2014 Pearson Education, Inc. Exposure to pathogens naturally activates the immune system. Takes days to be effective Pearson Education, Inc.

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1 The innate immune interact with the adaptive immune system 1. Damage to skin causes bleeding = bradykinin activated, resulting in inflammation 2. Dendritic phagocytose pathogens Adaptive immunity 4. Dendritic will travel to the lymph nodes to activate your adaptive immune system! 3. Inflammation results in vasodilation, and monocytes and neutrophils migrate to damaged area. Adaptive Immunity is the third line of defense You acquire your adaptive immunity during your life Active Adaptive immunity (also called acquired immunity) allows the body to recognize and mount an immune response to specific pathogens and toxins Involves WBCs called lymphocytes T lymphocytes (T ) Passive Exposure to pathogens naturally activates the immune system. Takes days to be effective. Antibodies from mother are passed to baby in womb and in breast milk B lymphocytes (B ) Vaccinations artificially activate the immune system. Takes days to be effective. lymphocyte tulane.edu Antibodies made in another organism (horse) are injected into person to give immediate protection T lymphocytes mature in thymus Red blood Other white blood Lymphocytes = 3rd line of defense Involved in second line of defense Lymphocytes are made in red bone marrow (ends of long bones in kids and centers of adult flat bones in adults) B lymphocytes mature in the bone marrow, T lymphocytes mature in the thymus, Both T and B circulate in the lymph and the blood 1

2 Overview of Adaptive Immunity Two categories of adaptive immune responses Antibody immune responses (aka humoral immune response); mediated by the B Cell-mediated immune responses; mediated by T The lymphatic system plays an important role in adaptive immunity Lymphatic system = lymphatic vessels, lymphatic, tissues, and organs Purpose: To screen the tissues of the body for foreign antigens The majority of your lymphocytes are found in the secondary lymphoid organs (lymph nodes, spleen, and MALT tissue) Long-lived B and T retain the ability to fight off specific pathogens, which is referred to as immunological memory Lymph is similar to blood plasma Made of fluid leaked out of blood vessels into intercellular spaces of body. Collected by lymphatic capillaries which flow in vessels and then into two large lymphatic ducts Lymph is collected from tissues that flows into lymphatic ducts Lymph nodes are concentrated near the many of the portals of entry of the body Lymphatic system has no pump and only flows one way (towards heart) Primary lymphoid organs (red bone marrow and thymus) are where lymphocytes mature. Secondary lymphoid organs and tissues are where mature lymphocytes are found. These areas include the lymph nodes, spleen, tonsils, mucosa associated lymphoid tissue Lymph nodes facilitate the interaction between lymphocytes and foreign particles and pathogens. You have 100 s in your body. The mucosa associated lymphoid tissue (MALT; appendix, lymphoid tissue of respiratory tract, vagina, urinary bladder, mammary glands, Peyer patches) contain most of the body s lymphocytes. Overview of adaptive immunity Mediated by B and T lymphocytes These use specialized receptors on the cell surface to detect foreign objects, including pathogens, toxins, dust, etc. The recognition these foreign objects (antigen) activates the immune cell and it will mount an immune response to rid the body of the object Mounting an effective immune response takes several days B and T will make memory, which will respond much faster to the same particle the next time around The adaptive immune response is directed against molecules called antigens, not the entire pathogen An antigen is any molecule that activates an immune response Antigens can be small portions of the cell wall, protein, etc. of an invading pathogen, toxin, or dust/food 2

