Barriers to microbial growth First line of defense Skin and mucus by keara

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									Barriers to microbial growth

First line of defense:
         Skin and mucus membranes
                 bacteria can't penetrate keratin of skin
                 mucus contains lysozyme that breaks down peptidoglycan
                 ciliated epithelial cells of respiratory tract, pulmonary macrophage remove
         bacteria

       Sebaceous (fat-secreting) glands
             produce organic acids that inhibit organisms
                    Undecylinic acid (produced by glands in feet, esp.) inhibits fungi.
                    Athlete's foot powders are sodium undecylinate

       Sweat glands make inhibitory secretions

       tears contain lysozyme

       stomach: acidity (pH=2 or less) kills many microbes

       normal resident flora inhibits invaders

Second and third lines of defense:

       Circulatory system
               transfers nutrients, O2, and removes waste

               Blood contains many components that inhibit microbial growth

                       whole blood consists of
                              cells
                              plasma (antibodies, clotting factors, proteins)

               Defense mechanisms: cells
                     Red Blood Cells (Erythrocytes)
                            transfer O2, CO 2
                     7.5 µm in diameter, 2 µm thick

                       White blood cells (Leukocytes)
                              part of immune system
                       7-20 µm in diameter

                       participate in chemotaxis (cells migrate to foreign proteins)
                       inflammation, phagocytosis
                       Some participate in cell-mediated immunity, others make antibodies

Resistance to disease:

       Can be lowered by a number of host-related factors:
             Age: both young and old are more susceptible
             malnutrition: protein and vitamin deficiencies make more susceptible
             Stress and fatigue
             hormone imbalance
             heredity
             extremes of temperature
             climate
             prior diseases (including cancer, diabetes, liver disease)
             surgery
             chemotherapy or immunosuppressive therapy (incl. corticosteroids)
Third line of defense:
       Specific immunity


Antibodies are produced against specific antigens

        Proteins
        made by host immune cells
        react specifically with a given antigen

Antigen: a material that causes production of specific antibodies when introduced into the
      tissues or fluids of an animal

        Foreign molecules, usually proteins, sometimes carbohydrates
        soluble
        large molecular weight


If antigen is simple, it may stimulate the production of a single type of antibody
If it is complex, like a bacterium or a virus, each protein (or part of a protein) may stimulate
          the production of a separate antibody


Kinds of immunity
      I. Natural immunity -- relatively unimportant
             a.k.a. 'racial' or 'species' immunity. Some populations are not susceptible to
             certain diseases

        II. Acquired immunity
                A. Passive immunity -- body does no work
                        1. natural
                                 a. placental transfer
                                 b. breast feeding
                        2. artificial
                                 a. antitoxin
                                 b. pooled or hyperimmune gamma globulin (antibody fraction
                                         of blood)

                B. Natural immunity -- body produces antibodies against antigen
                      1. natural
                                a. disease
                      2. artificial immunization program
                                a. living attenuated organism
                                                tuberculosis
                                                Sabin polio vaccine
                                                cholera
                                                chicken pox
                                b. dead organisms
                                                Salk polio vaccine
                                                Typhoid fever
                                                human rabies (old version)
                                                cholera (old version)
                                c. recombinant vaccines
                                                only surface proteins of organism are used to
                                                        make vaccine -- hepatitis B
                                d. toxins
                                        rarely used because of danger -- can be used for
                                                antitoxin production
                              e. toxoids
                                              diptheria
                                              tetanus


How does the immune response work?
     Immune system
            Systems
                  Blood system
                         Whole blood contains RBCs, leucocytes, proteins, nutrients,
                                hormones, water.
                  Plasma: liquid portion of blood without RBCs and leucocytes.
                  Serum: Plasma from which clotting factors have been removed
                  Leukocytes:
                         Granulocytes (show granules in cytoplasm when stained w/
                                        Wright's stain)
                                Neutrophils (phagocytes)
                                Eosinophils (cell response to worm and fungal
                                        infections)
                                Basophils (allergic response)

                              Agranulocytes
                                    monocytes (macrophage) -- phagocytize
                                    lymphocytes function is specific immune response
                                            B lymphocytes make antibodies
                                            T lymphocytes function in cell mediated
                                                   immunity

NOTE: It's not really this simple. The immune response requires a complex
     interaction of all sorts of leukocytes.

               Organs:
                      Thymus (site of maturation of T-lymphocytes)
                      Spleen (site of maturation of B-lymphocytes?)
                      Lymph nodes: filter lymph fluids to remove foreign particles
               Tissues:
                      Tonsils, gastrointestinal associated lymphoid tissue (site of
                             maturation of B-lymphocytes?)

How does the immune response function?
Every kind of cell and virus has specific proteins, carbohydrates, and other molecules on its
       surface that are present on no other kind of cell.
       Immune system cells can recognize non-self antigens and find the cells, viruses and
       other antigens that shouldn't be there.

