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Chapter21
 

Chapter21

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    Chapter21 Chapter21 Document Transcript

    • Chapter 21 The Immune System: Innate and Adaptive Body Defenses Immunity: Ability to provide resistance to disease Innate (nonspecific) system First line of defense: external body membranes; like skin and mucosae Second line of defense: antimicrobial proteins, phagocytes and other cells Adaptive (specific) system Third line of defense: attacks particular foreign substances Takes much longer Innate Defenses: Skin and Mucosae 1. Acidity of skin secretions 2. Stomach acid 3. Saliva and lacrimal fluid contains lysozyme, which destroys bacteria 4. Sticky mucus and ciliated cells of the upper respiratory system Phagocytes: Macrophages – derived from monocytes Free macrophages – wander through tissue spaces Alveolar macrophages Dendritic cells (Langerhan’s cells) of epidermis Fixed macrophages – permanent residents of particular organs Kupffer cells Microglia Neutrophils – Become phagocytic when encounter infectious material Eosinophils – Weakly phagocytic When they encounter parasitic worms, discharge contents of cytoplasmic granules all over them. Mast cells – can bind with, ingest and kill a wide range of bacteria Mechanism of Phagocytosis 1. Adherence 2. Opsonization 3. Respiratory burst Internal Defenses: Natural Killer cells
    • NK cells: can lyse and kill cancer cells and virus infected body cells before adaptive system is activated. NK cells are part of large group of granular lymphocytes, unlike lymphocytes of adaptive system, are nonspecific Done by recognizing surface markers as “non-self”. Release cytolytic chemicals called perforins Also release chemicals that elicit the inflammatory response Internal Defenses: Inflammation: Tissue Response to Injury Inflammatory response: triggered anytime tissues are injured by anything. examples: ___________________ Beneficial effects: 1. Prevents spread of damaging agents 2. Disposes of cell debris and pathogens This forces the injured part 3. Sets the stage for repair to rest, which aids healing. Impairment of function some Signs of inflammation: consider to be the 5th sign of redness, heat, swelling and pain. inflammation. Vasodilation and Increase Vascular Permeability: 1. More blood comes to the area Inflammatory chemicals are Vasodilation leads 2. fluid leaves the capillaries released by injured cells to symptoms of and enters the tissues inflammation 3. macrophages enter the area in great numbers, to engulf foreign matter. Sources of inflammatory mediators: most important: histamine, prostaglandins, complement Redness, Swelling, 1. Stressed tissue cells, Pain, Heat, 2. Phagocytes Impairment 3. Lymphocytes 4. Mast cells 5. Blood proteins Benefits of swelling 1. Helps dilute harmful substances 2. Brings large amounts of oxygen and nutrients
    • 3. Entry of clotting proteins β-defensin is released in larger quantities from mucosal cells to prevent infection Area is invaded my more phagocytes Complement and adaptive immunity is activated if inflammation was caused by pathogens 1. Leukocytosis 2. Margination Job: Clean up debris 3. Diapedesis and pathogens 4. Positive Chemotaxis Homeostatic Imbalance Pus Abcesses Infectious granulomas Antimicrobial Proteins Interferon – released by some cells infected with viruses 1. Stimulates nearby cells to interfere with viral replication 2. Activates macrophages and 3. mobilizes NK cells Complement – a group of at least 20 plasma proteins that normally circulate in the blood in an inactive state. Function: 1. If activated, it unleashes chemical mediators which amplify nearly all aspects of inflammatory response. 2. Kills bacteria and other cells by lysis (Our own cells can de- activate complement) Both pathways: How is it activated? 1. Lead to cell lysis 1. Classic Pathway: Binding of antibodies to foreign invaders. 2. Promote Complement binds to them (complement fixation) Phagocytosis 2. Alternate pathway: Interact with polysaccharides on 3. Enhance the surface of certain microorganisms. inflammation Fever Systemic response to invading microorganisms (Ch 24) Stimulated by Pyrogens – chemicals secreted by leukocytes and macrophages exposed to foreign substances Heat denatures enzymes – high fevers are dangerous!