3 Antigens have specific epitopes that are recognized by immune cell receptors. An epitope is a 3D shape of a particular region of an antigen Antigens are small portions of the cell wall, determinants) protein, etc. of an invading pathogen, toxin, or dust/food Epitopes (antigenic Exogenous antigens are proteins or other structures found on the outside of a virus or bacterium Bacteria Exogenous antigens Cytoplasmic membrane Nucleus Antigen Cytoplasm Exogenous antigens Epitopes are also called antigenic determinants because they determine the response to the antigen by the immune cell Virus Endogenous antigens are produced by pathogens that can infect the cell. Infected can use these antigens to warn the immune system. Autoantigens are molecules that are a part of the normal cell; however, they abnormally cause the immune system to mount a response against a cell Endogenous antigens expressed by cell to alert immune system Virus with antigens Normal cell (uninfected) Autoantigens (normal cell antigens) Infected cell A virally infected cell will express pieces of the pathogen on its surface to alter the immune system that it as a problem The response of the body to autoantigens is involved in autoimmune diseases. After phagocytosis, macrophages and dendritic use exogenous antigens from a phagocytized particle to warn other immune. This is called antigen presentation. The adaptive immune response is mediated by two types of lymphocytes Fragments of the destroyed pathogen are presented on the surface of the cell by a receptor. This is important for the activation of T lymphocytes. Antibody mediated response Make antibodies that neutralize pathogens such as bacteria and viruses. askabiologist.asu.edu Cell mediated response T can kill virally infected and tumors. Both T and B have specialized receptors that facilitate their ability to mount a specific immune response. 3

4 The antibody-mediated immune response is regulated by B lymphocytes (B cell) SEM of a B cell The B cell receptor (BCR) is unique to the B cell and important for its function BCR is an immunoglobulin B are found in the spleen, lymph nodes, and in MALT, some in blood The BCR of any particular B cell is unique (~500,000 receptors per cell) Major function is to secrete antibodies which have multiple roles neutralizing foreign particles. Each B cell can only recognize one specific epitope of an antigen Genes for BCR randomly recombine to make variability Covered with specialized B cell receptors BCR: B cell receptor Antigen The B cell receptor is an immunoglobulin and is made up of light chains and heavy chains Epitope Heavy chain Variable region Antigenbinding sites Light chain Antigen binding site Light chain Variable region Disulfide bonds hold polypeptide chains together in a Y shape Heavy chain Cytoplasmic membrane of B lymphocyte Transmembrane domain anchor The variable region is unique to a single B cell. It is specific to an epitope on an antigen of a foreign particle. Cytoplasm B- produce antibodies when activated Each of us has billions of B, each with a unique variable region. Antibodies are also immunoglobulins like the BCR B become activated by reacting with the epitopes of antigens through their unique BCR B can also be activated by Helper T Arm (Fab) Light chain Antigen-binding sites Variable region of heavy chain The B cell undergoes mitosis to make clones of itself Variable region of light chain The clones will synthesize antibodies that have the same variable Hinge Constant region of light chain region as the the original cell s BCR Constant region of heavy chain Stem (Fc) A B cell that is actively making and secreting antibodies is called a plasma cell Heavy chains The antibodies recognize the same epitope as the BCR and can coat an invading pathogen or toxin 4

5 Figure 16.6 Five functions of antibodies. Adhesin Bacterium proteins Function of antibodies Antibodies can have 5 types of antibody stems (Fc) Most common and long lasting, can enter extracellular spaces First made, activates complement Toxin Virus Neutralization Agglutination of multiple antigens and pathogens NK lymphocyte Pseudopod of phagocyte F c receptor protein Opsonization F c receptor protein Perforin allows granzyme to enter, triggers apoptosis and lysis Antibody-dependent cellular cytotoxicity (ADCC): activates NK that lyse invader with perforin Bacteria die Oxidation by antibodies Found in body secretions Act against parasites Act like BCRs The class IgM is the first class of antibody made by an activated B cell. As antibodies continue to be made, the B cell switches to class IgG (class switching) IgG is much more specific to the epitope, and is more efficient in neutralizing an infection. If you have a new infection, you will have IgM antibodies in your blood serum. For past infections, you will have IgG antibodies Memory B are produced by some of the B cell clones The other component of adaptive immune is the cell mediated adaptive immunity, regulated by T Some of the B cell clones do not participate in the immune response, they become memory Memory B do not produce antibodies Persist in lymph (20+ years), retaining the memory of the epitope of the pathogen in their BCR Vaccination activates your B-, and you are protected from additional infection because memory B allow for the immune system to respond quickly T lymphocyte T act directly against virally infected and abnormal body Mature in thymus Found in lymph nodes, spleen, Peyer s patches Have a T cell receptor (TCR), that similar to the BCR, are incredibly variable 5

