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2 CONCEPT: OVERVIEW OF HOST DEFENSES The human body contains three lines of against infectious agents (pathogens) 1. Mechanical and chemical boundaries (part of the innate immune system) - Includes, chemicals on body surface or inside the body which target infectious agents 2. Innate immune system components including: - Phagocytic cells (white blood cells, macrophages) which take up - Complement system that includes proteins that bind directly to pathogens for destruction - Inflammation of infected tissues 3. Adaptive immune system components including: - B cells which produce antibodies (antibody response) - T cells which can act to kill other infected cells, or the pathogen itself (T cell response) The innate immune response is more than the adaptive immune response - Typically, the innate immune response activates the adaptive immune response Page 2

3 PRACTICE: 1. True or False: The adaptive immune response is the first immune response a host initiates against a pathogen. a. True b. False 2. Which of the following immune system components are not a part of the innate immune system? a. B cells b. Phagocytic Cells c. Complement system d. Inflammatory cytokines Page 3

4 CONCEPT: INNATE IMMUNE RESPONSE There are three components to an immune response 1. Chemical and physical barriers - Examples include: the skin, acidic ph, mucus enzymes 2. Cell-intrinsic responses - These responses are done by a single cell to stop a pathogen that has infected the cell 3. Phagocytic cells - Recognize pathogens around the body and activate in order to destroy the pathogen After an infection many components of the innate immune system Pathogen-associated molecular patterns (PAMPs) are pathogenic sequences that the host cell can recognize - Pattern recognize receptors on the surface of cells recognize and bind PAMPs on the pathogen. - An example is the toll-like receptor (TLR) which triggers the innate immune response - Once bound it can stimulate the cell to kill it or to activate other cells, or the adaptive immune system Page 4

5 Complement system consists of a collection of 20 proteins that circulate in the blood - After an infection they become activated, and can help get rid of the pathogen. Phagocytic cells find, engulf, and destroy the Natural killer (NK) cells cause an infected cell to undergo apoptosis, killing itself and the pathogen Page 5

6 Inflammation results in pain, heat, swelling at the infectious site Dendritic cells have TLRs and can bind to pathogen and activate the adaptive immune system Page 6

7 PRACTICE: 1. Which of the following is not an innate immune response? a. The skin barrier b. Phagocytic cells c. Complement system d. Antibody production 2. What is the name of the pathogenic sequence that a host cell recognizes as foreign? a. Pattern recognition receptors b. PAMPs c. Toll-like receptors d. Complement sequences Page 7

8 CONCEPT: B CELL DEVELOPMENT B cells are antibody producing cells They are, and produce only one type of antibody - Further, this antibody is targeted towards one antigen, which is a specific pathogenic sequence B cells shouldn t produce antibodies against the host - Self-tolerance is the ability of an animal s immune system to not respond to its own cells - Autoimmune diseases arise when the immune system begins attacking itself Vaccination works by B cells - Primary immune response is a smaller immune response that occurs during the first exposure (vaccine) - Secondary immune response is a much larger immune response during the second exposure First Exposure Second Exposure The clonal selection theory explains the maturation of B cells This theory states that the body creates many B cells targeting many pathogens, but activates and amplifies only the B cells that can respond to the pathogens the body actually encounters Page 8

9 1. B cells produce one antibody type in absence of antigen exposure (naïve cells) 2. The body is exposed to a pathogen 3. The B cell that can respond to that pathogen becomes activated (effector cells), and begins proliferating 4. The B cell produces lots of antibody against that pathogen, eventually destroying it 5. A few of these B cells become memory cells and are stored incase of second exposure Page 9

10 PRACTICE: 1. True or False: Each B cell produces only one antibody which targets only one pathogen. a. True b. False 2. A B cell that becomes activated in response to a pathogen is called what? a. Naïve B cell b. Effector B cell c. Memory B cell d. Activated B cell Page 10

11 3. Which immune response is stronger? a. Primary immune response b. Secondary immune response c. Tertiary immune response d. Self-tolerate immune response Page 11

12 CONCEPT: ANTIBODY STRUCTURE AND VARIETY Antibody Structure Antibodies, also called immunoglobulins, are proteins secreted by B cells to pathogens for destruction Antibodies have a characteristic Y shape - Has two light chains, and two heavy chains - Both light and heavy chains interact to form the antigen binding surface Activated B cells secrete around 5000 antibodies per second - Each B cell produces only one type of antibody There are five classes of antibodies based upon different heavy chains Antibody Location Function IgM Plasma Membrane Present before activation IgD Plasma Membrane Can respond initially to antigens IgA Secreted Tears, saliva, milk, intestinal secretions IgE Secreted Blood; allergic reactions IgG Secreted Blood; Can be passed to fetus (bind Fc receptors) There are two types of light chains (k are l) and they are virtually indistinguishable Page 12

13 Antibodies bind antigens in their antigen binding Affinity (strength) of bond depends on collection of non-covalent bonds in light and heavy chains The light and heavy chains have two regions - Constant regions is around ~110 amino acids long, and remains constant in the same class of antibody - Variable regions are around ~110 amino acids long, and vary between each B cell - Hypervariable regions are three 5-10 aa long locations of the variable region the antigen binds Antibody Variety V (D) J recombination is responsible for forming the hypervariable regions Cells use special gene to produce antibodies against as many antigens as possible The antibody genes contain three main segments, and each is encoded in a different genomic location - V gene segment encodes for light chain variable regions - J gene segment encodes for light chain variable regions - D gene segment encodes for heavy chain variable regions Organisms have multiple V, J, and D regions which are recombined to form new antigen binding sites - Humans have 50 V segments, 5 J segment, and 35 D segments ~ 1.9 x 10 6 antigen binding sites Page 13

