Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Lymphopoiesis wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Immune system wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Adaptive immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Molecular mimicry wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
PowerPoint® Lecture Slides prepared by Janice Meeking, Mount Royal College CHAPTER 21 The Immune System: Innate and Adaptive:Body Defenses: Part A Copyright © 2010 Pearson Education, Inc. Immunity • Resistance to disease • Immune system has two intrinsic systems • Innate (nonspecific) defense system • Adaptive (specific) defense system Copyright © 2010 Pearson Education, Inc. Immunity 1. Innate defense system has two lines of defense • First line of defense is external body membranes (skin and mucosae) • Second line of defense is antimicrobial proteins, phagocytes, and other cells • Inhibit spread of invaders • Inflammation is its most important mechanism Copyright © 2010 Pearson Education, Inc. Immunity 2. Adaptive defense system • Third line of defense attacks particular foreign substances • Takes longer to react than the innate system • Innate and adaptive defenses are deeply intertwined Copyright © 2010 Pearson Education, Inc. Surface barriers • Skin • Mucous membranes Innate defenses Internal defenses • Phagocytes • NK cells • Inflammation • Antimicrobial proteins • Fever Humoral immunity • B cells Adaptive defenses Cellular immunity • T cells Copyright © 2010 Pearson Education, Inc. Figure 21.1 Innate Defenses • Surface barriers • Skin, mucous membranes, and their secretions • Physical barrier to most microorganisms • Keratin is resistant to weak acids and bases, bacterial enzymes, and toxins • Mucosae provide similar mechanical barriers Copyright © 2010 Pearson Education, Inc. Surface Barriers • Protective chemicals inhibit or destroy microorganisms • Skin acidity (pH of 3 – 5) • Lipids in sebum and Dermcidin in eccrine sweat glands • HCl and protein-digesting enzymes of stomach mucosae • Lysozyme of saliva and lacrimal fluid • Mucus Copyright © 2010 Pearson Education, Inc. Surface Barriers • Respiratory system modifications • Mucus-coated hairs in the nose • Cilia of upper respiratory tract sweep dust- and bacteria-laden mucus from lower respiratory passages Copyright © 2010 Pearson Education, Inc. Internal Defenses: Cells and Chemicals • Necessary if microorganisms invade deeper tissues • Phagocytes • Natural killer (NK) cells • Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals) • Antimicrobial proteins (interferons and complement proteins) • Fever Copyright © 2010 Pearson Education, Inc. Phagocytes: Macrophages • Macrophages develop from monocytes to become the chief phagocytic cells • Free macrophages wander through tissue spaces • E.g., alveolar macrophages • Fixed macrophages are permanent residents of some organs • E.g., Kupffer cells (liver) and microglia (brain) Copyright © 2010 Pearson Education, Inc. Phagocytes: Neutrophils • Neutrophils • Become phagocytic on encountering infectious material in tissues Copyright © 2010 Pearson Education, Inc. Mechanism of Phagocytosis Step 1: Adherence of phagocyte to pathogen • Facilitated by opsonization—coating of pathogen by complement proteins or antibodies • In order to adhere the phagocytic cell must recognize and be able to bind to something on the outside of the organism-generally the carbohydrate. Some organisms cannot be bound to like the pneumococcus unless it is already coated – opsonization. Copyright © 2010 Pearson Education, Inc. Innate defenses Internal defenses (a) A macrophage (purple) uses its cytoplasmic extensions to pull spherical bacteria (green) toward it. Scanning electron micrograph (1750x). Copyright © 2010 Pearson Education, Inc. Figure 21.2a 1 Phagocyte adheres to pathogens or debris. Lysosome Phagosome (phagocytic vesicle) Acid hydrolase enzymes (b) Events of phagocytosis. Copyright © 2010 Pearson Education, Inc. 2 Phagocyte forms pseudopods that eventually engulf the particles forming a phagosome. 3 Lysosome fuses with the phagocytic vesicle, forming a phagolysosome. 4 Lysosomal enzymes digest the particles, leaving a residual body. 5 Exocytosis of the vesicle removes indigestible and residual material. Figure 21.2b Mechanism of Phagocytosis • Destruction of pathogens • Acidification and digestion by lysosomal enzymes – Some organisms cannot be destroyed by the lysosome enzymes – like TB – so a granuloma formed. • Respiratory burst • Release of cell-killing free radicals • Activation of additional enzymes – generally by changes in pH (becomes more basic) and osmolarity in the lysosome • Oxidizing chemicals (e.g. H2O2) • Defensins (in neutrophils) – pierce membrane Copyright © 2010 Pearson Education, Inc. Respiratory Burst • Respiratory burst (is sometimes called oxidative burst) is the rapid release of reactive oxygen species (superoxide radical and hydrogen peroxide) from different types of cells. • Usually it denotes the release of these chemicals from immune cells, e.g., neutrophils and monocytes, as they come into