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ADVANCED PHYSIOLOGY IMMUNE SYSTEM Instructor Terry Wiseth IMMUNE SYSTEM Two major categories of immune mechanisms Nonspecific immunity Specific immunity 2 Nonspecific Immunity includes mechanisms that resist a variety of threatening agents or conditions Nonspecific Immunity means that these immune mechanisms do not act on one or two specific invaders, but rather provide a more general defense by simply acting against any thing recognized as not self 3 Specific Immunity involves mechanisms that recognize specific threatening agents and respond by targeting their activity against these specific agents These mechanisms often take some time to recognize their targets and react with sufficient force to overcome the threat 4 Cells of Nonspecific Immunity Natural-Killer (NK) cells Neutrophils Monocytes Macrophages 5 Nonspecific Immunity Skin and mucous membranes Antimicrobial substances Natural Killer Cells (NK) Phagocytosis Inflammation Fever 6 Nonspecific Immunity Skin and mucous membranes Antimicrobial substances Natural Killer Cells (NK) Phagocytosis Inflammation Fever 7 Skin and Mucous Membranes Internal environment of the human body is protected by a continuous mechanical barrier formed by the cutaneous membrane (skin) and mucous membranes 8 Skin and Mucous Membranes Often called the first line of defense Besides forming a protective wall, the skin and mucous membranes operate various additional immune mechanisms Mechanical barriers Chemical barriers 9 Mechanical and Chemical Barriers Sebum Contains pathogen-inhibiting agents Mucus Pathogens may stick and be swept away Viscosity inhibits microbe movements Enzymes May hydrolyze pathogens Lysozymes 10 Mechanical and Chemical Barriers Hydrochloric acid May destroy pathogens Sweat, tears, saliva Dilution and washing action Also contain enzymes which inhibit microbial growth 11 Nonspecific Immunity Skin and mucous membranes Antimicrobial substances Natural Killer Cells (NK) Phagocytosis Inflammation Fever 12 Antimicrobial Substances 2nd line of defense Contained within blood and interstitial fluid Transferrins Interferons Complement 13 Transferrins Fe++ binding proteins in blood Inhibit microbial growth by binding free Fe++ in blood ++ Fe Transferrin 14 Interferons Stimulates phagocytosis Inhibits viral replication 15 Interferon Cells invaded by viruses may respond rapidly by synthesizing the protein interferon and releasing it into circulation Interferon interferes with the ability of viruses to cause disease by preventing the viruses from multiplying in the cell 16 Interferon Interferon is produced within a cell that has been invaded by a virus Virus Anti viral protein Interferon 17 Interferon Intron A Kaposis sarcoma Genital herpes Hepatitis B and C Betaseron Slows progression of MS 18 Complement Is the name given to each of a group of about twenty (20) inactive enzymes in the plasma activated in a cascade of chemical reactions triggered by either specific or nonspecific mechanisms 19 Complement Complement or enhance immune, allergic and inflammatory reactions The complement cascade causes lysis of the foreign cell that triggered it 20 Complement Proteins are given names C1 through C9, B, D, P C3 activation is the key to the complement cascade 21 Complement C3 activation may occur in two ways Classical pathway Alternative pathway 22 Classical Pathway Complexes formed between antibodies and antigens of microbes 23 Classical Pathway Complexes formed between antibodies and antigens of microbes 24 Classical Pathway Complexes formed between antibodies and antigens of microbes 25 Alternative Pathway Polysaccharides on microbes can directly trigger C3 26 Complement and Alzheimer’s Disease Beta-amyloid is a peptide that is the major component of senile plaques within Alzheimer's disease brains May trigger an immune response that significantly contributes to the disease process 27 Complement and Alzheimer’s Disease Beta-amyloid binds very specifically to a protein which is part of the complementary protein group and activates the protein There is clear evidence of activated complement proteins near senile plaques and on damaged neurons in Alzheimer's disease, and it appears that beta-amyloid triggers this response by its binding to complementary proteins 28 Complement and Alzheimer’s Disease Complement proteins are