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Chapter 43 The Immune System travismulthaupt.com Pathogens Pathogens are viruses and other organisms that invade the body and cause disease. 2 Surface Proteins The surfaces of the pathogens that enter the body contain proteins that are recognized by our body’s defenses. These are called antigens. Antigens are recognized as foreign and stimulate an immune response. Antigens usually stimulate the production of antibodies by the immune system. 3 Protection From Invaders Your body has a variety of mechanisms to protect it from invasion. 1. The skin 2. Mucous 3. Ciliated lining of the trachea 4. Internal cellular and chemical defenses via phagocytes travismulthaupt.com 2 Major Types of Defense 1. Innate immunity 2. Acquired immunity travismulthaupt.com 1. Innate Immunity This type of immunity is present before any exposure to pathogens and is available at birth. Innate responses help slow the spread of microbes before the body can build acquired, specific responses. travismulthaupt.com QuickTime™ and a decompressor are needed to see this picture. 2. Acquired Immunity This immunity develops after exposure to foreign substances. Acquired defenses are highly specific. They have the ability to distinguish between very closely related inducing agents. Specificity is achieved by lymphocytes. travismulthaupt.com 1. The Skin--Innate The skin secretes oils and sweat. It has a normal pH of 3 to 5 which prevents colonization of bacteria on the skin. Secretions from the skin also contain lysozyme which digest the cell walls of many bacteria. It is found in tears, mucous, saliva, etc. travismulthaupt.com 2. & 3. Mucous and Cilia-Innate Mucous often traps invaders and cilia sweeps them out of the trachea. They are either swallowed where they usually fall victim to the low pH of the stomach. They may also be expectorated. travismulthaupt.com 4. Internal DefensesPhagocytes--Innate Phagocytes are certain types of WBC’s that produce antimicrobial proteins. Help initiate inflammation. This helps limit the spread of microbes in the body. Non phagocytic WBC’s are called natural killer cells. These play a key role in innate defenses. travismulthaupt.com QuickTime™ and a decompressor are needed to see this picture. 4. Internal DefensesPhagocytes Phagocytes bind to the surfaces of invading cells. They use surface receptors to recognize structures found on microorganisms, but not normal body cells. After binding the invader, the phagocyte engulfs the invader, forms a vacuole, travismulthaupt.com and fuses with a Lysosomes There are 2 ways lysosomes work: 1. They poison the invader. NO and other toxic forms of O2 are made in the lysosome. 2. Lysozyme and other enzymes degrade invader components. Some microbes make substances that allow them to go unnoticed against the body’s defenses.travismulthaupt.com Natural Killer Cells NK cells patrol the body and attack virus infected body cells and cancer cells. They recognize surface proteins and act to release chemicals into the cell triggering apoptosis. Not 100% effective. A human natural killer cell is shown conjugated to a tumor cell. The accumulation of actin filaments (blue) and CD2 (red) at the immunologic synapse can be seen preceding the localization of the cytolytic molecule perforin (green). travismulthaupt.com QuickTime™ and a decompressor are needed to see this picture. Physical injury or pathogens can cause tissue damage and localized swelling. Numerous chemical signals are released. The most active one is histamine which comes from mast cells. Tissue Damage www.aapspharmscitech.org/ view.asp?art=pt060361 travismulthaupt.com Histamine Triggers dilation and increased permeability of capillaries. Activated macrophages and other cells discharge other signals, such as prostaglandins. Prostaglandins promote more blood flow to the injury site. travismulthaupt.com The Injury Site The swelling and increased heat are critical to innate defense. They deliver the necessary components to the site of injury (clotting factor and antimicrobial protein). travismulthaupt.com Blood Clotting To plug a wound, the human body has a system in place that works together to try to stop blood loss. 20 Blood Clotting When a person is wounded, substances are released that stimulate the production of thrombin from prothrombin. 