contact with different bacteria or fungi. • To maximally activate the respiratory burst – T-helper cells stimulate phagocytes • The respiratory burst also increases the pH and osmolarity in the phagolysosome – thus activating other protein-digesting enzymes that digest the invader. Copyright © 2010 Pearson Education, Inc. Chronic granulomatous disease • a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds (most importantly, the superoxide radical) used to kill certain ingested pathogens. This leads to the formation of granulomata in many organs. CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year • There are over 410 known possible defects in the PHOX enzyme complex that can lead to chronic granulomatous disease • There are currently no studies detailing the long term outcome of chronic granulomatous disease with modern treatment. Without treatment children often die in the first decade of life. Copyright © 2010 Pearson Education, Inc. Granuloma Granuloma is a medical term for a roughly spherical mass of immune cells that forms when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as and bacteria and fungi as well as other materials such as keratin and suture fragments. A granuloma is therefore a special type of inflammation that can occur in a wide variety of diseases. Copyright © 2010 Pearson Education, Inc. Natural Killer (NK) Cells (CD 16 & CD 56) • Large granular lymphocytes - larger lymphocytes with small granules (stained vesicles) • Target cells that lack “self” cell-surface receptors or cells that display wrong MHCI or MICA • NK cell will not attack if a cell’s LY49 receptor is displayed and can be recognized by the NK cell’s MHCI • Secrete perforans and granzyme • Induce apoptosis in cancer cells and virus-infected cells • Secrete potent chemicals that enhance the inflammatory response Copyright © 2010 Pearson Education, Inc. Inflammatory Response • Triggered whenever body tissues are injured or infected 1. Prevents the spread of damaging agents 2. Disposes of cell debris and pathogens 3. Sets the stage for repair Copyright © 2010 Pearson Education, Inc. Inflammatory Response • Cardinal signs of acute inflammation: 1. Redness 2. Heat 3. Swelling 4. Pain (And sometimes 5. Impairment of function) Copyright © 2010 Pearson Education, Inc. Inflammatory Response • Macrophages and epithelial cells of boundary tissues bear Toll-like receptors (TLRs) • Eleven recognized TLR • TLRs recognize specific classes of infecting microbes – like Salmonella and TB • Activated TLRs trigger the release of cytokines that promote inflammation and attract WBCs Copyright © 2010 Pearson Education, Inc. Inflammatory Response • Inflammatory mediators • Histamine (from mast cells and Basophils) • Blood proteins • Kinins, prostaglandins (PGs), leukotrienes, and complement • Singulair is a leukotriene inhibitor • Released by injured tissue, phagocytes, lymphocytes, basophils, and mast cells Copyright © 2010 Pearson Education, Inc. Vasodilation and Increased Vascular Permeability • Inflammatory chemicals cause • Dilation of arterioles, resulting in hyperemia • Increased permeability of local capillaries and edema (leakage of exudate) – edema helps with sweep of organisms and chemicals into capillaries of the lymphatics • Exudate contains proteins, clotting factors, and antibodies Copyright © 2010 Pearson Education, Inc. Inflammatory Response: Edema • Functions of the surge of exudate • Moves foreign material into lymphatic vessels • Delivers clotting proteins to form a scaffold for repair and to isolate the area – by walling off the infected area • Streptococcus can produce Streptokinase to break down clot and open the walled off area Copyright © 2010 Pearson Education, Inc. Anti-inflammatory agents • NSAID – Non-steroidal antiinflammatory drugs – which are anti-prostaglandins • SAID – Steroidal anti-inflammatory drugs – which are natural and synthetic glucocorticoids Copyright © 2010 Pearson Education, Inc. NSAID • drugs with analgesic and antipyretic (feverreducing) effects and which have, in higher doses, anti-inflammatory effects (reducing inflammation). • There are two main types of NSAIDs, nonselective and selective. The terms nonselective and selective refer to different NSAIDs ability to inhibit specific types of cyclooxygenase (COX) enzymes. • Nonselective NSAIDs — Nonselective NSAIDs inhibit both COX-1 and COX-2 enzymes to a similar degree. Copyright © 2010 Pearson Education, Inc. • Nonselective NSAIDs — Nonselective NSAIDs inhibit both COX-1 and COX-2 enzymes to a similar degree. • Selective NSAIDs — Selective NSAIDs inhibit COX enzymes found at sites of inflammation (COX-2) more than the type that is normally found in the stomach, blood platelets, and blood vessels (COX-1). Copyright © 2010 Pearson Education, Inc. • Nonselective NSAIDs — Nonselective NSAIDs include commonly available drugs such as aspirin, ibuprofen (Advil®, Motrin®, Nuprin®), and naproxen (Aleve®), as well as some prescription-strength NSAIDs • Selective NSAIDs — Selective NSAIDs (also called COX-2 inhibitors) are as effective in relieving pain and inflammation as