usually released from liver cells but appear to originate in Alzheimer's disease brain from glial cells that surround senile plaques It is possible to inhibit the activation of complement by beta-amyloid without affecting the ability of complement to respond in the rest of the body 29 Complement and Alzheimer’s Disease The results suggest that it may be possible to develop drugs which specifically inhibit complement activation in the Alzheimer's disease brain without causing general immune suppression There is increasing evidence that much of the neuropathology seen in the Alzheimer's disease brain results from a chronic immunoinflammatory reaction to senile plaques 30 Complement Activated C3 will cascade the complement resulting in: Activation of the inflammatory response Opsonization Cytolysis 31 Activation of Inflammatory Response Arteriole dilation Cells release histamine Increases capillary permeability Enhances WBC mobility Complements act as chemostatic agents attracting other WBC 32 Opsonization C3 coats the microbes and promotes phagocytosis 33 Opsonization C3 coats the microbes and promotes phagocytosis 34 Cytolysis Numerous complement proteins form a membrane attack complex (MAC) Punches hole in the microbial membrane Microbe ruptures 35 Nonspecific Immunity Skin and mucous membranes Antimicrobial substances Natural Killer Cells (NK) Phagocytosis Inflammation Fever 36 Natural Killer Cells (NK) 3rd line of defense a group of lymphocytes that kill many types of tumor cells and cells infected by different kinds of viruses 37 Natural Killer Cells (NK) Found in the spleen, lymph nodes, red marrow Lack antigen receptors 38 Natural Killer Cells (NK) Release interferons Release perforins which cause cytolysis of the microbe 39 Natural Killer Cells (NK) Attack cells which lack MHC antigens NK cells are decreased in AIDS victims 40 Nonspecific Immunity Skin and mucous membranes Antimicrobial substances Natural Killer Cells (NK) Phagocytosis Inflammation Fever 41 Phagocytosis Is the ingestion and destruction of microorganisms or other small particles by phagocytes Neutrophils (phagocytes) Macrophage (scavenger) 42 Phagocytosis Macrophages are phagocytic monocytes that have grown to several times their normal size after migrating out of the blood stream Digestion and killing Fuses lysozyme vesicles with engulfed microbes in cytoplasm Release defensins Active against bacteria, fungi, viruses 43 Phagocytosis Three phases to phagocytosis Chemotaxis Adherence Ingestion 44 Chemotaxis Kinins, microbial products Chemical attraction 45 Adherence Attachment Opsonization by complement assists 46 Ingestion Engulf bacteria or antigen 47 Phagocytosis Some microbes are ingested but not killed Staphylococcus produce toxins which kill phagocytes TB multiply within the phagocytes Tularemia and brucellosis may lie dormant for months to years 48 Phagocytes The densest populations of phagocytes occur in the bone marrow, thymus gland, lymph nodes, and spleen From these structures, lymphocytes enter the blood and distribute themselves throughout the tissues of the body 49 Phagocytes After wandering throughout the tissue spaces, they eventually make their way into lymphatic tissues Lymph flow transports the lymphocytes through a succession of lymph nodes and lymph vessels and empties them into veins 50 Nonspecific Immunity Skin and mucous membranes Antimicrobial substances Natural Killer Cells (NK) Phagocytosis Inflammation Fever 51 Inflammatory Response tissue damage elicits many responses that counteract the injury and promote a return to normal Bacteria cause tissue damages triggers the release of mediators from cells such as mast cells found in connective tissue 52 Inflammation Response to stress of tissue damage Symptoms include: Loss of function in injured area Redness Pain Heat Swelling 53 Inflammation Inflammation helps to restore homeostasis Stages of inflammation 1) vasodilation 2) phagocyte migration 3) tissue repair 54 Vasodilation Blood vessels Become more permeable Dilate 55 Vasodilation Increased blood flow Allows defensive mediators to leave blood 56 Inflammation Defensive mediators Clot-forming chemicals Antibodies Phagocytes 57 Inflammation Histamine released by injured cells brings on vasodilation Also attract phagocytes 58 Inflammation Kinines, prostaglandins, leukotrienes and complement promote actions of histamine