    • Mild fever 1. Causes liver and spleen to sequester iron and zinc which bacteria require in large amounts to multiply 2. Speeds up cellular metabolism to increase regeneration Adaptive Defenses Must meet (be primed) by the pathogen – takes time. Meanwhile the nonspecific systems are activated and we feel bad 1. It is specific 2. It is systemic 3 It has memory Humoral Immunity (antibody mediated immunity) – provided by antibodies in the body’s “humors” Cellular Immunity (cell-mediated immunity) – lymphocytes themselves defend the body Both respond to the same antigens (substances that provoke an immune response – recognized as “nonself”) Antigens Complete antigens: 1. Immunogenicity – ability to stimulate specific lymphocytes and antibodies 2. Reactivity – ability to react with the activated lymphocytes ex: proteins (strongest), nucleic acids, some lipids large polysaccharides. Also, bacteria, fungi and viruses because of surface macromolecules. Incomplete antigens: Haptens small molecules (peptides, nucleotides, hormones) by themselves do not stimulate an immune response, but do if they combine with a body protein. (Allergies) 1. Have only reactivity ex: penicillin, poison ivy, animal dander, detergents, cosmetics … Antigenic Determinants Places on the antigen where antibodies and lymphocytes may bind Many different types on one antigen So one antigen may activate many different types of lymphocytes and antibodies
    • Self-Antigens: MHC Proteins Major Histocompatibility Proteins: Surface glycoproteins recognized as “self” by our immune system, (but not others’) Class I MHC proteins – found on nearly all body cells Class II MHC proteins – found on only certain body cells that act in immunity Cells of the Adaptive Immune System: An Overview 1. B-lymphocytes: produce antibodies - (humoral immunity) 2. T-lympocytes: do not produce antibodies - (cell mediated immunity) 3. Antigen presenting cells – present antigens to other cells Immature lymphocytes are essentially identical. Whether they become B-cells or T-cells depends on where in the body they become immunocompetent Immunocometence: ability to recognize foreign antigens by binding to it. T-cells 1. T-cells become immunocompetent in the thymus and mature under the direction of thymic hormones. 2. Only those with the sharpest MHC survive (only about 2%) Positive Selection: T-cells able to recognize self MHC (Major Histocompatibility Complex Proteins) survive, the rest undergo apoptosis. Negative Selection: Those passing positive selection do this Those that bind too strongly to MHC are eliminated Purpose: ensures that T-cells exhibit self tolerance. B-cells Become immunocompetent and self tolerant in the bone marrow. Little is known about the factors that control B-cell maturation in humans. Self reactive B-cells are inactivated – anergy, others are killed or undergo apoptosis (clonal deletion) Primary Lymphoid Organs: thymus and bone marrow Secondary Lymphoid Organs: all other lymphoid organs When B or T cells become immunocompetent, the display a unique type of receptor on their surface enable the cell to recognize and bind to a specific antigen.
    • Lymphocytes become immunocompetent before meeting antigens – so it is in our genes not antigens that determine what foreign substances our immune system will be able to recognize. Naïve immunocompetent T & B cells are exported to secondary lymph organs (lymph nodes, spleen…) where they encounter antigens and thus become fully functional (antigen activated cells). Antigen Presenting Cells Purpose – engulf antigens and present fragments on their surfaces to T- cells for destruction Types of APCs: 1. Dendritic cells (in CT) Located where they would more likely 2. Langerhans cells (epidermis) encounter antigens 3. Macrophages (lymphoid organs) 4. Activated B-cells 5. Reticular cells APCs and lymphocytes are found throughout lymphoid tissues, but some tend to be more numerous in certain areas. Humoral Immune Response Antigen Challenge: First encounter with an antigen B-cell: provokes humoral immune response – produces antibodies Clonal Selection and Differentiation of B-cells B-cells is activated (completes differentiation) during antigen challenge: until they meet their first antigen, they are not yet fully mature. The antigen “selects” the B cell with the receptors complementary to the antigen. This B cell makes many clones of itself. Many of these clones differentiate into plasma cells, which produce antibodies. Other B cells become memory B cells. These remain in the body in case the antigen invades again. Immunological Memory – provide memory cells Primary Immune response – Cellular proliferation and differentiation (to plasma cells which produce antibodies) on first exposure to antigen Lag time is 3-6 days Memory cells provide Peak levels within 10 days – then decline immunological memory Secondary Immune response – occurs upon re-exposure to same antigen Memory cells are already there and produce plasma cells within hours. Peak antibody levels occur within 2-3 days and antibody titers much higher than in primary response and remains high for weeks or months.