6 To understand how T function, we must also know how the body senses self MHC have two classes that are used to signal information to the immune system. One of the first people to receive a hand transplant stopped taking his anti-immune system drugs and his body rejected the hand. MHC molecules are found on the cell membrane of and are used to communicate to the immune system. How does this happen? MHC Class I is on every cell: it expresses a normal antigen to T that will identifies the cell as self bioethicsbytes.wordpress.com T can detect antigens on other that indicate that the cell belongs in the body These antigens (they are glycoproteins found on the surface of ) are called the Major Histocompatibility Complex (MHC) These MHCs are found on all except red blood Class I MHC Figure The processing of T-dependent endogenous antigens. expresses endogenous antigens which may be virus particles or the cell s own normal proteins 1 Polypeptide is catabolized. protein in membrane of endoplasmic reticulum The type of antigen expressed on a Class I MHC is endogenous Endogenous (means from inside ) Polypeptides from cell are broken down into 8-12 amino acid Epitopes protein epitope complex subunits and loaded on antigen-binding grove of These are usually normal subunits (telling immune that Lumen of endoplasmic reticulum 2 Epitopes are loaded onto complementary proteins in the ER. they are okay ) 3 Golgi bodies package protein epitope complexes into vesicles. They can also be from invading pathogens, including viruses or bacteria (telling immune that they are not okay ) 4 Vesicles fuse with cytoplasmic membrane. Expressing an abnormal, endogenous antigen is how a cell The antigens on will be used to signal a T cell that the cell is okay or not okay can alert immune system that it is infected with a virus protein epitope complexes on cell surface Cytoplasmic membrane 5 protein epitope complexes are displayed on cytoplasmic membranes of all nucleated. The second type of MHC is only found on certain types of immune Figure The processing of T-dependent exogenous antigens. Phagocytosis by APC Exogenous pathogen with antigens MHC Class II is on B and antigenpresenting : hold exogenous antigens from destroyed pathogens to alert T cell to a problem I protein epitope complex 1 I protein in membrane of vesicle Epitopes in phagolysosome 2 Vesicles fuse and epitopes bind to complementary I molecules. 3 Vesicle fuses with cytoplasmic membrane. I expresses exogenous from APCs, signaling T that there is a problem Class I MHC All Class II MHC I protein epitope complexes on cell surface Cytoplasmic membrane Some immune 4 I protein epitope complexes are displayed on cytoplasmic membranes of antigenpresenting cell. 6

