immune_physiology_lfc (2).ppt

1 IMMUNE SYSTEM Dr. Samantha Solecki, DC, MS Instructor, Biology Thinker. Learner. Motivator. Lover of Anatomy & Physiology [email protected] © 2019 Pearson Education...

1 IMMUNE SYSTEM Dr. Samantha Solecki, DC, MS Instructor, Biology Thinker. Learner. Motivator. Lover of Anatomy & Physiology [email protected] © 2019 Pearson Education, Inc.  2 Learning Objectives *Acquired from the Human Anatomy and Physiology Society (HAPS) with personal additions Compare and contrast innate (nonspecific) defenses with adaptive (specific) defenses. Define immunity and the immune system. Describe the roles of various types of leukocytes in innate and adaptive body defenses. Analyze ways in which the innate and adaptive body defenses cooperate to enhance the overall resistance to disease. Name the surface membrane barriers and describe their physical, chemical and microbiological mechanisms of defense Define diapedesis, chemotaxis, opsonization, and membrane attack attack complex and explain their importance for innate defenses. Describe the steps involved in phagocytosis and provide examples of important phagocytic cells in the body. Describe natural killer cells and discuss their function. Explain how complement and interferon function as antimicrobial chemicals. Explain the role of pattern-recognition receptors in innate defenses. With respect to the inflammatory response: Describe the mechanisms of inflammation initiation. Summarize the cells and chemicals involved in the inflammatory process. List and explain the cause of the four cardinal signs of inflammation. Explain why inflammation can be beneficial. With respect to fever: Describe the mechanism of fever and the role of pyrogens. Explain why fever can be beneficial.  3 Learning Objectives *Acquired from the Human Anatomy and Physiology Society (HAPS) with personal additions Distinguish between humoral and cell-mediated immunity. Describe the immunological memory response. Define antigen and antigen receptor. Distinguish among complete antigens, haptens, antigenic determinants and self- antigens. With respect to major histocompatibility complex (MHC): Define MHC. Describe where class I and class II MHC and MHC proteins are found. Explain the function of class I and class II MHC in adaptive immunity. Discuss the source of antigen receptor diversity. Explain the role of antigen-presenting cells (APCs) and provide examples of cells that function as APCs. Distinguish among the various types of lymphocytes, including helper T cells, cytotoxic T cells, regulatory (suppressor) T cells, B cells, plasma cells and memory cells. With respect to B cells and T cells: Define immunocompetence and self tolerance and distinguish between naïve and activated immune cells. Compare and contrast the sites where the cells originate and achieve their immunocompetence, and the primary location of the immunocompetent cells in the body. Compare and contrast the mechanisms of antigen challenge and the clonal selection processes, including effector cells, helper cells, memory cells and important cytokines. Compare and contrast the defense mechanisms and functions. Describe the contribution of clonal deletion to immunity.  4 Learning Objectives *Acquired from the Human Anatomy and Physiology Society (HAPS) with personal additions Describe antibody structure. Describe mechanisms of antibody action and correlate mechanisms with effector functions. List the five classes of antibodies and discuss structural and functional features that distinguish each class. Interpret a graph of the primary and secondary immune response, in terms of the relative concentrations of different classes of antibodies produced over time. Distinguish between active and passive immunity. Describe natural and artificial examples of both active and passive immunity. Provide examples of how applied immunology can be used to diagnose, treat and prevent diseases. Predict factors or situations affecting the lymphatic and immune systems that could disrupt homeostasis. Predict the types of problems that would occur in the body if the lymphatic and immune systems could not maintain homeostasis. Predict the types of problems that would occur in the body if the lymphatic and immune systems could not maintain homeostasis.  