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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