • cell makes copies of the virus, releases them for
        further infection
  – May be carried silently in cells for years, being
    passed on during ordinary mitosis
  – Activation of HIV life cycle destroys THelper cells
  – Weakened immune response to all foreign
    invaders, benign or aggressive
Pathologies: Autoimmune Diseases
• Multiple Sclerosis (MS) – myelin sheath
  (white matter) attacked and destroyed
• Myasthenia Gravis – neuro-muscular junction
  of skeletal muscle attacked and destroyed
• Graves Disease – thyroid cells’ TSH receptor
  attacked and stimulated causing excess thyroid
  hormone (T3 & T4) production
• Type I Diabetes - destruction of pancreatic
  islet cells
Pathologies: Autoimmune Diseases
• Systemic Lupus Erythematosus (SLE) –
  generalized attack on connective tissues and
  nuclear antigens
• Glomerulonephritis - destruction of the
  glomerular capillaries causes impaired renal
  function
• Rheumatoid Arthritis - destruction of the
  synovial membranes in joints
            Pathologies: Cancer
• The immune system probably evolved first to
  respond to cancer cells
  – when a new cancer cell develops, new surface
    marker proteins (tumor antigens) often appear
  – if the immune system recognizes these new surface
    markers as non-self, it will destroy the cell
    expressing them
  – this immune surveillance is most effective in
    eliminating virus-induced tumor cells because they
    tend to express viral antigens which are not “self”
• Leukemias and Lymphomas – cancers of
  leukocytes
    Pathologies: Hypersensitivities
• Immediate hypersensitivities (allergies)
  – First exposure merely sensitizes one to an allergen
     • APCs digest and present allergen
     • Abnormally large numbers of TH cells secrete IL-4,
       stimulating B cells to secrete IgE
     • IgE attaches to mast cells and basophils

  – Later exposures produce dramatic responses
     • Antigen binds to IgE on mast cells and basophils
     • Cells release huge amounts of histamine and other
       inflammatory chemicals
     • Local reactions - surface exposure
     • Systemic Reactions – body-wide – Anaphylactic shock
        – penicillin, bee stings, etc.
             Pathologies: Subacute
               Hypersensitivities
• Caused by IgG and IgM
• Occurs 1-3 hr after exposure and lasts 10-15 hr
• Cytotoxic reactions
  – Ab bind to Ag on specific cells causing phagocytosis and
    complement-activated lysis
  – May occur after transfusion of mismatched blood
• Immune-complex hypersensitivities
  – Ag’s are widely distributed or insoluble Ag-Ab complexes
    can’t be removed
  – Intense inflammation
  – Severe damage to local tissue
  – Also involved in autoimmune diseases
Pathologies: Delayed Hypersensitivities
• Occurs 1-3 days after exposure
• Cell-mediated immune response
• May be transferred with blood transfusions

• Causes mild swelling to serious cytotoxic tissue
  damage (poison ivy, latex gloves, etc.)
End Chapter 21

				
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