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Chapter 43 The Immune System Biology, Seventh Edition Neil Campbell and Jane Reece Lectures by Chris Romero Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Overview: Reconnaissance (inspection), Recognition, and Response • An animal must defend itself – From the many dangerous pathogens it may encounter in the environment or abnormal cells that might develop into cancer • Two major kinds of defense have evolved that counter these threats – Innate immunity and acquired immunity Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Innate immunity – Is present before any exposure to pathogens and is effective from the time of birth – Involves nonspecific responses to pathogens Figure 43.1; a macrophage ingesting a yeast cell. 3m Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Innate immune system • nonspecific defense: it does not distinguish between infective agents. • External consisting of epithelial tissue that cover skin and mucus membranes • Internal it get trigered by chemical signals and involves macrophages and other phagocytic ells. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Acquired immunity, also called adaptive immunity – Develops only after exposure to inducing agents such as microbes, toxins, or other foreign substances – Involves a very specific response to pathogens – The recognition involves WBC called lymphocytes that produces the humoral (B cells secreting antibodies) and the cellular (T cells such as cytotoxic cells that directly kill the microbe). Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings A summary of innate and acquired immunity INNATE IMMUNITY Rapid responses to a broad range of microbes External defenses Skin Internal defenses Phagocytic cells Mucous membranes Antimicrobial proteins Secretions Inflammatory response Invading microbes (pathogens) Figure 43.2 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings ACQUIRED IMMUNITY Slower responses to specific microbes Natural killer cells Humoral response (antibodies) Cell-mediated response (cytotoxic lymphocytes) • Concept 43.1: Innate immunity provides broad defenses against infection • A pathogen that successfully breaks through an animal’s external defenses – Soon encounters several innate cellular and chemical mechanisms that impede its attack on the body Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings External Defenses • Intact skin and mucous membranes – Form physical barriers that bar the entry of microorganisms and viruses • Certain cells of the mucous membranes produce mucus – A viscous fluid that traps microbes and other particles such as in lungs. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • In the trachea, ciliated epithelial cells – Sweep mucus and any entrapped microbes upward, preventing the microbes from entering the lungs 10m Figure 43.3 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Secretions of the skin and mucous membranes – Provide an environment that is often hostile to microbes • Secretions from the skin – Give the skin a pH between 3 and 5, which is acidic enough to prevent colonization of many microbes – Also include proteins such as lysozyme, an enzyme that digests the cell walls of many bacteria • Stomach acidity; kills many bacteria ingested with food, however, some pathogens survive this acidity such as Hepatitis A virus. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Internal Cellular and Chemical Defenses • Internal cellular defenses – Depend mainly on phagocytosis • Phagocytes, types of white blood cells – Ingest invading microorganisms – Initiate the inflammatory response and produce antimicrobial proteins – None phagocytic cells are called natural killers that play a role in the innate immunity Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Phagocytic Cells • Phagocytes attach to their prey via surface receptors – And engulf them, forming a vacuole that fuses with a lysosome Pseudopodia 1 surround microbes. Microbes 2 Microbes are engulfed into cell. MACROPHAGE Vacuole containing microbes forms. 3 Vacuole Lysosome containing enzymes 4 Vacuole and lysosome fuse. Toxic 5 compounds and lysosomal enzymes destroy microbes. Microbial debris is released by exocytosis. 6 Figure 43.4 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • When engulfing any bacteria or virus, the engulfed mateial fuses with lysozymes which kills by two ways; • Generates toxic forms of oxygen as the super oxide anion and nitric oxide. • Lysosomal enzymes including lysozyme that digests the engulfed material. • However some pathoges has systems to evade these enzymes or they are naturally resistant to such lysosome as the TB pathogen Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Four Types of Phagocytic Cells • Neutrophils; comprise 60-70% of total WBCs. – Attracted by chemical signals, they enter infected tissue by amoeboid movement. So they are atracted by chemotaxis – Only live for few days as they destroy themselves when destroying pathogens. • Macrophages; a specific type of phagocyte – Can be found migrating through the body – Can be found in various organs of the lymphatic system and comprise about 5% of WBC. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Macrophages • – Long lived phagocytosis – Most wander through interstitial fluid engulfing bacteria, viruses and cell debris by means of extending pseudopodia that can attach to polysaccharides in the bacterial or viral surface. – Some reside permanently in organs and connective tissues. Eosinophils; have lower phagocytic activity and are crucial against intracellular parasites such as schistosoma mansoni by secreting enzymes damaging the parasite. • Dendritic cells; can ingest microbes but their major role to stimulate development of acquired immunity. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The lymphatic system • Plays an active role in defending the body from pathogens 1 Interstitial fluid bathing the tissues, along with the white blood cells in it, continually enters lymphatic capillaries. Interstitial fluid Adenoid Lymphatic capillary Tonsil Lymphatic vessels 4 return lymph to the blood via two large ducts that drain into veins near the shoulders. Lymph nodes Blood capillary Spleen Tissue Peyer’s patches cells (small intestine) Appendix Figure 43.5 Lymphatic vessels Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Fluid inside the 2 lymphatic capillaries, called lymph, flows through lymphatic vessels throughout the body. Lymph node Lymphatic vessel Within lymph nodes, microbes and foreign 3 particles present in the circulating lymph encounter macrophages, dendritic cells, and lymphocytes, which carry out various defensive actions. Masses of lymphocytes and macrophages Antimicrobial Proteins • Numerous proteins function in innate defense – By attacking microbes directly or by impeding their reproduction such as lysozymes. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Complement System • About 30 proteins make up the complement system – Which can cause lysis of invading cells and help trigger inflammation. – The presence of invading microbes triggers a cascade of reactions leads to lysis of invaders – In absence of infection these proteins will be inactive • Interferons; produced by viral infected cells – Provide innate defense against viruses and help activate macrophages – There are two types of interferons; Α and β – Some other lymphocytes produce γ interferon that activates macrophages to produce defensins, another antibmicrobial protein that kills wide range of bacteria. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Inflammatory Response • • A localized inflammatory response occurs when there is a damage in a tissue due to physical injury or entry of microorganisms. – dilation of small vessels near the injury increases blood flow to the area (causes redness). – The dilated vessels become more permeable allowing fluids and antimicrobial proteins to move into surrounding tissues resulting in localized edema. Certain chemical signals are important in initiating inflammatory response: Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings – Histamine is released from injured circulating basophils and mast cells in the connective tissue. Histamine increase dialtion thus increase permiability of nearby capillaries. – Prostaglandins also released from white blood cells and damaged cells. These promote blood flow to the injured area and enhances the migration of phagocytic cells from blood into the injury site. – This increased blood flow delivers clotting elements that help block the spread of pathogens and begin the repair process. – Phagocytes are attracted to the damaged tissues by several chemical signals including small proteins called Chemokines. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • – Neutrophils arrive first, followed by monocytes which develop into phagocytes. – Neutrophils eliminate pathogens and then die. – Macrophages destroy pathogens and clean up the remains of damaged tissues. In sever infections, e.g. meningitis, • the bone marrow may be stimulated to release more neutrophils by molecules emitted by injured cells and several fold leukocytes will be produced within hours. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings – A fever may develop in response to toxins released by pathogens, or due to pyrogens released by certain leukocytes. The pyrogens sets the body thermostat at higher temperature. – Moderate fever inhibits the growth of some microorganisms and also facilitate phagocytosis and speed up tissue repair. However, sever fever is dangerous – Certain pathogenes can induce an overwhelming immune response causing what is called septic shock that is characterized by high fever and low blood pressure. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Major events in the local inflammatory response Blood clot Pin Pathogen Macrophage Chemical signals Phagocytic cells Capillary Blood clotting elements Phagocytosis Red blood cell 1 Chemical signals released 2 by activated macrophages and mast cells at the injury site cause nearby capillaries to widen and become more permeable. Fluid, antimicrobial proteins,3 and clotting elements move from the blood to the site. Clotting begins. Figure 43.6 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 4 Chemokines released by various kinds of cells attract more phagocytic cells from the blood to the injury site. Neutrophils and macrophage phagocytose pathogens and cell debris at the site, and the tissue heals. Natural Killer Cells • Natural killer (NK) cells – Patrol the body and attack virus-infected body cells and cancer cells – it is attached to a virus or a cancers cell due to surface receptors on them. – The attachment trigger the release of ceratin chemicals that cause apoptosis in the cells they attack Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Invertebrate Immune Mechanisms • Many invertebrates defend themselves from infection – By many of the same mechanisms in the vertebrate innate response – Fruit fly have similar mechanism to vertebrates, they contain hemocytes as equavlent to blood. – Invertbrates lacks lymphocytes, thus they depend heavily on innate immune mechanisms to defend themselves against invaders. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Concept 43.2: In acquired immunity, lymphocytes provide specific defenses against infection • Acquired immunity – Is the body’s second major kind of defense – Involves the activity of lymphocytes Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Antigen Concept • An antigen is any foreign moleculethat is specifically recognized by lymphocytes and elicits a response from them • A lymphocyte actually recognizes and binds to just a small, accessible portion of the antigen called an epitope or an antigenic determinant (4-5 a.a). Antigenbinding sites Antibody A Antigen Antibody B Antibody C Figure 43.7 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Epitopes (antigenic determinants) Antigen Recognition by Lymphocytes • The vertebrate body is populated by two main types of lymphocytes – B lymphocytes (B cells) and T lymphocytes (T cells) which circulate through the blood – B and T cells recognize antigens by means of antigen specific receptors in their plasma membranes. • The plasma membranes of both B cells and T cells have about 100,000 antigen receptors that all recognize the same epitope Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings B Cell Receptors for Antigens • B cell receptors bind to specific, intact antigens – Are often called membrane antibodies or membrane immunoglobulins and are similar to secreted antibodies Antigenbinding site Antigenbinding site Disulfide bridge Variable regions Light chain C C Heavy chains B cell Plasma membrane Cytoplasm of B cell (a) Figure 43.8a Constant regions Transmembrane region A B cell receptor consists of two identical heavy chains and two identical light chains linked by several disulfide bridges. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings T Cell Receptors for Antigens and the Role of the MHC • Each T cell receptor consists of two different polypeptide chains AntigenBinding site Variable regions Constant regions V V C C Transmembrane region Plasma membrane a chain b chain Disulfide bridge Cytoplasm of T cell Figure 43.8b (b) A T cell receptor consists of one a chain and one b chain linked by a disulfide bridge. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings T cell • T cells bind to small fragments of antigens – That are bound to normal cell-surface proteins called MHC molecules • MHC molecules – Are encoded by a family of genes called the major histocompatibility complex Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Infected cells produce MHC molecules inside the cell and while they are being exported to cell surface, they bind a fragment of protein from antigens and will present it on the surface. This process is called antigen presentation • A nearby T cell – Can then detect the antigen fragment displayed on the cell’s surface and will elicit the production of a clone of T- cells that are specific for this particular peptide. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Depending on their source – Peptide antigens are handled by different classes of MHC molecules Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Class I MHC molecules • Found on almost all nucleated cells of the body – Display peptide antigens to cytotoxic T cells – Infected and cancerous cells display such peptide antigens. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Class I MHC molecules Infected cell 11 Antigen fragment A fragment of foreign protein (antigen) inside the cell associates with an MHC molecule and is transported to the cell surface. 1 Class I MHC molecule 2 T cell receptor Figure 43.9a (a) Cytotoxic T cell Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 2 The combination of MHC molecule and antigen is recognized by a T cell, alerting it to the infection. Class II MHC molecules • Located mainly on dendritic cells, macrophages, and B cells (Antigen presenting cells, APC). – Bind peptides derived from foreign materials that have been internalized by phagocytosis. – Display antigens to helper T cells – Humans have large number of different MHC alleles in human population. – Any two people (except identical twins) are very unlikely to have same set of MHC molecules. – MHC provides fingerprint of each individual Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Class II MHC molecules Microbe Antigenpresenting cell 1 A fragment of foreign protein (antigen) inside the cell associates with an MHC molecule and is transported to the cell surface. Antigen fragment Class II MHC molecule 2 1 T cell receptor The combination of MHC molecule and antigen is recognized by a T cell, alerting it to the infection. 2 Helper T cell (b) Figure 43.9b Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Lymphocyte Development • Lymphocytes – Arise from pluripotent stem cells in the bone marrow • Newly formed lymphocytes are all alike – But they later develop into B cells or T cells, depending on where they continue their maturation. • There are three events in the life of a lymphocyte – First 2 events are;Lymphocyte maturation of B or T – Third event is the lymphocyte encounter with an antigen that leads to its activation, proliferation and differentiation, a process called clonal selection. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Development and Differentiation of lymphocyte Bone marrow Lymphoid stem cell Thymus T cell B cell Both circulate in Blood, lymph, and lymphoid tissues (lymph nodes, spleen, and others) Figure 43.10 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Generation of Lymphocyte Diversity by Gene Rearrangement • B and T lymphocytes recognize specific epitopes on antigens via their antigen receptors. • A single B or T cell has about 100,000 or these receptors. • The variable region at the tip of each antigen receptor chain (antigen binding site) forms this diversity. • The sequence of a.a. in these regions varies from cell to cell, thus it is estimated that each individual has as many as 1 million different B cells and 10 million T-cells each respond to different antigen. • Early in development, random, permanent gene rearrangement Forms functional genes encoding the different B or T cell antigen receptor chains. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Immunoglobulin gene rearrangement V4–V39 DNA of undifferentiated B cell V2 V1 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 V3 J5 Intron V2 C 2 Transcription of resulting permanently rearranged, functional gene pre-mRNA V3 J5 Intron 3 mRNA Cap V3 J 5 C RNA processing (removal of intron; addition of cap and poly (A) tail) C Poly (A) 4 Translation Light-chain polypeptide Figure 43.11 V C Variable Constant region region Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings B cell receptor B cell Summary of the immunoglobulin gene rearrangement • Immunglobulin light chain gene contains a series of 40 variable gene segments separated by long stretch of DNA from the 5 Joining (J) gene segments. • Down stream of the J segments there is an intron and an exon (C) that codes for the constant region. • Early in development, a set of enzymes called recombinase links one V gene to a J segment eliminating the long stretch of DNA and forming one exon • Recombinase acts randomly thus it could join any of the V gene segments to the J segments i.e 200 combinations with only one combination/cell. • Once this combination takes place, the gene can be transcribed mRNA processed and translated to a light chain with both variable and constant regions. • The light chain produced will randomly combine with a heavy chain that was made in the same way. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Testing and Removal of Self-Reactive Lymphocytes • As B and T cells are maturing in the bone and thymus – Their antigen receptors are tested for possible self-reactivity • Lymphocytes bearing receptors for antigens already present in the body – Are destroyed by apoptosis or rendered nonfunctional • The immune system exhibits the critical feature of self-tolerance. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Clonal Selection of Lymphocytes – Binding of antigen to a mature lymphocyte induces the lymphocyte’s proliferation and differentiation, a process called clonal selection. – Clonal selection generates; • a clone of short-lived activated effector cells • a clone of long-lived memory cells Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Clonal selection of B cells Antigen molecules B cells that differ in antigen specificity Antigen molecules bind to the antigen receptors of only one of the three B cells shown. Antigen receptor The selected B cell proliferates, forming a clone of identical cells bearing receptors for the selecting antigen. Some proliferating cells develop into long-lived memory cells that can respond rapidly upon subsequent exposure to the same antigen. Some proliferating cells develop into short-lived plasma cells that secrete antibodies specific for the antigen. Antibody molecules Clone of memory cells Figure 43.12 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Clone of plasma cells – The nature and function of the effector cell depends on whether the lymphocyte selected is a helper T cell, a cytotoxic T cell or a B cell. – The other clone consist of memory cells that live long and bear receptors for specific for same inducing antigen. – So the clonal selection can be defined as this; each antigen by binding to specific receptor, selectively activates a tiny fraction of cells from the body’s diverse pool of lymphocytes that is dedicated to destroy the antigen. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Primary Immune Response – Is the proliferation of lymphocytes to form effecter cells specific to an antigen during the body’s first exposure to the antigen. – There is 10-17 days lag period between initial exposure and maximum production of effecter cells. Mainly IgM – The lympnocytes selected by the antigen are differentiated into B and T cells during the lag period. – Activated B cells give rise to effecter cells called plasma cells which secrete antibodies (humoral response). Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Secondary immune response • Memory cells facilitate a faster, more efficient response that takes 2-7 days. IgG mainly 1 Day 1: First exposure to antigen A 2 Primary response to antigen A produces antibodies to A 3 Day 28: Second exposure to antigen A; first exposure to antigen B 4 Secondary response to antigen A produces antibodies to A; primary response to antigen B produces antibodies to B Antibody concentration (arbitrary units) 104 103 102 Antibodies to A Antibodies to B 101 100 0 Figure 43.13 7 14 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 21 28 35 Time (days) 42 49 56 • Secondary response leads to the production of very high amount of antibodies that have more affinity than the antibodies produced in the primary response. • The immunes system capacity to generate secondary immune