nonselective NSAIDs and are less likely to cause gastrointestinal injury. Celecoxib (Celebrex®) is the only selective NSAID currently available in the United States. Copyright © 2010 Pearson Education, Inc. SAID (Glucocorticoids) • Glucocorticoids influence all types of inflammatory events, no matter their cause. They induce the lipocortin1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. • Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mastocytes. Copyright © 2010 Pearson Education, Inc. Beta Defensins • Beta defensins are a family of mammalian defensins. The beta defensins are antimicrobial peptides implicated in the resistance of epithelial surfaces to microbial colonization. • Present in epithelial mucosal cells – and released when the epithelial cells are damaged • Most defensins function by binding to the microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients. • Alpha defensins are produced by neutrophils Copyright © 2010 Pearson Education, Inc. Innate defenses Tissue injury Internal defenses Release of chemical mediators (histamine, complement, kinins, prostaglandins, etc.) Release of leukocytosisinducing factor Leukocytosis (increased numbers of white blood cells in bloodstream) Initial stimulus Vasodilation of arterioles Increased capillary permeability Local hyperemia (increased blood flow to area) Capillaries leak fluid (exudate formation) Attract neutrophils, monocytes, and lymphocytes to area (chemotaxis) Leukocytes migrate to injured area Margination (leukocytes cling to capillary walls) Physiological response Signs of inflammation Leaked protein-rich fluid in tissue spaces Result Heat Redness Locally increased temperature increases metabolic rate of cells Pain Swelling Possible temporary limitation of joint movement Leaked clotting proteins form interstitial clots that wall off area to prevent injury to surrounding tissue Temporary fibrin patch forms scaffolding for repair Diapedesis (leukocytes pass through capillary walls) Phagocytosis of pathogens and dead tissue cells (by neutrophils, short-term; by macrophages, long-term) Pus may form Area cleared of debris Healing Copyright © 2010 Pearson Education, Inc. Figure 21.3 Phagocyte Mobilization • Neutrophils, then phagocytes flood to inflamed sites Copyright © 2010 Pearson Education, Inc. Phagocyte Mobilization • Steps for phagocyte mobilization 1. Leukocytosis: release of neutrophils from bone marrow in response to leukocytosis-inducing factors from injured cells 2. Margination: neutrophils cling to the walls of capillaries in the inflamed area (selectins) 3. Diapedesis of neutrophils 4. Chemotaxis: inflammatory chemicals (chemotactic agent) promote positive chemotaxis of neutrophils Copyright © 2010 Pearson Education, Inc. Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Leukocytosis. Neutrophils enter blood from bone marrow. 1 Copyright © 2010 Pearson Education, Inc. Margination. Neutrophils cling to capillary wall. 2 Chemotaxis. Neutrophils follow chemical trail. 4 Capillary wall Basement membrane Endothelium Diapedesis. Neutrophils flatten and squeeze out of capillaries. 3 Figure 21.4 Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Capillary wall Basement membrane Endothelium Leukocytosis. Neutrophils enter blood from bone marrow. 1 Copyright © 2010 Pearson Education, Inc. Figure 21.4, step 1 Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Leukocytosis. Neutrophils enter blood from bone marrow. 1 Copyright © 2010 Pearson Education, Inc. Capillary wall Basement membrane Endothelium Margination. Neutrophils cling to capillary wall. 2 Figure 21.4, step 2 Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Leukocytosis. Neutrophils enter blood from bone marrow. 1 Copyright © 2010 Pearson Education, Inc. Margination. Neutrophils cling to capillary wall. 2 Capillary wall Basement membrane Endothelium Diapedesis. Neutrophils flatten and squeeze out of capillaries. 3 Figure 21.4, step 3 Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Leukocytosis. Neutrophils enter blood from bone marrow. 1 Copyright © 2010 Pearson Education, Inc. Margination. Neutrophils cling to capillary wall. 2 Chemotaxis. Neutrophils follow chemical trail. 4 Capillary wall Basement membrane Endothelium Diapedesis. Neutrophils flatten and squeeze out of capillaries. 3 Figure 21.4, step 4 Antimicrobial Proteins • Interferons (IFNs) and complement proteins • Attack microorganisms directly • Hinder microorganisms’ ability to reproduce Copyright © 2010 Pearson Education, Inc. Interferons • Viral-infected cells are activated to secrete IFNs • IFNs enter neighboring cells • Neighboring cells produce antiviral proteins that block viral reproduction Copyright © 2010 Pearson Education, Inc. Innate defenses Virus Viral nucleic acid 1 Virus enters cell. Internal defenses New viruses 5 Antiviral proteins block viral reproduction. 