    • Much faster More prolonged More effective Antibodies bond much tighter to antibodies in secondary response Antibody titer much higher Titers remain high for weeks or months Active and Passive Humoral Immunity Plasma cells keep functioning much longer than the 4-5 days as in primary response You see the same Active: B-cells produce antibodies general response 1. Naturally acquired – by getting the disease in cellular 2. Artificially acquired – vaccines immunity Active Humoral Immunity: B-cells are actively producing antibodies Vaccines do not provide the life long immunity that naturally acquired immunity does! Why? Cellular memory is only poorly established. Why? Explained later. Passive Humoral Immunity B-cells not challenged so: No immunological memory Borrowed antibodies degrade in 2-3 weeks. Artificial Passive Immunity is Natural – through the placenta given for diseases that kill before Artificial – IgG shots or antivenom active immunity can be established – rabies, tetanus, botulism… All antibodies have: 2 identical heavy chains (H) 2 identical light chains (L) Chains make: A. Make a T or Y shape B. Have a V (variable) region – antigen binding site C. Have a C (constant) region – same (or nearly) in all antibodies 1. Forms the stem 2. Determines the class of antibody 3. Common functions of all antibodies in that class a. Effector regions here dictate Some can fix complement, 1. what cells and regions it can bind to some circulate in blood, or are 2. how this class of antibody functions in antigen found in body secretions or elimination. cross the placenta barrier… Antibody Classes MADGE Named for C regions on heavy chains IgD Always bound to B-cell surface so acts as B-cell receptor IgG Most abundant in plasma Only class that can cross the placenta
    • Can fix complement IgE Almost never found in blood Involved in allergies “trouble makers” IgA Occurs in both diner and monomer forms Dimer – secretory IgA: mucus and secretions to body surface Prevents pathogens from gaining entry IgM Occurs in both monomer and pentameter forms First released to blood from plasma cells Can fix complement Antibodies do NOT destroy antigens They form antigen-antibody complexes and inactivate them and tag them for destruction Defensive mechanisms used by antibodies Neutralization PLAN: Precipitation Agglutination Most important Lysis (Complement) Precipitation Agglutination Complement fixation Neutralization Complement Fixation Works against cellular antigens like bacteria, mismatched blood… 1. Antibodies bind to cells 2. This causes change in shape exposing complement binding sites 3. This triggers complement fixation to antigenic cell surface 4. This causes lysis of the cell Remember chemicals released during complement activation greatly enhance inflammatory response and promote phagocytosis and opsonization – a positive feedback mechanism Neutralization Antibody blocks specific sites on viruses or bacterial exotoxins The toxic effect is lost if the antigen cannot bind to tissue cell receptors Antibody complex later pahgocytized. Agglutination Because antibodies have more than one antigen binding site, they can bind to the same determinant on more than one antigen at a time. So antigen antibody complexes can form lattices – when they do this it is called agglutination. Precipitation Soluble molecules are cross-linked to large complexes that settle out (more easily engulfed now). Students read the section about commercially prepared Monoclonal Antibodies
    • Cell Mediated Immune Response (T-cells are much more diverse than B-cells) Antibodies provide only partial immunity. Useless against things like tuberculosis bacillus (it is inside body cells to multiply) T-cells: Two major types – CD 4 and CD 8 T4 cells (T helper) TH cells T8 cells cytotoxic TC cells destroy body cells that harbor anything foreign Other types that exist are suppressor T cells and memory T cells Antibodies work in the extra-cellular environment (in humors). Secretions, blood, ECF… and do not enter tissues unless a lesion is present and then it is a race: antibodies are specialized to attach to intact bacteria and soluble molecules. Antibodies do not destroy antigens! They just tag them and make it easier for other cells (phagocytes) to destroy them. What happens to T cells after Pathogens are destroyed? Proliferation peaks within a week after exposure to antigen trigger. Period of apoptosis 7-30 days (activated T cells die off – dangerous to keep them around since they produce huge amounts of inflammatory cytokines). Some 1000s of T clones become memory T cells that persist for life (for same antigen). Specific T cell Roles Helper T cells – central role in adaptive immunity Once activated (by an antigen) function to stimulate proliferation of T and B cells that have already bound to an antigen. Without T Helper cells, there is no Cytotoxic T cells immune response! See Table: Cells and molecules of the Adaptive immune system TC cells are the only ones that can attack and kill other cells. Search through blood, lymph and lymphoid tissues For cells infected with anything& transplants As long as antigen and co-stimulatory signal is present. See picture: how does it work? Different TC cells use different chemicals, but the result is the same in the end: Lysis. So, also called cytolytic T cells. Organ Transplants and Prevention of Rejection 1. Autografts: tissue grafts transplanted from one body site to another in the same person
    • 2. Isografts: grafts donated to a patient by a genetically identical individual, an identical twin. 3. Allografts: grafts transplanted from individuals that are not genetically identical but belong to the same species. 4. Xenografts: grafts taken from another species, such as transplanting a baboon heart into a human. Autografts and isografts are always successful and xenografts work only temporarily. Allografts are most commonly used, but finding a perfect match is virtually impossible. At least a 6-antigen match is required. Patient is then treated with immunosuppressant drug, which often have severe side effects. Homeostatic Imbalances of Immunity Immunodeficiency Hypersensitivity – allergies 1. SCID 1. Acute or Type I hypersensitivites 2. AIDS a. Anyphylaxis b. Anyphylactic shock Autoimmune diseases c. Atopy 1. Multiple Sclerosis 2. Subacute Hypersensitivities 2. Myasthenia gravis a. Cytotoxic (type II) reactions 3. Grave’s disease 3. Immume complex (type III hyrpersensitivity 4. Type I diabetes mellitus a. Farmer’s lung 5. Systematic lupus erythematosus 4. Delayed hypersensitivities (Type IV) reactions 6. Glomerulonephritis a. Transfusions of mismatched blood 7. Rheumatoid arthritis b. Allergic dermatitis c. Mantoux and tine tests for tuberculosis d. Cell-mediated hypersensitivity