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Chapter 43 The Immune System Reconnaissance, Recognition, and Response PowerPoint TextEdit Art Slides for Biology, Seventh Edition Neil Campbell and Jane Reece Copyright © 2005 PearsonEducation, Inc. publishing as Benjamin Cummings Two major kinds of defense that counter the threats. zInnate immunity: •present before any e xposure to pathogens and is effecti ve from the time of birth -quickly recognizing -nonspecific zAcquired immunity (adaptive immunity): •develops only after e xposure to inducing agents -specific -slow (~ 10-14 D) -achieved by lymphocyte s 1 Overview of vertebrate defenses against bacteria, viruses, and other pathogens second line first line third line INNATE IMMUNITY Rapid responses to a broad range of microbes - nonspecif ic External def enses Invading microbes (pathogens) ACQUIRED IMMUNITY Slower responses to specific microbes Internal def enses Skin Mucous membranes Antimicrobial proteins Phagocytic cells Secretions Inflammatory response Natural killer cells Humoral response (antibodies) Cell-mediated response (cytotoxic lymphocytes) External defenses (first line) 1. The skin: -Largest organ of the body -Makes up about 16% of body weight, Avg. surface area ~1.8 m2 -Epidermis, dermis and subcutis (fat) epider mis (waterpoof barrier) dermis sweat glands sebaceous (oil) glands 2 External defenses (first line) 2. Mucous membranes -mucus, a viscous fluid that traps microbes and other particles. -microvilli (cilia), sweep mucus and any entrapped microbes (Goblet10μm cells the trachea) External defenses (first line) 3. Secretions eg. mucus, saliva, and tears z Functions: •constantly bathe the surfaces to avoid microbial colonization • create acidic environments eg. skin, stomach So me pathogens would survive (hepatitis A virus) • contains antimicrobial proteins. eg. lysozy me: digests the cell walls of many bacteria 3 Internal defenses (second-line) 1 Pseudopodia surround microbes (recognized by receptors) 1. Phagocytosis Microbes 2 Microbes are engul fed into cell. MACROPHAGE Vacuole containing 3 microbes forms. Vacuole Lysosome containing enzymes Vacuole and lysosome 4 fus e. 5 Toxic compounds and lysosomal enzymes destroy microbes. 6 Microbial debris is releas ed by exocytosis. Internal defenses (second-line) Lysosome H+ Na+ -Found in both plant and animal cells, -Produced from the Golgi apparatus by budding. -Stabilizes the low pH4.8 by pumping in protons (H+) from the cytosol (pH7). Destroyed mechanisms in the lysosomes 1. nitric oxide and other toxic forms of oxygen -poison the engulfed microbes. 2. enzymes (only wok in low pH) -lysozyme, w hich digests the cell w alls of many bacteria -Lipase, w hich digests lipids, -Carbohydrases, w hich digest carbohydrates (e.g., sugars), -Proteases, w hich digest proteins, -Nucleases, w hich digest nucleic acids. 4 Internal defenses (second-line) z Introduction of Phagocytic Cells : (leukocytes) -neutrophils most abundant, about 60–70% of all WBC life span: ~ few days. self–destruct in the process of phagocytosis -macrophages develop from monocyte s, ~5% of circulating WB C. migrat ed reside permanently, eg. in the spleen, lymph nodes 3μ m Internal defenses (second-line) lymphatic system 1 Interstitial fluid bathing the tissues, along with the white blood cells in it, continually enters lymphatic capillaries. Interstitial fluid Lymphatic capillary 2 Fluid inside the lymphatic capillaries, called lymph, flows through lymphatic vessels throughout the body. Adenoid Tonsil Lymph nodes Blood capillary Spleen Peyer’s patches (small intestine) Tissue cells Lymphatic vessel Appendix Lymphatic vessels Lymph node Masses of lymphocytes and macrophages 5 Internal defenses (second-line) Eosinophils 嗜“伊紅”血球 (readily stained w ith eosin) -low phagocytic activity -defense against multicellular parasitic invaders eg. blood fluke血蛭) -discharge destructive enzymes rather than engulfing Dendritic cells -ingest microbes like macrophages do -primary role is to stimulate the development of acquired immunity. (learn