21 Blood Clotting Thrombin is an enzyme that then catalyzes the formation of fibrin from fibrinogen. Fibrinogen is a protein that is always circulating in the bloodstream. 22 Blood Clotting Fibrin is a fibrous protein that captures red blood cells and stops the flow of blood. When the blood is stopped at the wound site, it starts to coagulate. 23 Blood Clotting Coagulation captures platelets that send out sticky extensions that cling to other features of the wound. Over time, the platelets contract and the liquid portion of the blood is forced out of the wound and a scab begins to form. 24 Antigens Antigens are foreign molecules that are recognized by lymphocytes and elicit a response from them. Lymphocytes bind to the epitope on an antigen. travismulthaupt.com 2. Acquired ImmunityLymphocytes Lymphocytes produce 2 main types of immune responses: 1. Humoral response Circulating antibodies produced by Blymphocytes 2. Cell mediated response Antibodies produced by T-lymphocytes travismulthaupt.com 1. The Humoral Response Occurs when cells derived from Blymphocytes become activated and secrete defensive proteins called antibodies. Secreted antibodies accumulate in the blood and lymph. travismulthaupt.com 1. The Humoral Response Antibodies identify and bind to microbes and mark them for elimination. Clonal selection is also involved. travismulthaupt.com Clonal Selection The antibody-driven cloning of T & B lymphocytes is called clonal-selection and is fundamental to acquired immunity. When antigens bind to specific receptors, a small fraction of the body’s lymphocytes are activated. This stimulates the production of thousands of clones that work to eliminate an antigen. travismulthaupt.com QuickTime™ and a decompressor are needed to see this picture. Primary Immune Response The primary immune response is the first time exposure to an antigen. Proliferation of lymphocytes occurs. The individual may become sick. Eventually antibodies clear the antigen from the system. travismulthaupt.com Secondary Immune Response The 2° immune response occurs if an individual is exposed to an antigen again. It is an example of immunological memory. It depends on long lived T and B memory cells. They elicit a quick and specific response to the antigen. travismulthaupt.com Lymphocytes Lymphocytes are WBCs that mediate the immune responses. There are two main types of lymphocytes: 1. B-cells 2. T-cells They are concentrated in the spleen, lymph nodes, and other lymphoid travismulthaupt.com tissues. Lymphocytes Lymphocytes act to recognize antigens by a means of antigen specific receptors embedded in their membrane. They stimulate production of T & B cells. A single T or B cell has about 100,000 antigen-receptors. All of them are the same on a particular cell--they recognize the same epitope. travismulthaupt.com Lymphocytes Lymphocytes are derived from pluripotent stem cells in the bone marrow. Each lymphocyte displays specificity for a particular epitope on an antigen It defends against that antigen and other closely related antigens. travismulthaupt.com 1. B-Cell Lymphocytes Originate and mature in the bone marrow. B-cell chains are anchored into a membrane of the B-cell. They are sometimes called membrane antibodies or membrane immunoglobulins. B-cells recognize intact antigens. travismulthaupt.com B-Cell Receptors B-cell receptors for antigens are Y-shaped. They contain 4 polypeptide chains 2 heavy chains and 2 light chains. V regions are variable, their aa sequence varies extensively from one B-cell to the next. C regions are constant and have little variability in their sequence. travismulthaupt.com 1. B-Cell Lymphocytes B-cells help with presenting antigens to helper T-cells in the course of the humoral response. 39 http://en.wikipedia.org/wiki/File:B_cell_activation.png Immunoglobulins Immunoglobins are called Ig’s They are structurally very similar to B-cell receptors. They are made by B-lymphocytes (B-cells) in large quantities. travismulthaupt.com Immunoglobulins There are 5 main classes. IgA IgM IgG IgD IgE travismulthaupt.com IgA Found in serum, saliva, tears, breast milk, and mucous secretions. Neutralizes viruses and bacteria as they enter the body. travismulthaupt.com IgM Found in blood and lymph. First antibody produced following infection or immunization. Has numerous binding sites. Activates compliment-part of innate system. travismulthaupt.com IgG It is the main Ig in blood, lymph and tissue fluid. It neutralizes