Kinins and prostaglandins induce pain associated with inflammation 59 Cytokines Small protein homones Stimulate or inhibit growth or differentiation of cells Secreted by lymphocytes, APC, fibroblast, endothelial cells, monocytes 60 Cytokine Function Chemotactic factors attracts macrophages causing hundreds of then to migrate into the vicinity of the antigen bound, sensitized T-cells Macrophage activating factor causes the macrophages to destroy antigens by phagocytosing them at a rapid rate Lymphotoxin powerful poison that acts more directly, quickly killing any cell it attacks 61 Inflammation Pus Collection of dead cells, fluids Abscess develops when pus cannot drain away Pimples, boils 62 Inflammation Phagocytes arrive about 1 hour after inflammation Neutrophils Arrive first Die quickly Monocytes Arrive after neutrophils Modify into macrophages More powerful and longer lived than neutrophils 63 Atopic Dermatitis (Eczema) A skin disease characterized by itchy, red, inflammed portions of the skin Scientists have found that people with atopic dermatitis have a low level of a cytokine (a protein) that is essential to the healthy function of the body's immune system and a high level of other cytokines that lead to allergic reactions 64 Nonspecific Immunity Skin and mucous membranes Antimicrobial substances Natural Killer Cells (NK) Phagocytosis Inflammation Fever 65 Fever Abnormally high body temperature Bacterial toxins trigger release of interleukin Interleukins Reset body thermostats Intensify effects of interferons 66 Interleukin Causes fever Stimulates proliferation and activation of: Helper T-cells Killer T-cells B-cells 67 Specific Immune System The various types of specific immune mechanisms attack specific agents that the body recognizes as "not self" Antigens Substances that are recognized as foreign and invoke an immune response 68 Specific Immune System Two types of specific immune responses are mediated by two different types of cells The two types of immune responses are: 1) Antibody mediated 2) Cell mediated 69 Specific Immune System Specific immunity is orchestrated by two different classes of lymphocytes 70 Cells of Specific Immunity Lymphocytes are formed in red bone marrow and are derived from primitive cells called stem cells 71 Cells of Specific Immunity Stem cells destined to become lymphocytes follow two developmental paths and differentiate into two major classes of lymphocytes B-lymphocytes or B-cells T-lymphocytes or T-cells 72 B Cells Originate, mature and develop in bone marrow B-cells do not attack pathogens Produce antibodies that attack pathogens or direct other cells, such as phagocytes, to attack them 73 B Cells B-cell mechanisms are often classified as antibody-mediated-immunity (AMI) or humoral immunity 74 T Cells Originate in bone marrow Mature and develop in the thymus 75 T Cells Proliferate into “killer” T-cells and “helper” T-cells Attack pathogens more directly 76 T Cells T-cell immune mechanisms are classified as cell-mediated-immunity (CMI) 77 TWO TYPES OF SPECIFIC IMMUNE RESPONSE 78 TWO TYPES OF SPECIFIC IMMUNE RESPONSE 79 Antibody Mediated Immunity Functions in defense against: Dissolved antigens Extracellular pathogens Bacteria 80 Humoral Response Antibody Mediated 81 Humoral Response Antibody Mediated 82 Cell Mediated Immunity Functions in defense against: Intracellular pathogens Fungi, parasites, virus Cancer cells Foreign tissues 83 Cell Mediated Immunity 84 Specific Immune Response Antibody mediated and Cell mediated immune responses are very complex in how they function Both responses involve common or similar process and factors Antigens Cytokines Antibodies Epitopes Interleukins B-cells MHC Interferons T-cells APC Perforins 85 Antigens Substances which provoke the immune system 86 Antigens May consist of: 1) Microbes or parts of microbes 2) Bacterial toxins 3) Allergens pollen, egg white, etc 87 Antigens 4) Transplanted tissue cells 5) Large complex molecules proteins, glycoproteins, lipoproteins 88 Antigens 6) Some smaller substances can act as antigens if combined with a body protein Ex. Lipid toxin can combine with body protein to form a complex which initiates immune response Poison ivy Allergic reactions to drugs Penicillin 89 Antigens 7) Allergic reactions to chemicals in the environment 90 Non-antigenic Large molecules that have simple repeating units