2 Interferon genes switch on. DNA Nucleus mRNA 4 Interferon 3 Cell produces interferon 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 Copyright © 2010 Pearson Education, Inc. binding stimulates cell to turn on genes for antiviral proteins. Figure 21.5 Innate defenses Virus Viral nucleic acid Internal defenses 1 Virus enters cell. Nucleus Host cell 1 Infected by virus; makes interferon; is killed by virus Copyright © 2010 Pearson Education, Inc. Host cell 2 Binds interferon from cell 1; interferon induces synthesis of protective proteins Figure 21.5, step 1 Innate defenses Virus Viral nucleic acid Internal defenses 1 Virus enters cell. 2 Interferon genes switch on. DNA Nucleus Host cell 1 Infected by virus; makes interferon; is killed by virus Copyright © 2010 Pearson Education, Inc. Host cell 2 Binds interferon from cell 1; interferon induces synthesis of protective proteins Figure 21.5, step 2 Innate defenses Virus Viral nucleic acid Internal defenses 1 Virus enters cell. 2 Interferon genes switch on. DNA Nucleus mRNA 3 Cell produces interferon 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 Copyright © 2010 Pearson Education, Inc. Figure 21.5, step 3 Innate defenses Virus Viral nucleic acid Internal defenses 1 Virus enters cell. 2 Interferon genes switch on. DNA Nucleus mRNA 4 Interferon 3 Cell produces interferon 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 Copyright © 2010 Pearson Education, Inc. binding stimulates cell to turn on genes for antiviral proteins. Figure 21.5, step 4 Innate defenses Virus Viral nucleic acid 1 Virus Internal defenses New viruses enters cell. 5 Antiviral proteins block viral reproduction. 2 Interferon genes switch on. DNA Nucleus mRNA 4 Interferon 3 Cell produces interferon molecules. Host cell 1 Infected by virus; makes interferon; is killed by virus Copyright © 2010 Pearson Education, Inc. Interferon Host cell 2 Binds interferon from cell 1; interferon induces synthesis of protective proteins binding stimulates cell to turn on genes for antiviral proteins. Figure 21.5, step 5 Interferons • Produced by a variety of body cells • Lymphocytes produce gamma (), or immune, interferon – stimulates macrophages to killer status • Most other WBCs produce alpha () interferon – reduce inflammation • Fibroblasts produce beta () interferon – reduce inflammation • Interferons also activate macrophages and mobilize NKs Copyright © 2010 Pearson Education, Inc. Interferons • Functions • Anti-viral – in the cell being defended the cell produces PKR ( Protein Kinase RNA) – this blocks the virus from making new proteins in the host cell – blocks at the ribosome • Reduce inflammation • Activate macrophages and mobilize NK cells • Genetically engineered IFNs for • Antiviral agents against hepatitis and genital warts virus – alpha and Beta Interferons • Multiple sclerosis treatment – Beta Interferon Copyright © 2010 Pearson Education, Inc. Complement • ~20 blood proteins that circulate in an inactive form • Include C1–C9, factors B, D, and P, and regulatory proteins • Major mechanism for destroying foreign substances Copyright © 2010 Pearson Education, Inc. Complement • Amplifies all aspects of the inflammatory response • Kills bacteria and certain other cell types by cell lysis • Enhances both nonspecific and specific defenses • Opsonization – Inflammation and Lysis Copyright © 2010 Pearson Education, Inc. Complement Activation • Two pathways 1. Classical pathway • Antibodies bind to invading organisms or CRP Note: only two antibodies bind compliment –IgG and IgM • C1 binds to the antigen-antibody complexes (complement fixation) 2. Alternative pathway • Triggered when activated C3, B, D, and P interact on the surface of microorganisms Copyright © 2010 Pearson Education, Inc. Complement Activation • Each pathway involves activation of proteins in an orderly sequence • Each step catalyzes the next • Both pathways converge on C3, which cleaves into C3a and C3b Copyright © 2010 Pearson Education, Inc. Complement Activation • Activated complement • Enhances inflammation • Promotes phagocytosis • Causes cell lysis • C3b initiates formation of a membrane attack complex (MAC) • MAC causes cell lysis by inducing a massive influx of water • C3b also causes opsonization, and C3a causes inflammation Copyright © 2010 Pearson Education, Inc. Two IgG or CRP or 1 IgM Classical pathway Antigen-antibody complex + complex Opsonization: coats pathogen surfaces, which enhances phagocytosis Insertion of MAC and cell lysis (holes in target cell’s membrane) Surface not protected by sialic acid Alternative pathway Spontaneous activation + Stabilizing factors (B, D, and P) + No inhibitors on pathogen surface Enhances inflammation: stimulates histamine release, increases blood vessel permeability, attracts phagocytes by chemotaxis, etc. Pore Complement proteins (C5b–C9) Membrane of target cell Copyright © 2010 Pearson Education, Inc. Figure 21.6 C-Reactive Protein (CRP) • C-reactive protein (CRP) is a protein found in the blood, the levels of which rise in response to inflammation (an acute-phase protein). Its physiological role is to bind to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via the C1Q complex. • CRP is synthesized by the liver in response to factors released by fat cells. Copyright © 2010 Pearson Education, Inc. C-Reactive Protein (CRP) • CRP was