5 Learning Objectives for Immune System Compare mechanisms of nonspecific immunity Cells of nonspecific immunity Complement Interferons Inflammatory response. Compare systemic and local inflammation Cell Mediated Immune Response Cells of specific immunity Compare types of T lymphocytes by activation and function. Correlate major histocompatibility complexes to antigen presentation. Humoral Immune Response Examine structure and functions of antibodies. Classify antibodies by location and function. Compare primary and secondary immune responses. Identify the various clinical immune disorders, such as: Organ transplants, Immunodeficiencies, Hodgkin’s Disease, AIDS, Autoimmunity Hypersensitivities  6 Immunity Resistance to disease Immune system Serves to protect host against disease! Functional system rather than organ system Two intrinsic systems, closely intertwined: Innate (nonspecific) defense system Adaptive (specific) defense system Innate responses release proteins that alert cells of adaptive system to foreign molecules  7 Immunity Innate defense system has two lines of defense 1. First - external body membranes (skin and mucosae) 2. Second - antimicrobial proteins, phagocytes, and other cells Inhibit spread of invaders Stimulate/Promote Inflammation (most important mechanism) Adaptive defense system Third line of defense attacks particular foreign substances Takes longer to react than innate system Figure 21.1 Overview of innate and adaptive defenses. 8 Surface barriers Skin Mucous membranes Innate defenses Internal defenses Phagocytes Natural killer cells Inflammation Antimicrobial proteins Fever Humoral immunity B cells Adaptive defenses Cellular immunity T cells  9 INNATE DEFENSES  10 Innate Defenses Surface barriers ward off invading pathogens Skin, mucous membranes, and their secretions Physical barrier to most microorganisms Keratin resistant to weak acids and bases, bacterial enzymes, and toxins Mucosae provide similar mechanical barriers  11 1 Surface Barriers Protective chemicals inhibit or destroy microorganisms Acidity of skin and secretions – acid mantle – inhibits growth Enzymes - lysozyme of saliva, respiratory mucus, and lacrimal fluid – kill many microorganisms Defensins – antimicrobial peptides – inhibit growth Other chemicals - lipids in sebum, dermcidin in sweat – toxic Respiratory system modifications Mucus-coated hairs in nose Cilia of upper respiratory tract sweep dust- and bacteria-laden mucus toward mouth Surface barriers breached by nicks or cuts - second line of defense must protect deeper tissues  12 2 Internal Defenses: Cells and Chemicals Necessary if microorganisms invade deeper tissues Phagocytes Natural killer (NK) cells Antimicrobial proteins (interferons and complement proteins) Fever Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals)  13 Phagocytes Neutrophils Become phagocytic on exposure to infectious material Macrophages Develop from monocytes – chief phagocytic cells – Free macrophages wander through tissue spaces Fixed macrophages permanent residents of some organs  14 Mechanism of Phagocytosis Phagocyte must adhere to particle Some microorganisms evade adherence with capsule Opsonization marks pathogens—coating by complement proteins or antibodies Cytoplasmic extensions bind to and engulf particle in vesicle called phagosome Phagosome fuses with lysosome  phagolysosome Figure 21.2a Phagocytosis. 15 Innate defenses Internal defenses A macrophage (purple) uses its cytoplasmic extensions to pull rod-shaped bacteria (green) toward it. Scanning electron micrograph (4800x). Figure 21.2b Phagocytosis. 16 1 Phagocyte adheres to pathogens or debris. 2 Phagocyte forms pseudopods that Phagosome eventually engulf the (phagocytic particles, forming a vesicle) phagosome. Lysosome 3 Lysosome fuses with the phagocytic vesicle, forming a phagolysosome. Acid hydrolase enzymes 4 Lysosomal enzymes digest the particles, leaving a residual body. 5 Exocytosis of the vesicle removes indigestible and residual material. Events of phagocytosis.  17 Mechanism of Phagocytosis Pathogens killed by acidifying and digesting with lysosomal enzymes Helper T cells (Th) cause release of enzymes of respiratory burst, which kill pathogens resistant to lysosomal enzymes by Releasing cell-killing free radicals Producing oxidizing chemicals (e.g., H2O2) Increasing pH and osmolarity of phagolysosome Defensins (in neutrophils) pierce membrane  18 Natural Killer (NK) Cells Nonphagocytic large granular lymphocytes Attack cells that lack "self" cell-surface receptors Induce apoptosis in cancer cells and virus-infected cells Secrete potent chemicals that enhance inflammatory response  19 Review... 1. List the cells of the innate immune system. 2. Identify the difference between the innate and adaptive immune systems. 