are not antigenic (cellulose, plastics) That is why plastics work as artificial hearts and joints 91 Epitopes Specific portions of antigens trigger immune responses Immune system capable of recognizing at least a billion epitopes 92 Epitopes Receptor molecules complementary to antigen epitopes are located on cell membrane of T-cells and B-cells 93 MHC Antigens Major histocompatibility complex antigens are found on body cells 94 MHC Antigens Unique to the individual Number in the thousands Mark body cells as “self” Help T-cells recognize foreign invaders Found on cell membranes 95 MHC –I Markers of “self” Alert killer T-cells to presence of body cells that have changed due to viral infection or transformed to cancer cells 96 MHC-II B-cells, macrophages MHC-II is combined with ingested antigens and presented as a complex on the B-cell membrane to T-cells 97 Antigen If foreign antigen is detected by B-cells and T- cells the immune response is initiated B-cells can recognize and bind to antigens in extracellular fluids T-cells can recognize fragments of antigen only if presented in association with MHC by antigen presenting cells (APC) 98 Antigen Epitope binding and presentation of viral epitope on MHC-1 99 Antigen T-cell binding to MHC-1 molecule 100 Antigen T-cell recognition of MHC-2 molecule 101 Antigen B-cell activated antibody production 102 APC (Macrophages) After macrophages engulf antigen, pieces of antigen are associated with MHC and subsequently presented as MHC-antigen complex on cell membrane 103 APC After antigen processing, APC cells migrate to lymphatic tissue and present MHC-antigen complex to T-cells APC cells located in Skin Respiratory Urinary Reproductive tracts Lymph nodes 104 T-cells T-cells with correctly shaped receptors that match the presented MHC-antigen complex trigger: 1) Cell-mediated immune response (CMI) 2) Antibody-mediated immune response (AMI) 105 Immune Activation 106 Antibodies Antibodies are glycoproteins of the family called immunoglobulins (Igs) 107 Antibodies Each immunoglobulin molecule consists of four polypeptide chains joined together by disulfide bonds (S-S) 108 Antibodies Each polypeptide chain is folded to form globular regions that are joined together in such a way that the whole molecule is Yshaped 109 Antibodies Each of us is thought normally to have millions of different kinds of antibody molecules in our bodies Each of these has its own uniquely shaped combining sites Antigen binding sites are in variable regions 110 Antibodies It is this structural feature that enables antibodies to recognize and combine with specific antigens both of which are crucial first steps in the body's defense against microbes and other foreign cells 111 Functions of Antibodies The function of antibody molecules is to produce antibody-mediated immunity This type of immunity is also called humoral immunity because it occurs within the plasma 112 Antibodies Antibodies function to: 1) Neutralize toxins, viral attachments 2) Immobilization of bacteria, flagella, cilia 3) Agglutination, clumping of bacteria, cells 4) Activation of complement, classical pathway 5) Enhancing phagocytosis (opsinization) 6) Provide fetal newborn immunity 113 Antibody Function 114 Antigen-Antibody Reactions Antibodies fight disease by distinguishing non-self antigens from self antigens Recognition occurs when an antigen's epitopes fit into and bind to an antibody molecule's antigen-binding sites 115 Antigen-Antibody Reactions The binding forms an antibody-antigen complex that may produce one or more effects It transforms antigens that are toxins into harmless substances It agglutinates antigens that are molecules on the surface of microorganisms which makes them stick together so phagocytes can engulf them 116 Antigen-Antibody Reactions Neutralization of bacteria by antigen-antibody reactions 117 Classes of Antibodies There are five (5) classes of antibodies identified by letter names as immunoglobulins M G A E D 118 Ig M (Immunoglobulin M) 5-10 % of Igs Activate complement Is the antibody that immature B cells synthesize and insert into their plasma membranes Is the predominate class of antibody produced after initial contact with an antigen in the blood 119 Ig G (Immunoglobulin G) Most abundant circulating antibody Normally makes up about 75% of the antibodies in the blood Enhances phagocytosis Able to pass