originally discovered by Tillett and Francis in 1930 as a substance in the serum of patients with acute inflammation that reacted with the C polysaccharide of pneumococcus. • CRP is a member of the class of acute-phase reactants, as its levels rise dramatically during inflammation processes occurring in the body. • CRP rises up to 50,000-fold in acute inflammation, such as infection. It rises above normal limits within 6 hours, and peaks at 48 hours. Its halflife is constant, and therefore its level is mainly determined by the rate of production Copyright © 2010 Pearson Education, Inc. CRP versus ESR • The erythrocyte sedimentation rate (ESR is the rate at which red blood cells precipitate in a period of 1 hour. It is a common hematology test which is a non-specific measure of inflammation. To perform the test, anticoagulated blood is placed in an upright tube, known as a Westergren tube, and the rate at which the red blood cells fall is measured and reported in mm/h. • ESR – slower and more prolonged sign of inflammation than the CRP Copyright © 2010 Pearson Education, Inc. Fever • Systemic response to invading microorganisms • Leukocytes and macrophages exposed to foreign substances secrete pyrogens • Pyrogens reset the body’s thermostat upward Copyright © 2010 Pearson Education, Inc. Fever • Pyrogens generally microorganisms cause the release of fever inducing cytokines from cells such as WBC , smooth muscle cells, glial cells and some others • The cytokines are IL1, TNF, Interferon alpha, and IL6 • These travel in the circulation causing certain blood vessel endothelial cells in the thermal control center (Pre-optic nucleus) in the hypothalamus to produce PGE2 – which causes cyclic AMP to produced subsequently causing the cells of the pre-optic nucleus to raise the body temperature Copyright © 2010 Pearson Education, Inc. Fever • High fevers are dangerous because heat denatures enzymes • Benefits of moderate fever • Causes the liver and spleen to sequester iron and zinc (needed by microorganisms) • Increases metabolic rate, which speeds up repair • Kills certain organisms like syphilis Copyright © 2010 Pearson Education, Inc. Fever versus Hyperthermia • A fever is when the temperature set point in the hypothalamus is changed • Hyperthermia is a condition when normal metabolic heat cannot be dissipated – thus raising the body temperature Copyright © 2010 Pearson Education, Inc. Adaptive Defenses • The adaptive immune (specific defense) system • Protects against infectious agents and abnormal body cells • Amplifies the inflammatory response • Activates complement Copyright © 2010 Pearson Education, Inc. Adaptive Defenses • • Adaptive immune response • Is specific • Is systemic • Has memory Two separate overlapping arms 1. Humoral (antibody-mediated) immunity 2. Cellular (cell-mediated) immunity Copyright © 2010 Pearson Education, Inc. Antigens (Antibody Generating) • Antigen – substance that be recognized by the adaptive immune system (can be partial or complete) • Isoantigens (self MHC 1) and hetero-antigens • Immunogen – special type of antigen that can stimulate the 3rd line (adaptive immune system) by itself (complete antigen) • Substances that can mobilize the adaptive defenses and provoke an immune response • Most are large, complex organic molecules not normally found in the body (nonself) –proteins are generally the most antigenic Copyright © 2010 Pearson Education, Inc. Complete Antigens (Immunogenicity) • Important functional properties • Immunogenicity: ability to stimulate proliferation of specific lymphocytes and antibodies (complete antigen) • Reactivity: ability to react with products of activated lymphocytes and antibodies released (partial antigen if only can do reactivity and not immunogenicity) Examples: foreign protein, polysaccharides, lipids, and nucleic acids Copyright © 2010 Pearson Education, Inc. Haptens (Incomplete Antigens) Antigenicity • Small molecules (peptides, nucleotides, and hormones) – less than 1,000 AMU (Daltons) • Not immunogenic by themselves • Are immunogenic when attached to body proteins • Cause the immune system to mount a harmful attack • Examples: poison ivy, animal dander, detergents, and cosmetics Copyright © 2010 Pearson Education, Inc. Antigenic Determinants (Epitopes) • Certain parts of an entire antigen that are immunogenic • Antibodies and lymphocyte receptors bind to them Copyright © 2010 Pearson Education, Inc. Antigenic Determinants • Most naturally occurring antigens have numerous antigenic determinants that • Mobilize several different lymphocyte populations • Form different kinds of antibodies against it • Large, chemically simple molecules (e.g., plastics or metals – like a prosthesis) have little or no immunogenicity Copyright © 2010 Pearson Education, Inc. Multiple antigenic determinants on surface of the bacteria If each antigenic determinant is different – then a different antibody and /or T cell can attach to it. cell will attach Copyright © 2010 Pearson Education, Inc. Antibody A Antigenbinding sites Antigenic determinants Antigen Antibody B Antibody C Copyright © 