3. Explain what is meant by “first line of defense” and “second line of defense.”  20 Inflammatory Response Begins with chemicals released into ECF by injured tissues, immune cells, blood proteins Macrophages and epithelial cells bear specialized receptors (Toll-like receptors (TLRs)) 11 types of TLRs recognize specific classes of infecting microbes Activated TLRs trigger release of cytokines that promote inflammation  21 Inflammatory Response Triggered whenever body tissues injured 1. Prevents spread of damaging agents 2. Disposes of cell debris and pathogens 3. Alerts adaptive immune system 4. Sets the stage for repair  22 Inflammatory Response Cardinal signs of acute inflammation: 1. Redness (Rubor) 2. Heat (Calor) 3. Swelling (Tumor) 4. Pain (Dolor) 5. Impairment of function (Functio laesa)  23 Inflammatory Response Inflammatory mediators 1Kinins, 2prostaglandins (PGs), and 3complement Dilate local arterioles (hyperemia) Causes redness and heat of inflamed region Make capillaries leaky Many attract leukocytes to area Figure 21.3 Inflammation: flowchart of events. 24 Innate defenses Internal defenses Initial stimulus Physiological response Signs of inflammation Tissue injury Result Release of inflammatory chemicals Release of leukocytosis- (histamine, complement, inducing factor kinins, prostaglandins, etc.) Leukocytosis (increased numbers of white blood cells in bloodstream) Arterioles Increased capillary Attract neutrophils, dilate permeability monocytes, and lymphocytes to Leukocytes migrate to area (chemotaxis) injured area Local hyperemia Capillaries (increased blood leak fluid Margination flow to area) (exudate formation) (leukocytes cling to capillary walls) Diapedesis Leaked protein-rich Leaked clotting (leukocytes pass through fluid in tissue spaces proteins form interstitial capillary walls) clots that wall off area to prevent injury to surrounding tissue Phagocytosis of pathogens Heat Redness Pain Swelling and dead tissue cells (by neutrophils, short-term; by macrophages, long-term) Locally increased Possible temporary Temporary fibrin Pus may form temperature increases impairment of patch forms metabolic rate of cells function scaffolding for repair Area cleared of debris Healing Figure 21.4 Phagocyte mobilization. 25 Innate defenses Internal defenses Inflammatory chemicals diffusing 4 Chemotaxis. from the Neutrophils follow inflamed chemical trail. site act as chemotactic Capillary wall agents. Basement membrane Endothelium 1 Leukocytosis. 2 Margination. 3 Diapedesis. Neutrophils enter Neutrophils cling Neutrophils flatten blood from bone to capillary wall. and squeeze out of marrow. capillaries.  26 Antimicrobial Proteins Include 1interferons and 2complement proteins Some attack microorganisms directly Some hinder microorganisms' ability to reproduce  27 1 Interferons Family of immune modulating proteins Viral-infected cells secrete IFNs (e.g., IFN alpha and beta) to "warn" neighboring cells IFNs enter neighboring cells  produce proteins that block viral reproduction and degrade viral genetic components IFN alpha and beta also activate NK cells Figure 21.5 The interferon mechanism against viruses. 28 Innate defenses Internal defenses Virus Viral nucleic acid 1 Virus New viruses enters cell. 5 Antiviral proteins block viral reproduction. Antiviral 2 Interferon mRNA genes switch DNA on. Nucleus mRNA for interferon 4 Interferon binding stimulates cell to 3 Cell turn on genes for produces Interferon antiviral proteins. interferon receptor molecules. Interferon Host cell 2 Host cell 1 Binds interferon Infected by virus; from cell 1; interferon makes interferon; induces synthesis of is killed by virus protective proteins  29 2 Complement System (Complement) Serves as a major mechanism for destroying foreign substances Unleashes inflammatory chemicals that amplify all aspects of inflammatory response Kills bacteria and certain other cell types by cell lysis Enhances both innate and adaptive defenses Blood proteins (20) that circulate in inactive form Include C1–C9, factors B, D, and P, and regulatory proteins Our cells contain complement activation inhibitors  30 Complement Activation Three pathways to activation Classical pathway Antibodies bind to invading organisms and to complement components Called complement fixation First step in activation Lectin pathway Lectins - produced by innate system to recognize foreign invaders When bound to foreign invaders can also bind and activate complement Alternative pathway Activated spontaneously, lack of inhibitors on microorganism's surface allows process to proceed  31 Complement Activation Each pathway activates proteins in an orderly sequence Each step catalyzes the next Each pathway converges on C3, which cleaves into C3a and C3b Common terminal pathway: 1. Enhances inflammation, 2. Promotes phagocytosis, 3. Propagates cell lysis Figure 21.6 Complement activation. 