the placenta from mother to fetus Confers immune protection to newborn 120 Ig A (Immunoglobulin A) Constitutes about 15% Major class of antibody present in the mucous membranes of the body, in saliva, sweat, milk and in tears 121 Ig E (Immunoglobulin E) Minor in amount (less than 0.1%) Can produce harmful effects such as those associated with allergies and hypersensitivity 122 Ig D (Immunoglobulin D) Constitutes less than 1% Activates B-cells Protects against parasitic worms 123 B-Cells and AntibodyMediated Immunity B-cells start their development in the embryonic yolk sac, then the red marrow or fetal liver By the time a human infant is a few months old, its pre-B-cells have completed the first stage of development Are then known as inactive B-cells 124 B-Cells and AntibodyMediated Immunity Inactive B-cells synthesize antibody molecules but secrete few if any of them Instead, they insert on the surface of their plasma membranes perhaps 100,000 antibody molecules The combining sites of these surface antibody molecules are now ready to serve as receptors for a specific antigen if it comes by 125 B-Cell Activation 126 B-Cells and AntibodyMediated Immunity After being released from the bone marrow, inactive B-cells circulate to the lymph nodes, spleen, and other lymphoid structures Occurs when the inactive B-cells become activated 127 B-Cells and AntibodyMediated Immunity Activation of a B-cell must be initiated by an encounter between an inactive B-cell and its specific antigen The antigen binds to these antibodies on the B-cell's surface 128 B-Cells and AntibodyMediated Immunity Antigen-antibody binding activates the B-cell triggering a rapid series of mitotic divisions 129 B-Cells and AntibodyMediated Immunity By dividing rapidly, a single B-cell produces a clone mass Some of them become differentiated to form plasma cells Others do not differentiate completely and remain in lymphatic tissue as memory B-cells 130 Plasma B-Cells Plasma cells synthesize and secrete large amounts of antibody 2000 molecules/sec for 4-5 days or until plasma cell dies 131 Memory B-Cells Memory B-cells do not themselves secrete antibodies if they are later exposed to the antigen that triggered their formation memory B-cells become plasma cells and the plasma cells secrete antibodies that can combine with the initiating antigen 132 Memory B-Cells The ultimate function of B-cells is to serve as ancestors of antibody-secreting plasma cells 133 Humoral Immunity 134 Humoral Immunity 135 Humoral Immunity 136 Humoral Immunity 137 Humoral Immunity 138 T-Cells and CellMediated Immunity T-cells are lymphocytes that have made a detour through the thymus gland before migrating to the lymph nodes and spleen During their residence in the thymus, pre-Tcells develop into thymocytes 139 T-Cells and CellMediated Immunity Thymocytes divide up to three times/day and their numbers increase enormously in a relatively short period of time They leave the thymus and move into the blood and take up residence in lymph nodes and spleen now are known as T-cells 140 Activation and Function of T-Cells Each T-cell, like each B-cell, displays unique antigen receptors in its surface membrane When an antigen (preprocessed and presented by macrophages) encounters a Tcell whose surface receptors fit the antigen's epitopes, the antigen binds to the T-cell's receptors 141 Activation and Function of T-Cells An antigen bound T-Cell activates or sensitizes the T-cell, causing it to divide repeatedly to form a clone of sensitized T-cells The sensitized T-cells then travel to the site where the antigen originally entered the body 142 Activation and Function of T-Cells There in inflamed tissue, the sensitized T-cells bind to antigens of the same kind that led to their formation T-cells will bind to their specific antigen only if the antigen is presented by a macrophage 143 Activation and Function of T-Cells The antigen-bound sensitized T-cells then release chemical messengers into the inflamed tissues called cytokines 144 Types of T-cells Helper T-cells Killer T-cells Suppressor T-cells Memory T-cells 145 Helper T-cells TH Cooperate with B-cell to amplify antibody production by plasma cells Secrete interleukins which stimulates proliferation of T and B cells 146 Helper T-cells TH Cooperate with B-cell to amplify antibody production by plasma cells Secrete interleukins which