14 Variation also arises in other Somatic hypermutation occurs at the variable gene segments - B cells mutated the variable region segments about once per division - Some will have increased antigen affinity All B cells undergo class switching during development - B cells first only produce IgM or IgD (Primary antibody repertoire) - Somatic hypermutation will trigger the B cell to produce IgE, IgA, or IgG (Secondary antibody repertoire) Page 14

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16 PRACTICE: 1. Which of the following processes allows for the creation of so many diverse antibodies? a. V(D)J recombination b. V(J) recombination c. Class switching d. Constant regions 2. Which of the following antibodies is secreted into the blood for an allergic reaction? a. IgM b. IgD c. IgA d. IgE e. IgG Page 16

17 3. Which of the following variable gene segments encodes for the variable sequence on the heavy chain? a. V b. D c. J d. M Page 17

18 CONCEPT: T CELLS T cells are a main immune system cell used to target and kill pathogens Antigen presenting cells (APC) which present antigens to T cells, are required for T cell activation - Ex: Dendritic cells - T cell receptors must directly contact APC with antigen - Also undergo V(D)J recombination to recognize different antigens T cells are in the thymus - Naïve T cells come in contact with APCs with antigens in the thymus - To be activated the T cell must come in contact with: - The antigen - Co-stimulatory molecules - Cell-cell adhesion molecules - If all three do not contact then this will lead to T cell inactivation or death Page 18

19 There are three of T cells Cytotoxic T cells (Tc) are responsible for directly killing cells that come in contact with an intracellular pathogen - Recognize antigen presented on surface of infected cells (binds via T cell receptor) - Induces the infected cell to kill itself - Perfornin: forms pores or Fas ligand: stimulates apoptosis Helper T cells (Th) are responsible for stimulating the responses of other cells - Activates other cells like B cells, macrophages, dendritic cells - To activate, Th cells release or express co-stimulatory molecules to support activation Regulatory T cells are responsible for suppressing the activity of other T cells - Suppresses activity of other cells and self-reactivity of other cells Page 19

20 There are two very important accessory molecules that all T cells contain CD8 is found on cytotoxic T cells - Binds to Class I MHC molecules CD4 is found on helper T and regulatory T cells - Binds to Class II MHC molecules These accessory receptors are requires to stabilize the binding and activation of T cells Page 20

21 PRACTICE: 1. Cytotoxic T cells are responsible for which of the following responses? a. Suppressing other T cells b. Activating B cells c. Killing other infected cells d. Activating antigen presenting cells 2. Which of the following cell types is responsible for suppressing the activity of T cells? a. Antigen presenting cells b. Cytotoxic T cells c. Helper T cells d. Regulatory T cells Page 21

22 3. CD4 molecules are found on which of the following cell types? a. Antigen presenting cells b. Cytotoxic T cells c. Helper T cells d. Regulatory T cells Page 22

23 CONCEPT: MHC AND ANTIGEN PRESENTATION Class I Class I major histocompatibility complex (MHC) bind to antigens and activate Tc cells Structure consists of a single polypeptide chain with a non-mhc peptide (b2-microglobulin) - Single peptide binding site that fits 8-10 amino acids (binds peptide ends) Uses 6 steps to present antigens 1. Intracellular pathogen is present in cytosol (from infected cell, or cell expressing viral genes) 2. Pathogen is targeted for destruction by ubiquitin 3. The pathogen is degraded via the proteasome 4. The antigen is transported into the ER (via the TAP complex) 5. In the ER the antigen binds to the MHC class I molecule 6. The MHC-antigen complex is expressed on the plasma membrane Patogen Proteasome Destruction nucleus Endoplasmic Reticulum MHC class I Page 23

24 Class II Class II major histocompatibility complex (MHC) bind to antigens and activate Th cells and T regulatory cells Structure consists of a heterodimer encoded by MHC genes - Single peptide binding site that fits amino acids (binds entire peptide length) Uses 6 steps to present antigens 1. Extracellular pathogen is taken up by the cell 2. The pathogen is moved to the lysosome for destruction 3. The pathogen is degraded into tiny antigens 4. The MHC class II molecule is made in the ER and complex with a small protein called Li 5. The MHC class II enters the lysosome and Li is cleaved to leave small molecule called CLIP 6. CLIP is replaced with the antigen in the lysosome 7. The MHC-antigen complex is moved to the cell surface. Pathogen nucleus MHC Class II +Li Lysosomal Destruction MHC +CLIP Endoplasmic Reticulum Page 24

25 PRACTICE: 1. Which MHC class presents intracellular pathogens? a. MHC class I b. MHC class II 2. MHC class I is used to activate which of the following cell types? a. Antigen presenting cells b. Cytotoxic T cells c. Helper T cells d. Regulatory T cells Page 25

26 CONCEPT: IMMUNE SYSTEM COLLABORATION The innate immune system responds to a pathogen Toll Like Receptors (TLRs) recognize pathogens - Causes WBCs to take up pathogen, and begin breaking it apart, and presenting it via MHC molecules Dendritic cells are antigen presenting cells (innate immune system) that antigens to Th cells - Th cells then secrete inflammatory molecules (cytokines) which increase: - Numbers of WBC - Migration of WBC into infection site - Increase cell-adhesion molecules so WBC can attach to infection site - Th cells can also activate cells - Th1 cells activate macrophages and Tc cells to kill internalized pathogens - Th2 cells activate B cells to secrete antibodies to target extracellular pathogens Page 26

27 PRACTICE: 1. Choose the following with the proper order of immune system activation. a. B cell T cell Dendritic cell infection b. Infection T cell Dendritic cell B cell c. Infection dendritic cell T cell B cell d. Infection B cell dendritic cell T cell Page 27