later) Internal defenses (second-line) Antimicrobial Proteins •com plement system contains~30 serum proteins -triggered by some surface markers of microbes and lyse them -trigger inflammation or play a role in acquired defense •Interferon: defense against viral infections interferon (α and β) secreted by virus –infected body cells and induce neighboring uninfected cells to produce substances that inhibit viral reproduction. interferon (γ) secreted by some ly mphocytes -activate macrophages, enhancing their phagocytic ability. •defensins secreted by activated macrophages (and neutrophils) Mechanis m: Cationic. Chemotactic. Stabilize clotting …… 6 Internal defenses (second-line) Inflammatory Response ( Figure 43.6) Blood clot Pin Pathogen Macrophage Chemical signals Phagocytic cells Capillary Blood clotting elements Phagocytosis Red blood cell 1 Chemical signals released by activated macrophages and mast cells at the injury site cause nearby capillaries to widen and become more permeable. 2 Fluid, antimicrobial proteins, and clotting elements move from the blood to the site. Clotting begins. 3 Chemokines released by various kinds of cells attract more phagocytic cells from the blood to the injury site. 4 Neutrophils and macrophages phagocytose pathogens and cell debris at the sit e, and the tissue heals. Step1: dilation and sw elling triggered by chemical signals Histam ine: secreted by mast cells found in connective tissues. Æ triggering dilation and increased per meability of nearby capillar ies prostaglandins: secreted by activated macrophages and other cells Æ promote blood flow to the injured site. Internal defenses (second-line) Inflammatory Response ( Figure 43.6) Blood clot Pin Pathogen Macrophage Chemical signals Phagocytic cells Capillary Blood clotting elements Phagocytosis Red blood cell 1 Chemical signals released by activated macrophages and mast cells at the injury site cause nearby capillaries to widen and become more permeable. 2 Fluid, antimicrobial proteins, and clotting elements move from the blood to the site. Clotting begins. 3 Chemokines released by various kinds of cells attract more phagocytic cells from the blood to the injury site. 4 Neutrophils and macrophages phagocytose pathogens and cell debris at the sit e, and the tissue heals. Step 2: deliver clotting elements and antimicrobial proteins Blood clotting: block the enter ing and the spread of microbes Antim icrobial proteins (complements, defensins…) Ælyse microbes, promote the release of histamine, stabilize the clotting… 7 Internal defenses (second-line) Inflammatory Response ( Figure 43.6) Blood clot Pin Pathogen Macrophage Chemical signals Phagocytic cells Capillary Blood clotting elements Phagocytosis Red blood cell 1 Chemical signals released by activated macrophages and mast cells at the injury site cause nearby capillaries to widen and become more permeable. 2 Fluid, antimicrobial proteins, and clotting elements move from the blood to the site. Clotting begins. 3 Chemokines released by various kinds of cells attract more phagocytic cells from the blood to the injury site. 4 Neutrophils and macrophages phagocytose pathogens and cell debris at the sit e, and the tissue heals. Step 3: chemotaxis chem okines : secreted from blood vessel endothelial and other cells near a site of injury or infection. Æ direct the migration of the phagocytes (neutrophils and macrophages) Internal defenses (second-line) Inflammatory Response ( Figure 43.6) Blood clot Pin Pathogen Macrophage Chemical signals Phagocytic cells Capillary Blood clotting elements Phagocytosis Red blood cell 1 Chemical signals released by activated macrophages and mast cells at the injury site cause nearby capillaries to widen and become more permeable. 2 Fluid, antimicrobial proteins, and clotting elements move from the blood to the site. Clotting begins. 