stimulates proliferation of T and B cells 147 Killer T-Cells TC Cytotoxic , Killer T-cells 148 Killer T-Cells Recognize foreign antigens presented by: 1) body cells infected by virus 2) some tumor cells 3) cell of tissue transplant Requires Helper T-cells to be activated Sensitized T-cells then release lymphotoxin which kill target cells 149 Suppressor T-Cells TS Inhibit proliferation of T-cells Dampens immune response 150 Memory T-Cells Programmed to recognize original invading antigens Able to initiate a swift reaction on subsequent infections 151 T-Cell Summary Slide show is over Animated slide show has 5 seconds between each slide 152 Types of Specific Immunity Inherited immunity Immunity to certain diseases develops before birth Acquired immunity Exposure to the causative agent is not deliberate Natural Artificial 153 Natural Acquired Immunity Active A child develops measles and acquires an immunity to subsequent infection Passive A fetus receives protection from the mother through the placenta, or an infant receives protection by way of the mother's milk 154 Artificial Acquired Immunity Exposure is deliberate Active Injection of the causative agent, such as vaccination against polio, confers immunity Passive Injection of immunoglobulins (antibodies) that were developed by another individual's immune system 155 Disorders of the Immune System AIDS Chronic Fatigue Syndrome Severe Combined Immunodeficiency (SCID) Allergy Tissue Rejection Hodgkin’s Disease Autoimmune Disease Lupus Multiple Sclerosis Myasthenia Gravis Graves Disease 156 AIDS HIV attack T-cells 157 Chronic Fatigue Syndrome Extreme fatigue Lowered levels of corticotropin releasing hormone and cortisol 158 Severe Combined Immunodeficiency Both B-cells and T-cells are missing or inactive Caused by mutated genes Infusions of red marrow from sibling provide normal stem cells David “bubble boy” 159 Allergy Overly reactive to antigen that is tolerated by most others 160 Type I Allergies Anaphylaxis Most common allergic reaction Cells release histamine which causes bronchiole constriction Bee sting Treated with epinephrine 161 Type II Allergies Cytotoxic Cells damaged by lysis Incompatible transfusion reactions 162 Type III Allergies Immune complex Complexes of antigen-antibody which are small and escape phagocytosis Accumulate in blood vessel lining causing inflammation Rheumatoid arthritis, systemic lupus, glomerulonephritis 163 Type IV Allergies Delayed type hypersensitivity Carried by macrophages which have been activated by T-cells Symptoms occur 12-72 hours after exposure Skin tests for TB 164 Tissue Rejection Immune system recognizes transplanted tissues as antigens Immunosuppressive drugs suppress entire immune system Cyclosporin Inhibits secretion of interleukins by Helper T-cells but does not impact B-cells 165 Hodgkin’s Disease Cancer usually arising in lymph nodes Considered a curable disease Lymph node Malignant cells 166 Autoimmune Disease Lupus Multiple Sclerosis Myasthenia Gravis Grave’s Disease 167 Lupus Inflammatory, non-contagious disease of connective tissue Blood vessel damage results in release of chemicals causing inflammation Skin lesions, rashes 168 Multiple Sclerosis immune cells mistake myelin as a foreign invader and attack it the protective coating on nerve fibers (myelin) becomes detached and eventually destroyed MS can affect vision, sensation, coordination, movement and bladder and bowel control 169 Myasthenia Gravis Disease affecting the neuromuscular junction and producing weakness of voluntary muscles Receptors for acetylcholine at the muscle surface are destroyed Healthy Ach receptors Destroyed Ach receptors 170 Myasthenia Gravis Voluntary muscles of the eyes are commonly affected Three different serial pictures to demonstrate fatigue of eyelid muscles as the patient keeps looking up After a few minutes of rest, the eyelids have returned to near-normal position 171 Grave’s Disease Antibodies are produced against certain proteins on the surface of thyroid cells Stimulating those cells to overproduce thyroid hormones Results in an overactive thyroid 172 Grave’s Disease The immune system also attacks the tissue behind the eyes and the skin of the lower legs Tissues behind the eye attract and hold water When this happens, the tissues and muscles swell, causing the eyeball to move forward in the orbit 173 End Immune System