I. Surveillance
        Macrophage recognize non self antigens and engulf them
                Non self antigens include:
                        bacteria, fungi, worms, toxins, cancer cells, etc.
II. Presentation
        Macrophage take the surface antigens from the things they engulf and embed them in
        their own cell membranes, where they can be recognized by lymphocytes

III. Recognition (Clonal selection)
        Each B and T cell can recognize only one antigen. The B and T cells that can
        recognize the antigen on the surface of the macrophage attach to it. This stimulates
        many changes in the cells, including rapid cell division (blast transformation). These
        changes are stimulated by cell signaling compounds secreted by macrophage and T
        cells (interleukins).
       Important point: A specific subclass of T lymphocytes, called T-helper cells, must
       interact with the macrophage and the B lymphocytes for the B cells to produce
       antibodies.

IV. Clonal expansion
       The specific B and T lymphocytes that recognize the antigens on the surface of the
       macrophage divide rapidly, and produce many identical cells that recognize that
       specific antigen.

V. Lymphocyte activation
      Rapidly dividing B cells are called plasma cells. Plasma cells produce antibodies
      specifically against the antigens presented on the macrophage. (at the peak, each B
      cell can produce about 2,000 antibodies/sec) Some plasma cells differentiate into
      "memory cells", which do not divide, but which wait around in large numbers for the
      next time they encounter the antigen. The more B cells that can recognize an antigen,
      the more antibodies can be produced.

       Rapidly dividing T cells differentiate into either memory cells or into four kinds of
       immune lymphocytes.
              helper T cells assist in responding to immune challenges
              cytotoxic T cells destroy specific target cells
              suppressor T cells help suppress the immune response (hey, something has
                       to turn it off)
              delayed hypersensitivity T cells function in allergic response

Important points:
       Lymphocytes have antibodies on their cell surfaces. Those antibodies are specific
       for the antigen that the cell will be able to recognize. All of the antibodies on the
       surface of any one cell recognize the same single antigen.

       The surface antibodies are made randomly. Some lymphocytes are primed to
       recognize antigens that may not even exist yet.

       Some antigens are extremely large. Some lymphocytes may recognize only a small
       part of the antigen, known as the antigenic determinant.

       T helper cells have a surface glycoprotein called CD4 that allow them to function in
       the immune response. CD4 is also the receptor for HIV.



Anamnestic Response

If an animal is presented with a new antigen, the first antibodies begin to appear in the
       blood in about 7-10 days. The concentration of antibodies reaches moderate
       heights.

The second time the animal sees the antigen, the first antibodies can appear in 2-3 days,
       and reach much higher concentrations in the blood.

This is known as the anamnestic response. (not forgetting response)
        Reason: The first time the animal encountered the antigen, only one or two B and T
        cells were primed to recognize it. The second time, there were hundreds, thousands,
        or millions of memory cells primed to recognize the same antigen.

       Practical application: booster shots can raise numbers of circulating antibodies, and
       numbers of memory cells!!
Applications of the immune response

Immune serum globulin (gamma globulin)
     blood proteins can be separated into four categories: albumin, and alpha, beta, and
     gamma globulins. antibodies are gamma globulins.
             Pooled gamma globulins contain the gamma globulins from about 1000
     individual donors. These 1000 people have produced antibodies to a wide variety
     of antigens.
             Uses: measles, hepatitis A
             Drawbacks: possible bloodborne pathogens
             Hyperimmune gamma globulins come from convalescing patients who
     have large concentrations of antibodies to a specific disease.
             Uses: whooping cough, rabies, tetanus, chickenpox, hepatitis B
             Drawbacks: limited availability, possible bloodborne pathogens (but lower
     risk than pooled gamma globulins)

Vaccinations
      Vaccinations can prevent individuals from getting a disease. BUT: we can never
      vaccinate 100% of the population (various reasons for this)

       Q: Will those unvaccinated people get disease?

       A: refer to population growth figure from p.1 of notes.
               Disease can spread when the density of susceptible people in the
       population exceeds some critical number. If enough of the population has been
       immunized, the possibility of a non-immune individual encountering a carrier is very
       low. That individual receives the benefits of immunization without being immunized.
       Called herd immunity.

Testing:
      Does a person have a particular antibodies in their system?
             Antibodies can cause particulate antigens (e.g. cells) to clump, or
      agglutinate, making a precipitate that can be seen with the naked eye.
             Uses: blood typing, typhoid fever (Salmonella), syphillis (VDRL), latex bead
                    agglutination (Candida, staph, strep, gonococcus)

       Western Blots: separate serum proteins by electrophoresis, and identify specific
       ones with antibodies
             Uses: Many, including primary screen for HIV

       Fluorescent antibodies: tag antibodies with a fluorescent dye. only structures that
       contain the specific antigen will glow.
              Uses: serotyping salmonella, testing for presence of pathogens in tissues or
       other samples.