32 Classical pathway Lectin pathway Alternative pathway Activated by antibodies Activated by lectins Activated spontaneously. Lack of coating target cell binding to specific sugars inhibitors on microorganism’s on microorganism’s surface surface allows process to proceed Together with other complement proteins and factors C3 C3a C3b C3b Opsonization: Enhances inflammation: C5b C5a Stimulates histamine Coats pathogen surfaces, which release, increases blood MAC C6 enhances phagocytosis vessel permeability, C7 attracts phagocytes by C8 chemotaxis, etc. C9 MACs form from activated complement components (C5b and C6–C9) that insert into the target cell membrane, creating pores that can lyse the target cell. Pore Complement proteins (C5b–C9) Membrane of target cell  33 Fever Abnormally high body temperature Response to invading microorganisms Leukocytes and macrophages exposed to foreign substances secrete pyrogens  act on body's thermostat in hypothalamus (central control), raising body temperature Benefits of moderate fever Causes liver and spleen to sequester iron and zinc (needed by microorganisms) Increases metabolic rate  faster repair  34 Review... 1. What is complement? 2. List the three terminal “fates”/goals of the complement system. 3. What is the significance of fever? How is a fever beneficial?  35 ADAPTIVE DEFENSES  36 Adaptive Defenses Adaptive immune (specific defense) system 1. Protects against infectious agents and abnormal body cells 2. Amplifies inflammatory response 3. Activates complement 4. Must be primed by initial exposure to specific foreign substance Priming takes time  37 Adaptive Defenses Specific – recognizes and targets specific antigens Systemic – not restricted to initial site Have memory – stronger attacks to "known" antigens Two separate, overlapping arms 1. Humoral (antibody-mediated) immunity 2. Cellular (cell-mediated) immunity  38 1 Humoral Immunity Antibodies, produced by lymphocytes (plasma cells), circulating freely in body fluids Bind temporarily to target cell Temporarily inactivate Mark for destruction by phagocytes or complement Humoral immunity has extracellular targets  39 2 Cellular Immunity Lymphocytes act against target cell Directly – by killing infected cells Indirectly – by releasing chemicals that enhance inflammatory response; or activating other lymphocytes or macrophages Cellular immunity has cellular targets  40 Antigens Substances that can mobilize adaptive defenses and provoke an immune response Targets of all adaptive immune responses Most are large, complex molecules not normally found in body (nonself)  41 Complete Antigens Important functional properties: Immunogenicity: ability to stimulate proliferation of specific lymphocytes Reactivity: ability to react with activated lymphocytes and antibodies released by immunogenic reactions Examples: foreign protein, polysaccharides, lipids, and nucleic acids  42 Haptens (Incomplete Antigens) Small molecules (haptens) not immunogenic by themselves E.g., peptides, nucleotides, some hormones May be immunogenic if attached to body proteins and combination is marked foreign Examples: poison ivy, animal dander, detergents, and cosmetics  43 Antigenic Determinants Only certain parts (antigenic determinants) of entire antigen are immunogenic Antibodies and lymphocyte receptors bind to them Most naturally occurring antigens have numerous antigenic determinants that Mobilize several different lymphocyte populations Form different kinds of antibodies against them Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity Figure 21.7 Most antigens have several different antigenic determinants. 44 Antigen- Antigenic determinants binding sites Antibody A Antigen Antibody B Antibody C  45 Self-antigens: MHC Proteins Protein molecules (self-antigens) on surface of cells not antigenic to self but antigenic to others in transfusions or grafts Example: MHC glycoproteins Coded by genes of major histocompatibility complex (MHC) and unique to individual Have groove holding self- or foreign antigen T lymphocytes can only recognize antigens that are presented on MHC proteins  46 Cells of the Adaptive Immune System Three types of cells Two types of lymphocytes B lymphocytes (B cells)—humoral immunity T lymphocytes (T cells)—cellular immunity Antigen-presenting cells (APCs) Do not respond to specific antigens Plays a role in immunity  47 Lymphocyte Development, Maturation, and Activation Five general steps Origin – all originate in red bone marrow Maturation Seeding secondary lymphoid organs and circulation Antigen encounter and activation Proliferation and differentiation Figure 21.8 Lymphocyte development, maturation, and activation. 