2010 Pearson Education, Inc. Figure 21.7 Self-Antigens (Isoantigens) : MHC Proteins • Protein molecules (self-antigens) on the surface of cells • Antigenic to others in transfusions or grafts • Example: MHC proteins • Coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual Copyright © 2010 Pearson Education, Inc. MHC Proteins • In humans, the 3.6-Mb (3,600,000 base pairs) MHC region on chromosome 6 contains 140 genes • Classes of MHC proteins • Class I MHC proteins, found on virtually all body cells • Class II MHC proteins, found on certain cells in the immune response • Class MHC III – code for immune components such as complement, and some cytokines like TNF • MHC proteins display peptides (usually self-antigens) • In infected cells, MHC proteins display fragments of foreign antigens- MICA, which help mobilize • MICA – MHC Class I Chain – related Gene A Copyright © 2010 Pearson Education, Inc. MHC I and II • The MHC surface markers are proteins that have a groove in their surfaces exposed to the outside of the cell • The groove is filled with some substance – if the MHC I – it is filled with a piece of a protein formed from the inside of the cells (endogenous antigens) – proteins formed on the inside of the cell could be normal or abnormal (virus or tumor) • If MHC II – it is filled with some coming from the outside of the cell (exogenous antigens) Copyright © 2010 Pearson Education, Inc. Copyright © 2010 Pearson Education, Inc. Cells of the Adaptive Immune System • Two types of lymphocytes • B lymphocytes (B cells)—humoral immunity • T lymphocytes (T cells)—cell-mediated immunity • Antigen-presenting cells (APCs) • Do not respond to specific antigens • Play essential auxiliary roles in immunity Copyright © 2010 Pearson Education, Inc. Lymphocytes • Originate in red bone marrow • B cells mature in the red bone marrow (B originally came from the studies done in the Bursa of Fabricius of the chicken) • T cells mature in the thymus Copyright © 2010 Pearson Education, Inc. Proportions of Lymphocytes • Natural Killer - 7% (2-13%) • T helper – T4 – 46% (28 – 59%) • T cytotoxic T8 – 19% (13-32%) • T gamma –delta – no number • B – cells - Copyright © 2010 Pearson Education, Inc. 23% (18 – 47%) • When Lymphocytes are mature, they have • Immunocompetence; they are able to recognize and bind to a specific antigen (recognize where to look for an antigen and bind tight if foreign) • Self-tolerance – unresponsive to self antigens • Naive (unexposed) B and T cells are exported from the primary lymphoid organs (Thymus and Bone marrow) to lymph nodes, spleen, and other lymphoid organs • Terminology - before immunocompetence – immature – after immunocompetence but have not met an antigen – naïve – after meeting antigen but no costimulation- active idling – after costimulation – fully active Copyright © 2010 Pearson Education, Inc. Adaptive defenses Immature lymphocytes Red bone marrow: site of lymphocyte origin Humoral immunity Cellular immunity Primary lymphoid organs: site of development of immunocompetence as B or T cells Secondary lymphoid organs: site of antigen encounter, and activation to become effector and memory B or T cells Red bone marrow 1 Lymphocytes destined to become T cells migrate (in blood) to the thymus and develop immunocompetence there. B cells develop immunocompetence in red bone marrow. Thymus Bone marrow 2 Immunocompetent but still naive Lymph nodes, spleen, and other lymphoid tissues lymphocytes leave the thymus and bone marrow. They “seed” the lymph nodes, spleen, and other lymphoid tissues where they encounter their antigen. 3 Antigen-activated immunocompetent lymphocytes (effector cells and memory cells) circulate continuously in the bloodstream and lymph and throughout the lymphoid organs of the body. Copyright © 2010 Pearson Education, Inc. Figure 21.8 T Cells (Have TCR – T cell receptor –CD3) • In the thymus under the influence of thymic hormones (Thymosins) get educated and get CDs (CD3 and other specific CD like 4, 8, 10 or gamma delta) on cell surface have 104 to 105 • Thymic education process involves two processes – positive and negative selection (no outsiders – Blood-Thymic barrier) • Positive selection • Selects T cells capable of loosely binding to the self-MHC proteins themselves (MHC restriction) –– This is a recognition and restriction process • Negative selection • Prompts apoptosis of T cells that bind too tightly to selfthe self antigens displayed by self-MHC proteins • Ensures self-tolerance Copyright © 2010 Pearson Education, Inc. MHC restriction further clarified • 1. Good T-lymphocytes should be restricted to only view antigens associated with an MHC I or MHC II • 2. If the cell is a T helper cell it should be restricted to only view antigens (foreign) on an MHC II • 3. If the T cell is any other variety like the T-cytotoxic – then it should only be restricted to view antigens (endogenously produced) on MHC I – and only view it if the antigen presented is endogenous. Some endogenous antigens (proteins) are cut up proteins displaying trouble (virus, intracellular parasite or tumor) Copyright © 