microorganisms, viruses, and bacterial toxins by binding to them. Promotes engulfment by macrophages. Activates compliment-part of innate system. travismulthaupt.com IgD Found on the surface of antibody secreting B-cells. Found in low concentrations. Works with IgM as an antigen receptor. travismulthaupt.com IgE Found in low concentrations in serum and connective tissues. Plays a crucial role in allergic reactions. Binds to mast cells causing a histamine release in response to an antigen. The histamines produce all of the symptoms associated with allergies: Swelling, redness, runny nose and eyes. travismulthaupt.com The Complement System The complement system comprises part of the innate defense. It becomes activated as a result of the humoral system (IgG, IgM). Numerous inactive serum proteins. travismulthaupt.com The Complement System Infected cells secrete numerous types of proteins as a part of the Compliment System. They quickly become active and lyse foreign invaders when detected. Example: and interferon. Interferon There are 2 main types ( and ) which provide innate defense against viral infection. They act to stimulate neighboring cells to produce substances to prevent further infection. This is the body’s way of preventing the spread of the infection. Membrane Attack Complex The MAC is triggered by substances from the body’s innate defenses. MAC is triggered by the antigen-antibody response. This complex forms pores in the membrane, and they allow H2O and ions to rush in and lyse an infected cell. travismulthaupt.com MHC Major histocompatibility complex genes code for MHC molecules. When MHC molecules are synthesized, they get transported to the plasma membrane. On the way, they bind with fragments of antigen protein within a cell and bring it to the surface. travismulthaupt.com MHC MHC is what is called antigen presentation. Due to antigen presentation, nearby T-cells can recognize the fragment on the cell surface and act accordingly. MHC proteins are very polymorphic. travismulthaupt.com Foreign Antigens There are 2 ways foreign antigens end up inside cells of the body. Their source determines which MHC molecule gets used and which T-cell assists in its removal. 1. Foreign antigens synthesized within the cell (viruses, cancer). 2. Foreign materials can become internalized by phagocytosis or endocytosis travismulthaupt.com Class I MHC Molecules These are found on most nucleated cells in body. They bind antigens synthesized within the cell. Infected cells and cancerous cells display such antigens. Cytotoxic T-cells destroy cells displaying Class I MHC molecules. travismulthaupt.com travismulthaupt.com Class II MHC Molecules Class II MHC molecules are made by only a few types of cells-dendritic cells, macrophages, and B-cells. These bind peptides derived from foreign materials that have been fragmented and internalized. travismulthaupt.com Class II MHC Molecules Class II MHC molecules display these antigens to helper T-cells. Helper T cells alert nearby B-cells and cytotoxic T cells by secreting cytokines. travismulthaupt.com travismulthaupt.com travismulthaupt.com Immunoglobulin Gene Rearrangement There are many different types of B-cell and T-cell antibodies. This is due to the random nature of the recombinase enzyme. It can create a number of different gene products which are the B-cell (or T-cell) antigen receptors. travismulthaupt.com travismulthaupt.com B-Cell & T-Cell Activation When B-cells and T-cells become activated by antigens, they are stimulated to divide many times. 2 clones of daughter cells are created. 1 is short lived, antibody secreting cell. The other is a memory cell that is long lived and bears receptors for the same antigen. travismulthaupt.com B-Cell Activation Many antigens recognized by B-cells contain multiple epitopes. Exposure to a single antigen can stimulate a variety of different B-cells. This gives rise to a clone of thousands of plasma cells (effector and memory). These clones secrete antibodies specific to the epitope that provoked their production. travismulthaupt.com B-Cell Activation Activated B-cells secrete antibodies that have a Y-shaped antigen-binding structure, but no transmembrane region. These binding sites are responsible for identifying specific antigens. Identification of antigens facilitates their removal. travismulthaupt.com 2. The Cell Mediated Response When the cell