48 Humoral immunity Primary lymphoid organs Adaptive defenses (red bone marrow and thymus) Cellular immunity Secondary lymphoid organs (lymph nodes, spleen, etc.) Red bone marrow 1 Origin Both B and T lymphocyte precursors originate in red bone marrow. Lymphocyte precursors 2 Maturation Lymphocyte precursors destined to become T cells migrate (in blood) to the thymus and mature there. B cells mature in the bone marrow. During maturation lymphocytes develop immunocompetence Thymus and self-tolerance. Red bone marrow 3 Seeding secondary lymphoid organs and circulation Immunocompetent but still naive lymphocytes leave the thymus and bone marrow. They “seed” the secondary lymphoid organs and circulate through blood and lymph. Antigen 4 Antigen encounter and activation Lymph node When a lymphocyte’s antigen receptors bind its antigen, that lymphocyte can be activated. 5 Proliferation and differentiation Activated lymphocytes proliferate (multiply) and then differentiate into effector cells and memory cells. Memory cells and effector T cells circulate continuously in the blood and lymph and throughout the secondary lymphoid organs.  49 Maturation "Educated" to become mature; B cells in bone marrow, T cells in thymus Immunocompetence – lymphocyte can recognize one specific antigen by binding to it B or T cells display only one unique type of antigen receptor on surface when achieve maturity – bind only one antigen Self-tolerance Lymphocytes unresponsive to own antigens  50 T cells T cells mature in thymus under negative and positive selection pressures ("tests") Positive selection Selects T cells capable of recognizing self-MHC proteins (MHC restriction); failures destroyed by apoptosis Negative selection Prompts apoptosis of T cells that bind to self-antigens displayed by self-MHC Ensures self-tolerance Figure 21.9 T cell education in the thymus. 51 Adaptive defenses Cellular immunity 1. Positive Selection T cells must recognize self major histocompatibility proteins (self-MHC) Antigen- presenting Developing thymic cell T cell Failure to recognize self- MHC results in apoptosis (death by cell suicide). Self-MHC T cell receptor Self-antigen Recognizing self-MHC results in survival. Survivors proceed to negative selection. 2. Negative Selection T cells must not recognize self-antigens Recognizing self-antigen results in apoptosis. This eliminates self-reactive T cells that could cause autoimmune diseases. Failure to recognize (bind tightly to) self-antigen results in survival and continued maturation.  52 B cells B cells mature in red bone marrow Positively selected if successfully make antigen receptors If self-reactive  Eliminated by apoptosis  53 Seeding Secondary Lymphoid Organs and Circulation Immunocompetent B and T cells not yet exposed to antigen called naive Exported from primary lymphoid organs (bone marrow and thymus) to "seed" secondary lymphoid organs (lymph nodes, spleen, etc.) Increases chance of encounter with antigen  54 1 Antigen Encounter and Activation Clonal selection Naive lymphocyte's first encounter with antigen  selected for further development If correct signals present, lymphocyte will complete its differentiation  55 Proliferation and 2 Differentiation Activated lymphocyte proliferates  exact clones Most clones  effector cells that fight infections Few remain as memory cells Able to respond to same antigen more quickly second time B and T memory cells and effector T cells circulate continuously  56 Antigen Receptor Diversity Genes, not antigens, determine which foreign substances immune system will recognize Immune cell receptors result of acquired knowledge of microbes likely in environment Lymphocytes make up to billion different types of antigen receptors  57 Antigen-presenting Cells (APCs) Engulf antigens Present fragments of antigens to T cells for recognition Major types Dendritic cells in connective tissues and epidermis Macrophages in connective tissues and lymphoid organs B cells  58 Activation and Differentiation of B Cells B cell activated when antigens bind to its surface receptors and cross-link them  Receptor-mediated endocytosis of