2010 Pearson Education, Inc. T-cells • When a cell enters the thymus gland it receives many T cell receptors (CD 3) – the T cell receptors are of different varieties (variety determines whether it can view only MHC I or MHC II) – but each cell has one variety with somewhere between 100,000 – 1,000,000 copies of the receptors on the cell membrane • During positive selection – only the variety of T-cells having a T cell receptor that recognizes our own MHC isoantigen proteins (only the MHC itself – not anything bound to it) displayed on the epithelial cells in the Thymus outer cortex are retained – those that do not undergo apoptosis – MHC restriction – T cells should only view MHC receptors • During positive selection T helper cells should be directed to only view MHC II and all the others MHC I (like the T cytotoxic) Copyright © 2010 Pearson Education, Inc. Negative Selection • Occurs in inner thymic cortex as cells move downward from the outer cortical area where positive selection occurred. • In negative selection – non T helper –cells that bind to (especially too tightly) MHC I receptors with one of our own proteins in its groove are eliminated (apoptosis) – this is how we develop tolerance Copyright © 2010 Pearson Education, Inc. Types of T cells • While positive and negative selection is occurring in the thymus the immature T cells are also expressing CD4 or CD8 antigens on their surface. Initially the pre-T cell that enters the thymus is CD4-CD8-. In the thymus it becomes CD4+CD8+ and as positive and negative selection proceeds a cell becomes either a CD4+ or CD8+ cell. • The commitment to become either a CD4+ or CD8+ cells depends on which class of MHC molecule the cell encounters. If a CD4+CD8+ cell is presented with a class I molecule it will down regulate CD4 and become a CD8+ cell. If a cell is presented with a class II MHC molecule it will down regulate CD8 and become a CD4+ cell Copyright © 2010 Pearson Education, Inc. Thymic education occurs in cortex • Outer cortex – Positive Selection • Inner cortex – Negative Selection Thymic education is a 2 -3 day process. Only 2% graduate – 98% undergo apoptosis Copyright © 2010 Pearson Education, Inc. Adaptive defenses Cellular immunity Positive selection: T cells must recognize self major histocompatibility proteins (self-MHC). AntigenDeveloping presenting T cell thymic cell Failure to recognize self-MHC results in apoptosis (death by cell suicide). MHC T cell receptor Self-antigen Recognizing self-MHC results in MHC restriction—survivors are restricted to recognizing antigen on self-MHC. Survivors proceed to negative selection. 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. Copyright © 2010 Pearson Education, Inc. Figure 21.9 B Cells (B-cell receptors are surface antibodies – CD 19 and 21) • B cells mature in red bone marrow • Self-reactive B cells • Are eliminated by apoptosis (clonal deletion) or • Undergo receptor editing – rearrangement of their receptors • Are inactivated (anergy) if they escape from the bone marrow Copyright © 2010 Pearson Education, Inc. B cells should only recognize foreign substances – not self at all! Copyright © 2010 Pearson Education, Inc. Antigen Receptor Diversity • Lymphocytes make up to a billion different types of antigen receptors • Coded for by only ~20,000 - 25,000 genes (Domain genes) • The haploid human genome contains 23,000 protein-coding genes, far fewer than had been expected before its sequencing. In fact, only about 1.5% of the genome codes for proteins, while the rest consists of non-coding RNA genes, regulatory sequences, introns, and (controversially named) "junk" DNA • Gene segments are shuffled by somatic recombination • Genes determine which foreign substances the immune system will recognize and resist Copyright © 2010 Pearson Education, Inc. Karyotype Copyright © 2010 Pearson Education, Inc. Introns act as spacers for genetic recombination of domains (exons) Copyright © 2010 Pearson Education, Inc. Antigen-Presenting Cells (APCs) • Have MHC II on their cell surfaces • Engulf antigens • Present fragments of antigens to be recognized by T cells • Major types • Dendritic cells in connective tissues and epidermis • Macrophages in connective tissues and lymphoid organs • Some B cells Copyright © 2010 Pearson Education, Inc. Copyright © 2010 Pearson Education, Inc. Dendritic cell like the Langerhans cell Figure 21.10 Macrophages and Dendritic Cells • Present antigens and activate T cells • Macrophages mostly remain fixed in the lymphoid organs • Dendritic cells internalize pathogens and enter lymphatics to present the antigens to T cells in lymphoid organs • Activated T cells release chemicals that • Prod macrophages to become insatiable phagocytes and to secrete bactericidal chemicals Copyright © 2010 Pearson Education, Inc. Adaptive Immunity: Summary • Uses lymphocytes, APCs, and specific molecules to identify and destroy nonself substances • Depends upon the ability of its cells to • Recognize antigens by binding to them • Communicate with one another so that the whole system mounts a specific response Copyright © 2010 