7 The type of antigen expressed on a MHC Class II is exogenous Exogenous (means from outside ) A phagocytic cell (macrophage, dendritic ) destroys a pathogen and loads subunits from pathogen onto antigenbinding groove of I The phagocytic cell will then use this exogenous particle to alert T to a particular pathogen When phagocytic used the I to present an exogenous antigen to another immune cell, they are referred to as antigen presenting Dendritic are a type of antigen presenting (APCs) found near surface of skin. They will phagocytose invaders, then travel to lymph to communicate with lymphocytes. They will express an exogenous antigen on the I to tell the lymphocytes to mount a response against that specific invader. The T cell receptor (TCR) interacts with the MHCs to screen for potentially infected All T have a T cell receptor (TCR) T can only be activated when they interact with antigens on the MHC of another cell, they cannot bind antigens independently like B TCRs can only bind to antigens associated with a major histocompatibility complex (MHC) Helper T cell (CD4) exogenous antigen I TCRs primarily act against infected There are 10 9 different TCRs and a single T cell only has one type T cell receptor (TCR) Cytotoxic T cell (CD8) endogenous antigen MHC class II (found on Antigen presenting immune ) T cell receptor (TCR) MHC class I (found on all ) All T have TCRs, but have different functions due to the presence of additional glycoproteins on the cell surface Cytotoxic T (have glycoprotein CD8+) Respond to infected that are expressing foreign endogenous antigen on ; they will kill infected and cancerous Helper T (have glycoprotein CD4+) Respond to antigen-presenting that are expressing exogenous antigens processed from an invader Help regulate B and cytotoxic T Type 1 (Th1) help activate cytotoxic T and innate immunity (macrophages, neutrophils, etc.) Type 2 (Th2) help activate B Regulatory T (have glycoproteins CD4+, CD25+) Involved in prevention of autoimmune disease by policing B and T Cytotoxic T (Tc) are a very important subset of T Destroy cancer or that are infected with viruses APCs activate them by expressing a viral or cancerous antigen on the MHC class I They kill by secreting enzymes or making the cell undergo apoptosis (apoptosis = cell suicide) A single Cytotoxic T cell can kill many target These are NOT Natural Killer (which are nonspecific and typically function by secreting toxins) 7

8 After the Tc cell engages the infected cell, it will secrete two enzymes into the cell (perforin and granzyme), that will force the cell into apoptosis (cell suicide) Tc cell Perforin Activated Tc can also force the cell into apoptosis by the activation of a second receptor, CD95 Apoptosis = programmed cell death Tc cell Granzyme Perforin Granzyme Tc cell CD95L Perforin complex (pore) Inactive apoptotic enzymes Granzymes activate apoptotic enzymes Active enzymes induce apoptosis Virally infected cell With this incredible power to kill other, cytotoxic T- must be carefully regulated in your body Perforin complex (pore) Inactive apoptotic enzymes Virally infected cell Active enzymes induce apoptosis CD95 Inactive apoptotic enzymes Active enzymes induce apoptosis Virally infected cell How does AIDS affect the immune system? To be activated, Tc must have the proper activation Attachment factor (GP120) is used to bind and gain access to Helper T (CD4+ ; some macrophages and dendritic also have CD4+) signal ( or II) Helper T (CD4+), must also be activated, which HIV harms immune system by destroying these, and also turning the other immune against infected secrete cytokines to further activate the Tc Multiple sclerosis, an autoimmune disease, is caused by Tc attacking the myelin sheath that insulates brain and Person with AIDS loses cell mediated immunity and they are prone to increased infections and cancer spinal cord neurons Granzymes activate apoptotic enzymes So how do all of these work together? Ex: antibody-mediated response (humoral immunity) Immune system recap These interactions are occurring in the lymph organs (usually the lymph nodes). Once a T cell is activated, it makes clones of itself and also produces memory T 8

9 Leukocyte review Recap: are found on all, and I are found on only certain immune All in body Macrophage, dendritic cell, others I is like a hall pass. The cell is showing the immune system that it is either okay or not okay Immune have to prove that they are okay too through the I is a flag to alert other in the immune system that the macrophage has encountered an invader Some T act like hall monitors, checking to make sure the other belong in the body TCRs can only bind to antigens associated with a major histocompatibility complex (MHC) Different classes of T interact with either (cytotoxic T ) or I (helper T ) due to other glycoproteins found in association with their TCR All in body TCR T cell T interact with MHCs and check to determine if they are okay or infected. All in body CD8 TCR T cell Cytotoxic T (Tc)= kill infected Macrophage, dendritic cell, others I TCR T cell Immune that have phagocytized a pathogen can flag down a T cell with their I to activate a more profound immune response. Macrophage, dendritic cell, others I CD4 TCR T cell Helper T = help activated Tc and B 9