cross-linked antigen-receptor complexes (clonal selection)  Proliferation and differentiation into effector cells  59 Fate of the Clones Most clone cells become plasma cells Secrete specific antibodies at rate of 2000 molecules per second for four to five days, then die Antibodies circulate in blood or lymph Bind to free antigens and mark for destruction by innate or adaptive mechanisms Clone cells that do not become plasma cells become memory cells Provide immunological memory Mount an immediate response to future exposures to same antigen Figure 21.11a Clonal selection of a B cell. 60 Adaptive defenses Humoral immunity Primary response Antigen (initial encounter Antigen binding with antigen) to a receptor on a specific B lymphocyte (B lymphocytes with Proliferation to noncomplementary form a clone receptors remain Activated B cells inactive) Plasma cells Memory B cell— (effector B cells) primed to respond to same antigen Secreted antibody molecules  61 Immunological Memory Primary immune response Cell proliferation and differentiation upon first antigen exposure Lag period: three to six days Peak levels of plasma antibody are reached in 10 days Antibody levels then decline  62 Immunological Memory Secondary immune response Re-exposure to same antigen gives faster, more prolonged, more effective response Sensitized memory cells respond within hours Antibody levels peak in two to three days at much higher levels Antibodies bind with greater affinity Antibody level can remain high for weeks to months Figure 21.11 Clonal selection of a B cell. 63 Adaptive defenses Humoral immunity Primary response Antigen (initial encounter Antigen binding with antigen) to a receptor on a specific B lymphocyte (B lymphocytes with noncomplementary Proliferation to receptors remain form a clone Activated B cells inactive) Plasma cells Memory B cell— (effector B cells) primed to respond to same antigen Secreted antibody molecules Secondary response Clone of cells Subsequent (can be years later) challenge by same identical to antigen results in ancestral cells more rapid response Plasma cells Secreted antibody Memory molecules B cells Figure 21.12 Primary and secondary humoral responses. 64 Secondary immune response to Primary immune antigen A is faster and larger; primary response to antigen immune response to antigen B is A occurs after a delay. similar to that for antigen A. Antibody titer (antibody concentration) 104 in plasma (arbitrary units) 103 102 101 Anti- Anti- Bodies Bodies to A to B 100 0 7 14 21 28 35 42 49 56 First exposure Second exposure to antigen A; to antigen A first exposure to antigen B Time (days)  65 HUMORAL IMMUNITY  66 Active Humoral Immunity When B cells encounter antigens and produce specific antibodies against them Two types of active humoral immunity: Naturally acquired—response to bacterial or viral infection Artificially acquired—response to vaccine of dead or attenuated pathogens  67 Active Humoral Immunity Vaccines Most of dead or attenuated pathogens Spare us symptoms of primary response Provide antigenic determinants that are immunogenic and reactive  68 Passive Humoral Immunity Readymade antibodies introduced into body B cells are not challenged by antigens Immunological memory does not occur Protection ends when antibodies degrade Two types 1. Naturally acquired—antibodies delivered to fetus via placenta or to infant through milk 2. Artificially acquired—injection of serum, such as gamma globulin Protection immediate but ends when antibodies naturally degrade in body Figure 21.13 Active and passive humoral immunity. 69 Humoral immunity Active Passive Naturally Artificially Naturally Artificially acquired acquired acquired acquired Infection; Vaccine; Antibodies Injection of contact dead or passed from exogenous with attenuated mother to antibodies pathogen pathogens fetus via (gamma placenta; or globulin) to infant in her milk  70 Antibodies Immunoglobulins (Ig)—gamma globulin portion of blood Proteins secreted by plasma cells Capable of binding specifically with antigen detected by B cells Grouped into one of five Ig classes B cells can switch antibody classes but retain antigen specificity IgM at first; then IgG Almost all secondary responses are IgG  71 Classes of Antibodies IgM Pentamer (larger than others); first antibody released Potent agglutinating agent Readily fixes and activates complement IgA (secretory IgA) Monomer or dimer; in mucus and other secretions Helps prevent entry of pathogens  72 Classes of Antibodies IgD Monomer attached to surface of B cells Functions as B cell receptor IgG Monomer; 75–85% of antibodies in plasma From secondary and late primary responses Crosses placental barrier IgE Monomer active in allergies and parasitic infections Causes mast cells and basophils to release histamine  73 Antibody Targets and Functions Antibodies inactivate and tag antigens; do not destroy them Form antigen-antibody (immune) complexes Defensive mechanisms used by antibodies Neutralization Agglutination Precipitation Complement fixation Figure 21.15 Mechanisms of antibody action. 