mediated response and clonal selection occurs: Cytotoxic lymphocytes directly destroy infected body cells, cancer cells, or foreign tissue. There are 2 main types of T-cells 1. Helper T-cells 2. Cytotoxic T-cells travismulthaupt.com 2. T-Cell Lymphocytes T-cell lymphocytes originate in the bone marrow and mature in the thymus. They consist of 2 polypeptide chains, & . They, too, are linked into a cell’s plasma membrane. They also have V and C regions. T-cells recognize fragments of antigens that are bound to normal cell-surface proteins called MHC molecules. Helper T-Cells Helper T-cells are central to the network of cellular interactions. They respond to peptide antigens displayed on antigen presenting cells. They stimulate activation of B-cells and cytotoxic T-cells. travismulthaupt.com Helper T-Cells When helper T-cells encounter a class II MHC molecule-antigen complex, they stimulate the production of clones of helper T-cells and memory helper T-cells. This promotes the removal of infected cells. travismulthaupt.com Helper T-Cells Helper T-cells secrete many different cytokines (signals) to stimulate other lymphocytes. This promotes humoral and cell mediated responses. travismulthaupt.com Cytotoxic T-Cells When activated, cytotoxic T-cells secrete proteins which destroy the infected cell. Circulating antibodies then mark the exposed pathogens for disposal. Cytotoxic T-cells are the effectors. travismulthaupt.com Ways to Prevent Infection There are 2 types of immunization: 1. Active immunity 2. Passive immunity travismulthaupt.com 1. Active Immunity This is immunity conferred by a natural exposure to an infectious agent. It also can develop following immunization. travismulthaupt.com 2. Passive Immunity Passive immunity results from the transfer of antibodies from an immune individual to someone who isn’t. Transferred antibodies are immediately available to attack antigens to which they are specific. travismulthaupt.com Edward Jenner English physician in the late 1700’s. Noticed that milkmaids who had contracted cowpox were resistant to smallpox. http://upload.wikimedia.org/wikipedia/commons/4/49/Cowpox_Engraving_%28detail%29.png http://en.wikipedia.org/wiki/File:Cowpox_eruption.jpg Edward Jenner Jenner took fluid from a cowpox sore and scratched the arm of a healthy farmboy with it. When the boy was later exposed to smallpox, he was immune. 77 http://en.wikipedia.org/wiki/File:Child_with_Smallpox_Bangladesh.jpg Monoclonal Antibody Production Monoclonal antibodies are large quantities of a single type of antibody made to a specific antigen. They are derived from a single B-cell clone. 79 Monoclonal Antibodies: Production mAb production begins when an animal is injected with the desired antigen and then produces a specific plasma cell. The animal’s plasma cells are then removed and fused with immortal tumor cell lines such as He La cells. This results in the production of what is known as a hybridoma. 80 http://www.ib.bioninja.com.au/higher-level/topic-11-human-health-and/111-defence-againstinfecti.html Monoclonal Antibodies The hybridoma, which can now divide endlessly, synthesizes vast quantities of the specific antibody which can be used for diagnostic and treatment purposes. These antibodies can be isolated and purified and given to sick individuals. 82 Monoclonal Antibodies Use: Emergency treatment of rabies. An individual sick with rabies is given mAb made specific to the virus. The mAb bind to the virus and are collected by the cells of the immune system. The body’s immune system is allowed to catch up and eventually the person gets better. 84 Monoclonal Antibodies Other uses: Diagnosis of malarial infection, pregnancy testing, HIV, heart attack, etc. 85 Allergies These are exaggerated responses to certain antigens. The most common allergies involve antibodies of the IgE class. When plasma cells secrete IgE antibodies specific for antigens on the surface of pollen grains, hay fever results. travismulthaupt.com Allergies Some antibodies are attached to mast cells which are found in connective tissue. When allergens enter the body, they become attached to the mast cell-IgE association. This triggers the release of histamine and other inflammatory substances. travismulthaupt.com Allergies Histamine causes dilation and increased permeability of small blood vessels. This causes the common symptoms of allergy responses. travismulthaupt.com