3 Chemokines released by various kinds of cells attract more phagocytic cells from the blood to the injury site. 4 Neutrophils and macrophages phagocytose pathogens and cell debris at the sit e, and the tissue heals. Step 4: phagocytosis •Neutrophils and macrophages phagocytose pathogens and cell debris •Bring signals for acquired immunity 8 Inflammatory Response zInjured cells put out a call fo r reinforcements and signal amplification Î Swelling and fever • Local inflammation Fasten the cleaning process of infection • Systemic inflammation: caused by a severe infection eg. meningitis (腦膜炎) or appendicitis Æ the number of WBC increase severalfold within hours Æ high fever eg. Septic shock: Æ very high fever and low blood pressure Æ a co mmon cause of death after surgery or bacteria infect ion Internal defenses (second-line) z Natural killer (NK) cells Target to virus–infected body cells and cancer cells by their surface receptors. NK cells release chemicals that lead to the death of the stricken cell by apoptosis z Cell surface markers recognized by NK cells •Oligosaccaride •MHC (major histocompatibility complex) 9 major histocompatibility complex (MHC) • Discovery: fro m the phenomena of skin graft rejection • Function: carry s mall peptide to provide a biochemical fingerprint Class I MHC molecules Class II MHC molecules - on almost all nucleated cells phagocytes, eg: dendritic cells, macrophages (身份証) (懸賞公告) Protein vesicle proteosome lysosome Peptide Peptide ER ER Express yourself or die: peptides, MHC molecules, and NK cells. Science. 1995 Feb 17;267(5200):978-9. normal cell Ænot kille d oligosaccaride conjugate self MHC class I triggering receptor NK + foreign cell Æ kille d foreign peptide NK + inhibitory receptor self peptide foreign MHC class I mutant (cancer) cell Æ kille d NK virus-infecte d cell Æ kille d + NK + viral peptide 10 Acquired immunity (third-line) z Lymphocytes provide specific defenses induced by (1) Direct contact with microbes (2) Signals from active innate defenses cause lymphocytes to join the fight. first line second line third line INNATE IMMUNITY Rapid responses to a broad range of microbes - nonspecif ic Phagocyte signals External def enses Skin Mucous membranes Secretions Invading microbes (pathogens) ACQUIRED IMMUNITY Slower responses to specific microbes Internal def enses Phagocytic cells Antimicrobial proteins Inflammatory response Natural killer cells Humoral response (antibodies) Cell-mediated response (cytotoxic lymphocytes) zAntigens Antigens: Molecules that was recognized by lymphocytes and elicits a response zEpitope (antigenic determinant): A small portion where a lymphocyte actually recognizes and binds Antigenbinding sites Antibody A Epitopes (antigenic determinants) Antigen Antibody B Antibody C Figure 43.7 Epitopes 11 Lymphocytes (B cells and T cells) The vertebrate body is populated by two types of lymphocytes: -- B lymphocytes (B cells) and T lymphocytes (T cells) receptor receptor Antigens zA single B or T cell bears about 100,000 antigen receptors zAll the receptors on a single cell are identical Lymphocytes (B cells and T cells) Difference 1: receptor conformation 2H2LÆ2 Ag binding sites V V Antigenbinding site V C C Light chain Disulfide bridge C C Heavy chains B cell Antigenbinding site V Antigenbinding site 1α1βÆ1 Ag binding site Variable regions Constant regions Transmembrane region V V C C Plasma β chain membrane α chain Disulfide bridge membrane immunoglobulins (a) A B cell receptor consists of two identical heavy chains and two identical light chains linked by sev eral disulf ide bridges. T cell (b) A T cell receptor consists of one α chain and one β chain linked by a disulfide bridge. Figure 43.8 12 Difference 2: antigen recognition z B cell receptors recognize an intact antigen in its native state zT cell receptors recognize small Ag fragments that are bound to MHC presented by Ag presenting cells. MHC Ag Ag ER Why antigen presentation?? z Easier to kill virus-infected cells before virus amplification than to kill individual virus particles Why MHC needed?? zDuel-specificity model Tcr MHC 13 Two types of MHC molecules (antigen–presenting cells) (all nucleated cells) mainly dendritic cells, macrophages, and B cells Infected cell Antigenpresenting cell Microbe 1 A