74 Adaptive defenses Humoral immunity Antigen-antibody Antigen Antibody complex Inactivates by Fixes and activates Neutralization Agglutination Precipitation Complement (masks dangerous (cell-bound antigens) (soluble antigens) parts of bacterial exotoxins; viruses) Enhances Enhances Leads to Phagocytosis Inflammation Cell lysis Chemotaxis Histamine release  75 Summary of Antibody Actions Antigen-antibody complexes do not destroy antigens, but prepare them for destruction by innate defenses Antibodies do not invade solid tissue unless lesion present Can act intracellularly if attached to virus before it enters cell Activate mechanisms that destroy virus  76 CELLULAR IMMUNE RESPONSE  77 Cellular Immune Response T cells provide defense against intracellular antigens Some T cells directly kill cells; others release chemicals that regulate immune response Two populations of T cells based on which glycoprotein surface receptors displayed CD4 cells usually become helper T cells (TH); activate B cells, other T cells, macrophages, and direct adaptive immune response Some become regulatory T cells – which moderate immune response Can also become memory T cells  78 Cellular Immune Response CD8 cells become cytotoxic T cells (TC) Destroy cells harboring foreign antigens Also become memory T cells Helper, cytotoxic, and regulatory T cells are activated T cells Naive T cells simply termed CD4 or CD8 cells Figure 21.16 Major types of T cells. 79 Adaptive defenses Cellular immunity Immature lymphocyte Red bone marrow T cell T cell receptor receptor Maturation Class II MHC CD8 Class I MHC protein displaying CD4 protein displaying cell cell antigen Thymus antigen Activation Activation APC (dendritic cell) Memory APC cells (dendritic cell) CD4 CD8 CD4 cells become Lymphoid either helper T CD8 cells become tissues and cytotoxic T cells or organs regulatory T cells cells Effector cells Blood plasma  80 MHC Proteins Two types of MHC proteins important to T cell activation Class I MHC proteins – displayed by all cells except RBCs Bind with fragment of protein synthesized in the cell (endogenous antigen) Crucial for CD8 cell activation Inform cytotoxic T cells of microorganisms hiding in cells (cytotoxic T cells ignore displayed self-antigens) Class II MHC proteins – displayed by APCs (dendritic cells, macrophages, and B cells) Bind with fragments of exogenous antigens that have been engulfed and broken down in a phagolysosome Recognized by helper T cells Signal CD4 cells that help is required Table 21.5 Role of MHC Proteins in Cellular Immunity 81  82 T cell Activation T cell activation two-step process Antigen binding Co-stimulation Both occur on surface of same APC Both required for clonal selection  83 T cell Activation: Co- stimulation Without co-stimulation, anergy occurs T cells Become tolerant to that antigen Are unable to divide Do not secrete cytokines  84 T cell Activation: Proliferation and Differentiation Primary T cell response peaks within a week T cell apoptosis occurs between days 7 and 30 Benefit of apoptosis: activated T cells are a hazard – produce large amount inflammatory cytokines  hyperplasia, cancer Memory T cells remain and mediate secondary responses  85 Cytokines Chemical messengers of immune system Mediate cell development, differentiation, and responses in immune system Include interferons and interleukins Interleukin 1 (IL-1) released by macrophages co- stimulates T cells to: Release interleukin 2 (IL-2) Synthesize more IL-2 receptors  86 Cytokines IL-2 key growth factor, acting on cells that release it and other T cells Encourages activated T cells to divide rapidly Other cytokines amplify and regulate innate and adaptive responses E.g., tumor necrosis factor – cell toxin E.g., gamma interferon – enhances killing power of macrophages  87 Roles of Helper T (TH) cells Play central role in adaptive immune response Activate both humoral and cellular arms Once primed by APC presentation of antigen, they Help activate T and B cells Induce T and B cell proliferation Their cytokines recruit other immune cells Without TH, there is no immune response Figure 21.18a The central role of helper T cells in mobilizing both humoral and cellular immunity. 