       ELISA (Enzyme Linked ImmunoSorbent Assay):
                antibody is linked to an enzyme. If it sticks to an antigen, then the enzyme
       will catalyze a reaction that causes a color change that can be read with naked eye or
       machine. EXTREMELY sensitive for detecting small amounts of antigen.
Kinds of Antibodies

All antibodies have a basic 'Y' shape. The two arms of the Y are involved in antigen binding
         and are called the antigen binding fragment (F ab). F ab's vary depending on the
         antigen the antibody recognizes. The base of the Y is the same for all antibodies of
         a given class, and is called the constant fragment (Fc).

Antibody types
             IgG
                       soluble, circulating antibody comprises most of serum antibodies
                       Fc can bind to phagocyte membranes
               IgM
                       pentameric antibody (5 Ys joined at bases)
                       is first antibody produced, then cell switches to new Fc, and makes
                       IgG with same antigen specificity
                       Fc can bind to B lymphocytes
               IgA
                       either a monomer in serum, or a dimer in mucus. Found in high
                       concentration in mucus membranes
                       Fc can bind to phagocytes

               IgD     Is the B cell receptor

               IgE     important in allergic response, fights worm infections. Most frequently
                       found attached to mast cells and basophils by the Fc fragment.


Immune Disorders

       Allergic reactions
                4 categories
                        I. atopic and anaphylactic
                        II. hypersensitivities that lyse foreign cells
                        III. immune complex reactions, autoimmune disease
                        IV. Delayed hypersensitivities (cell mediated)



               Atopic allergies
                       allergies that have a local effect (e.g., hay fever, asthma, eczema)
               Anaphylactic allergies
                       allergies that have widespread effects throughout body
                       (e.g., food allergies, wasp stings, etc.)

Allergens:
        antigens or haptens that stimulate an allergic response
                 hapten: molecule that is too small to stimulate primary antibody response
        by itself, but will stimulate primary response if attached to a larger molecule. It can
        then react with antibodies by itself.

       Common allergens:
            Inhalants:
                    pollen, dust, mold spores, animal hair, insect parts, drugs, enzymes
            Ingestants
                    foods, food additives, drugs
            Injectants
                    bee, wasp venoms, drugs, vaccines, enzymes, hormones.
            Contactants
                    Drugs, cosmetics, detergents, solvents, dyes
Mode of allergic response:
      First, get a sensitizing dose:
               first encounter with allergen. makes plasma cells, memory B and T cells
                        plasma cells produce IgE, instead of usual IgM and IgG

               IgE binds to mast cells and basophils (granulocytes). Each cell can bind
                      10,000 to 40,000 IgE molecules

       Second dose (provocative dose)
             gives initial symptoms. When IgE binds the allergen, it causes the mast cell
                     or basophil to release the contents of its granules.

What's in the granules?

       Histamine
              constricts muscles in bronchioles and intestine
              relaxes smooth muscles in veins and arteries
              Result: itching, headache, redness
              Massive histamine release: shock, low blood pressure, circulatory failure

       Serotonin
              increases permeability of blood vessels, contracts smooth muscles,
                     diminishes CNS activity

       Platelet Activating Factor
               similar in action to histamine

       Prostaglandins
              inflammatory agents
              act like histamine and serotonins

       Bradykinin
              smooth muscle contraction of bronchioles
              dilation of blood vessels, capillary permeability, increased mucous secretion.

Antihistamines:
        counteract action of histamine by blocking it from binding to histamine receptors on
        target cells.

Desensitization therapy
     small quantities of allergen are injected to raise IgG response
     believe this works by creating enough IgG to bind the allergen before it can bind to
     the IgE on mast cells and basophils.

III. Immune complex Disease:
        Autoimmunity
        The B and T lymphocytes that would normally recognize "self" antigens seem to be
        eliminated during embryogenesis, before the immune system develops. BUT certain
        types of cells are separated from the immune system:
                lens of the eye, the central nervous system, thyroid, and testes.

       If these tissues later come into contact with the immune system, they could be seen
       as nonself, and antibodies raised against them.

               examples:
               Lupus erythematosis              Multiple organs and tissues are antigenic
               Rheumatoid arthritis             IgM directed against other antibodies
               Graves disease                   thyroid gland
              Diabetes mellitus               pancreas, insulin
              Myasthenia gravis               acetylcholine receptors on muscles
              Multiple sclerosis              myelin sheath of nerves


IV. Cell Mediated Hypersensitivities

       Mediated by TD cells

       contact dermatitis (poison ivy, detergents, jewelry, etc.)

              TD cells release lymphokines that attract inflammatory cells to site of contact


Immunodeficiency diseases
     Genetic deficiencies of B cells
     Genetic deficiencies of T cells
     Abnormal development of thymus
     SCID - Severe combined immunodeficiencies
            lack of lymphocyte precursors in bone marrow
            adenosine deaminase deficiency
                     toxic byproducts build up and specifically kill lymphocytes
     AIDS - Helper T cells are the targets of a virus infection and are destroyed.

								
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