fragment of foreign protein (antigen) inside the cell associates with an MHC molecule and is transported to the cell surface. Antigen fragment 1 Class I MHC molecule Antigen fragment 1 Class II MHC molecule T cell receptor 2 2 2 The combination of MHC molecule and antigen is recognized by a T cell, alerting it to the infection. T cell receptor Helper T cell (a) Cytotoxic T cell (b) Figure 43.9 Cytotoxic T cell MHC II CD4 Tcr Ag MHC I phagocytes CD8 Tcr Ag nucleated cells Helper T cell zCluster of differentiation (CD) markers, CD8 and CD4, help the selection of MHC molecules Cytotoxic T cell (CD4 -/CD8 +) Æ MHC class I Hel perT cell (CD4 +/CD8 -) Æ MHC class II help for two 14 Overview of lymphocyte development z Lymphocytes originate from pluripotent stem cells in the bone marrow Bone marrow Thymus Ly mphoid stem cell B cell T cell Blood, lymph, and lymphoid tissues (ly mph nodes, spleen, and others) Lymphocyte development •It is estimated that each person has ~ 1 million different B cells and 10 million different T cells Three key events in the life of a lymphocyte 1. Generation of Diversity by Gene Rearrangement 2. Testing and Removal of Self–Reactive Lymphocytes 3. Clonal Selection of Lymphocytes Induced by encountered antigens 15 1. Generation of Lym phocyte Diversity by Gene Rearrangement eg. immunoglobulin (Ig) genes V –V 4 DNA of undifferentiated B cell V1 V2 39 V40 V3 J1 J2 J3 J4 J5 Intron C 1 Deletion of DNA between a V segment and J segment and joining of the segments DNA of differentiated B cell V1 V2 V3 J5 Intron recomb inases C 2 Transcription of res ulting permanentl y rearranged, functional gene pre-mRNA V3 J5 Intron C 3 RNA processing (removal of intron; addition of cap and poly (A) tail) mRNA Cap V3 J5 C Poly (A) 4 Translation Light-chain polypeptide V V C Variable Constant region region C B cell receptor B cell 2. Testing and Removal of Self– Self–Reactive Lymphocytes z The rearrangements of antigen receptor genes are random, which may generate receptors against self antigens. Î Failure of selection can lead to autoimmune diseases z B cells and T cells are maturing and are tested for potential self–reactivity in the bone marrow, thymus, and even lymphoid organs Î Lymphocytes with self-targeting receptors will be destroyed 16 Clonal selection of B cells (antigen–driven cloning of lymphocytes ) Antigen molecul es B cells that differ in antigen specificity Antigen receptor Some proliferating cells develop into long-lived Antibody memory cells that can molecules respond rapidl y upon subsequent exposure to the same antigen. Long-lived memory cells Short-lived effector cells Some proliferating cells develop into short-lived plas ma cells that secrete antibodies specific for the antigen. secondary immune response (2-7D) The specificity of immunological memory •Antibodies produced in the secondary response tend to have greater affin ity than those secreted in the primary response. 1 Day 1: First exposure to antigen A 3 Day 28: 2 Primar y Second exposure response to to antigen A; first antigen A exposure to produces antiantigen B bodies to A 4 Secondar y response to antigen A produces antibodies to A; primar y response to antigen B produces antibodies to B Antibody concentration (arbitrary units) 104 103 Antibodies to A 102 Antibodies to B 101 100 0 7 14 21 28 35 Time (days) 42 49 56 17 An overview of the acquired immune response Cell-mediated immune response Humoral immune respo nse First exposure to antigen Helper T cell Intact antige ns Antigens displayed Antigens engulfed and displayed by dendritic cells by infected cells Activate Activate B cell Gives rise to Gives rise to Plas ma cells Helper T cell Activate Secreted cytokines activate Memory B cells Active and me mory helper T cells Secrete antibodies that defend a gainst patho gens a nd toxins in extracellular fluid Cytotoxic T cell Gives rise to Memory cytotoxic T cells •re cognize peptide antigens displayed on phagocytes • in turn stimulates the activation of nearby B cells and cytotoxic T cells Active cytotoxic T cells Defend against