88 Slide 1 Helper T cells help in humoral immunity Helper T cell 1 TH cell binds T cell receptor (TCR) with the self-nonself complexes of a B cell that has encountered Helper T cell its antigen and is CD4 protein displaying it on MHC II on its surface. MHC II protein of B cell displaying processed antigen 2 TH cell releases interleukins as co- IL-4 and other stimulatory signals to cytokines complete B cell activation. B cell (being activated)  89 Helper T cells: Activation of CD8 cells CD8 cells require TH cell activation into destructive cytotoxic T cells Cause dendritic cells to express co-stimulatory molecules required for CD8 cell activation Figure 21.18b The central role of helper T cells in mobilizing both humoral and cellular immunity. 90 Slide 1 Helper T cells help in cellular immunity CD4 protein Helper T cell 1 TH cell binds Class II MHC protein dendritic cell. APC (dendritic cell) 2 TH cell IL-2 stimulates dendritic cell to express co-stimulatory molecules. 3 Dendritic cell can now activate Class I CD8 CD8 cell with the MHC protein protein help of interleukin 2 CD8 T cell secreted by TH cell. (becomes TC cell after activation)  91 Helper T cells: Amplification of Innate Defenses Amplify responses of innate immune system Activate macrophages  more potent killers Mobilize lymphocytes and macrophages and attract other types of WBCs  92 Helper T cells: TH1 – mediate most aspects of cellular immunity TH2 – defend against parasitic worms; mobilize eosinophils; promote allergies TH17 – link adaptive and innate immunity by releasing IL-17; may play role in autoimmune disease  93 Cytotoxic T (TC) cells Directly attack and kill other cells Activated TC cells circulate in blood and lymph and lymphoid organs in search of body cells displaying antigen they recognize Targets Virus-infected cells Cells with intracellular bacteria or parasites Cancer cells Foreign cells (transfusions or transplants) Bind to a self-nonself complex Can destroy all infected or abnormal cells  94 Cytotoxic T cells Lethal hit – two methods: TC cell releases perforins and granzymes by exocytosis Perforins create pores through which granzymes enter target cell Granzymes stimulate apoptosis TC cell binds specific membrane receptor on target cell, and stimulates apoptosis  Figure 21.19 Cytotoxic T cells attack infected and cancerous cells. 95 Adaptive defenses Cellular immunity Cytotoxic 1 2 TC releases 3 Perforin molecules insert into T cell (TC) TC identifies perforin and the target cell membrane, foreign antigens granzyme polymerize, and form transmembrane on MHC I proteins molecules from its pores (cylindrical holes) similar to and binds tightly granules by those produced by complement to target cell. exocytosis. activation. Granule Perforin TC cell membrane Cytotoxic T cell Target cell membrane Target Cancer cell cell Perforin pore Granzymes 4 Granzymes enter the 5 The TC detaches target cell via the pores. and searches for Once inside, granzymes another prey. activate enzymes that trigger apoptosis. A mechanism of target cell killing by TC cells. Scanning electron micrograph of a TC cell killing a cancer cell (2100x).  96 Regulatory T (TReg) cells Dampen immune response by direct contact or by inhibitory cytokines Important in preventing autoimmune reactions Suppress self-reactive lymphocytes in periphery (outside lymphoid organs) Figure 21.20 Simplified summary of the primary immune response. 97 Cellular Humoral Antigen (Ag) intruder immunity immunity Inhibits Inhibits Triggers Adaptive defenses Innate defenses Surface Internal barriers defenses Free Ags may directly activate B cell Ag-infected body cell engulfed by dendritic cell Antigen- activated Becomes B cells Present Ag to activated helper T cells Clone and Co-stimulate and release cytokines give rise to Ag-presenting cell (APC) presents self-Ag complex Activates Activates Memory B cells Naive Naive CD8 CD4 T cells T cells Activated to clone Activated to clone and give rise to Induce and give rise to Memory Plasma cells Memory co-stimulation CD4 (effector B cells) CD8 T cells T cells Secrete Cytotoxic Helper T cells T cells Cytokines stimulate Nonspecific killers (macrophages and Antibodies (Igs) Together the nonspecific killers and cytotoxic T cells mount a NK cells of innate Circulating lgs along with complement physical attack on the Ag immunity) mount a chemical attack on the Ag