Pearson Education, Inc. Humoral Immunity Response • Antigen challenge • First encounter between an antigen and a naive immunocompetent lymphocyte • Usually occurs in the spleen or a lymph node • If the lymphocyte is a B cell • The antigen provokes a humoral immune response • Antibodies are produced Copyright © 2010 Pearson Education, Inc. Clonal Selection 1. B cell is activated when antigens bind to its surface receptors and cross-link them 2. Receptor-mediated endocytosis of crosslinked antigen-receptor complexes occurs 3. Stimulated B cell grows to form a clone of identical cells bearing the same antigenspecific receptors (T cells are usually required to help B cells achieve full activation) Copyright © 2010 Pearson Education, Inc. Fate of the Clones • Most clone cells become plasma cells • secrete specific antibodies at the rate of 2000 molecules per second for four to five days Copyright © 2010 Pearson Education, Inc. Fate of the Clones • Secreted antibodies • Circulate in blood or lymph • Bind to free antigens • Mark the antigens for destruction Copyright © 2010 Pearson Education, Inc. Fate of the Clones • Clone cells that do not become plasma cells become memory cells • Provide immunological memory • Mount an immediate response to future exposures of the same antigen Copyright © 2010 Pearson Education, Inc. Adaptive defenses Humoral immunity Primary response (initial encounter with antigen) Activated B cells Plasma cells (effector B cells) Secreted antibody molecules Copyright © 2010 Pearson Education, Inc. Antigen Proliferation to form a clone Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with non-complementary receptors remain inactive) Memory B cell— primed to respond to same antigen Figure 21.11 (1 of 2) Immunological Memory • Primary immune response • Occurs on the first exposure to a specific antigen • Lag period: three to six days • Note – the lag period is the time it takes for the selected B cells to proliferate to approximately 12 generations and to differentiate into plasma cells • Peak levels of plasma antibody are reached in 10 days • Antibody levels then decline quickly Copyright © 2010 Pearson Education, Inc. Immunological Memory • Secondary immune response • Occurs on re-exposure to the same antigen • 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 Copyright © 2010 Pearson Education, Inc. Adaptive defenses Humoral immunity Primary response (initial encounter with antigen) Activated B cells Proliferation to form a clone Plasma cells (effector B cells) Memory B cell— primed to respond to same antigen Secreted antibody molecules Secondary response (can be years later) Antigen Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with non-complementary receptors remain inactive) Clone of cells identical to ancestral cells Subsequent challenge by same antigen results in more rapid response Plasma cells Secreted antibody molecules Copyright © 2010 Pearson Education, Inc. Memory B cells Figure 21.11 Secondary immune response to antigen A is faster and larger; primary immune response to antigen B is similar to that for antigen A. Primary immune response to antigen A occurs after a delay. Antibodies to B Antibodies to A First exposure to antigen A Second exposure to antigen A; first exposure to antigen B Time (days) Copyright © 2010 Pearson Education, Inc. Figure 21.12 Active Humoral Immunity • Occurs when B cells encounter antigens and produce specific antibodies against them • Two types • Naturally acquired—response to a bacterial or viral infection • Artificially acquired—response to a vaccine of dead or attenuated pathogens Copyright © 2010 Pearson Education, Inc. Active Immunity (Artificially Acquired) - Vaccines See Vaccine PowerPoint Copyright © 2010 Pearson Education, Inc. Passive Humoral Immunity • B cells are not challenged by antigens • Immunological memory does not occur • Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases Copyright © 2010 Pearson Education, Inc. Passive Humoral Immunity • Two types 1. Naturally acquired—antibodies delivered to a fetus via the placenta or to infant through milk 2. Artificially acquired—injection of serum, such as gamma globulin • Protection is immediate but ends when antibodies naturally degrade in the body Copyright © 2010 Pearson Education, Inc. • Artificially acquired passive immunity (termed Gamma Globulin injection) is a short-term immunization achieved by the transfer of antibodies, which can be administered in several forms; as 1. human or animal blood plasma or serum, as 2. pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, as 3. high-titer human IVIG or IG from immunized or from donors recovering from the disease, and as 4. monoclonal antibodies (MAb). Copyright © 2010 Pearson Education, Inc. Humoral immunity Active Passive Naturally acquired Artificially acquired Naturally acquired Artificially acquired Infection; contact with pathogen Vaccine; dead or attenuated pathogens Antibodies pass from mother to fetus via placenta; or to infant in her milk Injection of immune serum (gamma globulin) Copyright © 2010 Pearson Education, Inc. Figure 21.13