infected cells, cancer cells, and trans planted t iss ues The central role of helper T cells 18 The central role of helper T cells immune responses Dendritic cells effective in presenting antigens to naive helper T cells in p rimary immune response Cytotoxic T cell Dendritic cell Bacterium Peptide antigen Class II MHC molecule Helper T cell Cell-mediated immunity (attack on infected cells) T CR 2 3 Humoral immunity (secretion of antibodies by plasma cells) 1 CD4 Dendritic cell Cytokines 3 T he cells in this clone secrete other cytokines that help activate B cells and cytotoxic T cells. Macrophages 3μ m B cell effective in presenting antigens to memory helper T cells in secondary immune response Cytotoxic T Cells: A Response to Infected Cells and Cancer Cells •Cytokines secreted from nearby helper T cells promote cytotoxic T cells to release perforins and proteolytic enzy mes (granzymes). Cytotoxic T cell Released cytotoxic T cell Perforin Cancer cell Granzymes 1 T CR Class I MHC molecule T arget cell 3 CD8 2 Apoptotic target cell Pore Peptide antigen Cytotoxic T cell •Certain cancers and viruses actively reduce the number of class I MHC molecu les on affected cells, help ing them escape detection by cytotoxic T cells. 19 Express yourself or die: peptides, MHC molecules, and NK cells. Science. 1995 Feb 17;267(5200):978-9. normal cell Ænot kille d oligosaccaride conjugate mutant (cancer) cell Æ kille d triggering receptor NK self MHC class I + NK + inhibitory receptor self peptide virus-infecte d cell Æ kille d foreign cell Æ kille d NK foreign MHC class I + NK + viral peptide foreign peptide B Cells: A Response to Extracellular Pathogens Bacterium Macrophage Peptide antigen Class II MHC molecule B cell 2 1 T CR 3 Clone of plasma cells Secreted antibody molecules Endoplasmic reticulum of plasma cell CD4 Cytokines Helper T cell Activated helper T cell Clone of memory B cells •Each plasma cell secretes an estimated 2,000 antibody molecules per second over the cell’s 4– to 5–day life span. 20 The five classes of immunoglobulins (antibodies) IgM (pentam er) First Ig class prod uced after i niti al exp osur e to antig en; then its co ncentr ation i n the bl oo d dec lin es J chain IgG (monom er) Promotes n eutral izati on a nd a ggl utin ation of antig ens; very effective i n comp lem ent activati on (see Figu re 43.1 9) Most abun da nt Ig class in b loo d; also p rese nt in tissue flui ds Only Ig class that crosses plac enta, thus co nferri ng passiv e immu nity on fetus Promotes o pson izati on, ne utral izatio n, and a gg luti natio n of antige ns; less effective in com plem ent activ ation th an IgM (see Figur e 43.1 9) IgA (dimer) Secretory compo ne nt Present i n secreti ons suc h as tears, sal iva, mucus, and br east milk J chain Provid es loc al ized d efens e of muco us membr anes by agg lutin atio n an d neutr aliz atio n of antig ens (se e Figure 4 3.19) Presenc e in br east milk c onfers p assiv e immu nity on nursi ng i nfant IgE (monomer) IgD (monom er) Transmem bran e regi on Triggers r ele ase from mast cel ls an d bas oph ils of histami ne a nd oth er chem ical s that cause a ll ergic reactio ns (see Fi gure 4 3.20) Present pr imari ly on surf ace of na ive B cel ls that have not bee n exp ose d to antig ens Acts as antige n rece ptor in a ntig en-stim ulate d prol iferati on an d differe ntiati on of B cel ls (clo nal selecti on) Four antibodyantibody- mediated mechanisms of antigen disposal 21 Antibody-- mediated mechanisms of antigen disposal Antibody Binding of antibod ies to antigens inactivates antigens by Viral neutralization Agglutination of (blocks binding to host) antigen-bearing particles, and opsonization (increases such as microbes phagocytosis) Precipitation of soluble antigens Complement proteins Bacteria Virus Activation of complement system and pore formation MAC Pore Soluble antigens Bacterium Foreign cell Enhances Leads to Phagocytosis Cell lysis Macrophage Positive immune feedback antibodies promote phagocytosis, enables A PC to present antigens and stimulate helper T cells, w hich in turn stimulate the very B cells. Activate complement proteins To generate a m em brane attack com plex (MAC) that forms a pore in the membrane. Applications of immunology z Blood Groups and Transfusions •Blood types: A, B, AB, O A-antigen individuals naturally have antibodies against the B antigen, even if they have never been exposed to type B blood! Q: w here are the antibodies from ?? •Explanation The antibodies arise in response to bacterial inhabitants of the body that have epitopes very similar to blood group antigens. Polysaccharides on bacteria Y anti-A Y A-type person bone marrow Y Y Y Y Y Y YY Y anti-B Ab anti-B 22 Blood Groups That Can and Cannot Be Safely Combine d in Transfusion Transfusion Type AB: “universal recipient” Type O: “universal donor” z Epitopes: polysaccharides. Î No memory cells are generated. Î Antibodies are always IgM. IgM does not cross the placenta Difference between T– T– dependent and T– T– independent antigens zT–dependent antigens: Antigens that induce antibody production by B cells with assistance from helper T cells zT–independent antigens Antigens evoke a B cell response without involvement of helper T cells. eg. polysaccharides of many bacterial capsules proteins that make up bacterial flagella -generates no memory B cells 23 Blood Group that can induce IgG and memory response z Rh factor a protein antigen allows immune responses to induce IgG and memory cells •Rh(+): contain Rh factor •Rh( ): lacks the Rh factor, will induce anti-Rh antibody A potentially dangerous situation Rh( ) mother carries a Rh(+) child Î Rh IgG antibodies can cross the placenta and destroy fetus red blood cells Strategy: Î mother is injected with anti–Rh antibodies around the seventh month of pregnancy and again just after delivering Problems during Tissue and Organ Transplants z Major histocompatibility complex (MHC) Î No two people have identical MHC, except identical twins and “clones” Strategy: The recipient takes medicines that suppress immune responses z Bone marrow transplant Strategy: The recipients are treated with irradiation to eliminate their own bone marro w cells, including any abnormal cells. Side effect New donated lymphocytes will react against the recipient z New hope Î stem cells and clone 24 Autoimmune Diseases Immune system turns against certain molecules of the body Systemic lupus erythematosus (lupus) •Self-antibodies against a wide range of self mo lecules, including histones and DNA released by the normal breakdown of body cells. Î skin rashes, fever, arthritis, and kidney dysfunction. •1 million sufferers in the U.S. •Strikes women nine times more often than men Butterfly rash of lupus Damaged kidney (left) caused by immunoglobulin deposits (right) Autoimmune Diseases z rheumatoid arthritis 類風濕性關節炎 Self-antibodies target to the cartilage and bone of joints rheumatoid arthritis 25 z Inborn (Primary) Immunodeficiencies •An immunodeficiency disease caused by a genetic or developmental defect in the immune system •Treatment: bone marrow transplant z Acquired (Secondary) Immunodeficiencies •Immune dysfunction develops later in life following exposure to various chemical and biological agents •AIDS (acquired immunodeficiency syndrome ): caused by a virus •Certain cancers that damage the lymphatic system. •Drugs used to fight autoimmune diseases or to prevent the rejection of a transplant z Human Immunodeficiency Virus (HIV ( HIV)) a retrovirus (reverse–transcribed, integrated, production of new virus) z HIV infected mechanism Use three proteins that participate in normal immune responses. 1. CD4 mo lecule on the helper T cells 2. co–receptor 1: chemokine receptor fusin (CXCR4) Æ on all the cell types infected by HIV 3. co–receptor 2: chemokine receptor CCR5 Æ only on macrophages and helper T cells Partially defective CCR5 confers increased HIV Resistance 26 Death of the helper T cells: -damaging effects of virus reproduction, -both infected and uninfected cells may undergo inappropriately timed apoptosis triggered by the virus. 1µm Figure 43.22 A T cell infected with HIV 27