response is called Immmunological memory Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Concept 43.3: Humoral and cell-mediated immunity defend against different types of threats • Acquired immunity includes two branches – The humoral immune response involves the activation and clonal selection of B cells, resulting in the production of secreted antibodies – The cell-mediated immune response involves the activation and clonal selection of cytotoxic T cells Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings An overview of the acquired immune response Cell-mediated immune response Humoral immune response First exposure to antigen Intact antigens Antigens engulfed and displayed by dendritic cells Antigens displayed by infected cells Activate Activate Activate B cell Gives rise to Plasma cells Figure 43.14 Memory B cells Helper T cell Gives rise to Active and memory helper T cells Secrete antibodies that defend against pathogens and toxins in extracellular fluid Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Secreted cytokines activate Cytotoxic T cell Gives rise to Memory cytotoxic T cells Active cytotoxic T cells Defend against infected cells, cancer cells, and transplanted tissues Helper T Cells: A Response to Nearly All Antigens • Helper T cells produce CD4, a surface protein – That enhances their binding to class II MHC molecule– antigen complexes on antigen-presenting cells • When helper T-cell encounters a class II MHC moleculeantigen complex, TH proliferates and differentiate into a clone of activated TH and memory TH. • Class II MHC molecules found mainly on dendritic cells, B cells and Macrophages. \ • Dendritic cells are particularly effective in triggering primary immune response. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Activated helper T cells – Secrete several different cytokines that stimulate other lymphocytes thereby promoting cell mediated and humoral response. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The role of helper T cells in acquired immunity 1 After a dendritic cell engulfs and degrades a bacterium, it displays bacterial antigen fragments (peptides) complexed with a class II MHC molecule on the cell surface. A specific helper T cell binds to the displayed complex via its TCR (T-cell receptor) with the aid of CD4. This interaction promotes secretion of cytokines by the dendritic cell. Cytotoxic T cell Peptide antigen Dendritic cell Class II MHC molecule Bacterium Helper T cell Cell-mediated immunity (attack on infected cells) TCR 2 3 1 CD4 Dendritic cell Cytokines 2 Proliferation of the T cell, stimulated by cytokines from both the dendritic cell and the T cell itself, gives rise to a clone of activated helper T cells (not shown), all with receptors for the same MHC–antigen complex. Figure 43.15 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings B cell 3 The cells in this clone secrete other cytokines that help activate B cells and cytotoxic T cells. Humoral immunity (secretion of antibodies by plasma cells) Cytotoxic T Cells: A Response to Infected Cells and Cancer Cells • Cytotoxic T cells make CD8 – A surface protein that greatly enhances the interaction between a target cell and a cytotoxic T cell – The role of class I MHC molecules and the CD8 is similar to that for class II MHC and CD4 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Cytotoxic T cells – Bind to viral infected cells , cancer cells, and transplanted tissues • Binding to a class I MHC complex on an infected body cell – Activates a cytotoxic T cell and differentiates it into an active killer – Nearby helper T cells secrete cytokines that promote this activation. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The activated cytotoxic T cell secretes proteins • that destroy the infected target cell and present its fragments to circulating antibodies for long immunity. 1 A specific cytotoxic T cell binds to a 2 The activated T cell releases perforin class I MHC–antigen complex on a molecules, which form pores in the target cell via its TCR with the aid of target cell membrane, and proteolytic CD8. This interaction, along with enzymes (granzymes), which enter the cytokines from helper T cells, leads to target cell by endocytosis. the activation of the cytotoxic cell. Cytotoxic T cell 3 The granzymes initiate apoptosis within the target cells, leading to fragmentation of the nucleus, release of small apoptotic bodies, and eventual cell death. The released cytotoxic T cell can attack other target cells. Released cytotoxic T cell Perforin Cancer cell Granzymes 1 TCR Class I MHC molecule Target cell 3 CD8 2 Apoptotic target cell Pore Peptide antigen Figure 43.16 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Cytotoxic T cell • Cancerous cells also display class I MHC moleules on their surface. • These are abnormal thus are recognized by cytotoxic T-cells which destroys them and presenting them to curculating antibodies. • Some cancerous cells minimize their production of class I MHC molecules to avoid body’s immune system. • In this case NK cells which are part of non-specific immune system will kill these cells. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings B Cells: A Response to Extracellular Pathogens • Antigens that elicit a humoral response are typically proteins and polysaccharides present on surface of bacteria or from pollens or transplanted tissues. • Activation of B cells is aided by cytokines and antigen binding to helper T cells • Upon stimulation, active B cells proliferate and differentiate into a clone of antibody secreting plasma cells and a clone of memory cells. This is called the clonal selection of B-cells. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • When an antigen binds to a receptor on surface of B cells, cells takes in a few molecules from the fragmented molecule by endocytosis. • Cell presents these antigen fragments to HT which will guarantee a direct binding between HT and the B-cell which is necessary for their activation. • Antigens that induce antibody production only with assistance of HT are called T-dependent antigens. • Some other antigens can evoke B-cell response without involvment of TH such polysaccharides and flagellar antibodies of bacterial are called T-independent antigens. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 1 After a macrophage engulfs and degrades a bacterium, it displays a peptide antigen complexed with a class II MHC molecule. A helper T cell that recognizes the displayed complex is activated with the aid of cytokines secreted from the macrophage, forming a clone of activated helper T cells (not shown). 2 3 The activated B cell proliferates A B cell that has taken up and degraded the same bacterium displays class II MHC–peptide and differentiates into memory antigen complexes. An activated helper T cell B cells and antibody-secreting bearing receptors specific for the displayed plasma cells. The secreted antigen binds to the B cell. This interaction, antibodies are specific for the with the aid of cytokines from the T cell, same bacterial antigen that activates the B cell. initiated the response. Bacterium Macrophage Peptide antigen Class II MHC molecule B cell 2 3 1 TCR Clone of plasma cells Endoplasmic reticulum of plasma cell CD4 Cytokines Helper T cell Secreted antibody molecules Activated helper T cell Figure 43.17 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Clone of memory B cells Antibody Classes • The five major classes of antibodies, or immunoglobulins – Differ in their distributions and functions within the body Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The five classes of immunoglobulins IgM (pentamer) First Ig class produced after initial exposure to antigen; then its concentration in the blood declines J chain Promotes neutralization and agglutination of antigens; very effective in complement activation (see Figure 43.19) Most abundant Ig class in blood; also present in tissue fluids Only Ig class that crosses placenta, thus conferring passive immunity on fetus IgG (monomer) Promotes opsonization, neutralization, and agglutination of antigens; less effective in complement activation than IgM (see Figure 43.19) Present in secretions such as tears, saliva, mucus, and breast milk IgA (dimer) Secretory component J chain Provides localized defense of mucous membranes by agglutination and neutralization of antigens (see Figure 43.19) Presence in breast milk confers passive immunity on nursing infant IgE (monomer) IgD (monomer) Figure 43.18 Transmembrane region Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Triggers release from mast cells and basophils of histamine and other chemicals that cause allergic reactions (see Figure 43.20) Present primarily on surface of naive B cells that have not been exposed to antigens Acts as antigen receptor in antigen-stimulated proliferation and differentiation of B cells (clonal selection) Antibody-Mediated Disposal of Antigens • The binding of antibodies to antigens Is also the basis of several antigen disposal mechanisms. – The simplest of these is viral neutralization (Ab binds the virus, thus making it unable to inter the cell). – Ab binds to pathogens thus coating its surface. This process called oposnization. – Opsonization leads to elimination of microbes by phagocytosis and complement-mediated lysis – Ab mediated clumping of pathogens is another mechanism. IgM is the best to do this. – Antibodies could also precipitate soluble antigens thus making them available for phagocytosis. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Antibody-mediated mechanisms of antigen disposal Binding of antibodies to antigens inactivates antigens by Viral neutralization (blocks binding to host) and opsonization (increases phagocytosis) Agglutination of antigen-bearing particles, such as microbes Precipitation of soluble antigens Complement proteins Bacteria Virus Soluble antigens Bacterium Activation of complement system and pore formation MAC Pore Foreign cell Enhances Leads to Phagocytosis Cell lysis Figure 43.19 Macrophage Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Active and Passive Immunization • Active immunity – Develops naturally in response to an infection – Can also develop following immunization, often called vaccination Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • In immunization – A nonpathogenic form of a microbe or part of a microbe elicits an immune response to an immunological memory for that microbe – Developed by Edward Jenner in 1796. Later become the savor of hundreds of millions of people all over the world. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Passive immunity, which provides immediate, short-term protection – Is conferred naturally when IgG crosses the placenta from mother to fetus or when IgA passes from mother to infant in breast milk – Can be conferred artificially by injecting antibodies into a nonimmune person – Example; people bitten by rabid dogs get passive immunity to keep virus at bay and active to develop person’s own immune system. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Concept 43.4: The immune system’s ability to distinguish self from non-self limits tissue transplantation • The immune system – Can wage war against cells from other individuals • Transplanted tissues – Are usually destroyed by the recipient’s immune system Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Blood Groups and Transfusions • Certain antigens (glycoproteins) on red blood cells – Determine whether a person has type A, B, AB, or O blood – Type A contains antigen A on its surface – Type B contain antigen B on in its surface – Type AB contains antigens A and B on its surface – Type O contains NO antigens on its surface Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Antibodies to nonself blood types – Already exist in the body!!!! How can some thing like that happen? – These antibodies might have arise in response to normal bacterial inhibitants of the body that have epitopes very similar to blood group antigens. • Transfusion with incompatible blood – Leads to destruction of the transfused cells due to the presence of the preexisting antibodies against different blood gropus. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Recipient-donor combinations; Can be fatal or safe Table 43.1 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Antibodies against blood groups are always IgMs. This is a blessing as these does not cross the placenta, thus does not destroy the fetus even when his/her blood does not match the mothers. • Another red blood cell antigen, the Rh factor – Creates difficulties when an Rh-negative mother carries successive Rh-positive fetuses – Rh negative persons do not have Rh antigens – Rh negative mothers with negative fetus creates No problem – Rh negative mothers with positive fetus will have a reaction that destroys fetus – Rh positive mothers with +ve or –ve fetus does not create a problem Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Tissue and Organ Transplants • MHC molecules – Are responsible for stimulating the rejection of tissue grafts and organ transplants – The polymorphism of MHC molecules garantees that no two people have the same set of MHC molecules – To prevent rejection of grafts, donors and recipients must have similar (as much as possible) MHC, and immunosuppressive drugs are to be used. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • In bone marrow transplantation, the immune system of recepients will be wiped out completely by radiation to kill both normal and abonromal cancerous cells. • The fear here is that the donors cells will react against the host, therefore, it is necessary to have two people with matched MHC molecules as possible. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Concept 43.5: Exaggerated, self-directed, or diminished immune responses can cause disease • If the delicate balance of the immune system is disrupted – The effects on the individual can range from minor such as allergy to often fatal consequences of serious autoimmune diseases and immunodeficiency diseases. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Allergies • Allergies are exaggerated (hypersensitive) responses – To certain antigens called allergens – Most common allergies involve IgE class antibodies Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • In localized allergies such as hay fever – IgE antibodies produced after first exposure to an allergen attach to receptors on mast cells • The next time the allergen enters the body – It binds to mast cell–associated IgE molecules • The mast cells then release histamine and other mediators – That cause vascular changes and typical symptoms of allergy. Figure 43-20. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The allergic response IgE Histamine Allergen 1 3 2 Granule Mast cell 1 IgE antibodies produced in response to initial exposure to an allergen bind to receptors or mast cells. 3 2 On subsequent exposure to the same allergen, IgE molecules attached to a mast cell recognize and bind the allergen. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Figure 43.20 Degranulation of the cell, triggered by cross-linking of adjacent IgE molecules, releases histamine and other chemicals, leading to allergy symptoms. • An acute allergic response sometimes leads to anaphylactic shock – A whole-body, life-threatening reaction that can occur within seconds of exposure to an allergen – Anaphylactic shock develops when a widespread mast cell degranulation triggers abrupt dilation of peripheral blood vessels. – Allergic to bee venom or penicillin or even peanuts or fishcan lead to such anaphylactic shock in people who are extremely allergic to such substances. – People with such type of allergy carry syringes with epinephrine hormone that counteracts such allergy. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Autoimmune Diseases • In individuals with autoimmune diseases – The immune system loses tolerance for self and turns against certain molecules of the body Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Other examples of autoimmune diseases include – Systemic lupus erythematosus where the immune system generates antibodies against a wide range of self molecules including histones and DNA released by normal breakdown of body cells. This disease is characterized by skin rashes (butterfly shape on the face), fever, arthritis and kidney disfunction. – Multiple sclerosis is the most common chronic disease in developed countries; in this disease T cells infiltrate the CNS and destroy myelin sheath that surrounds some neurons. – Insulin-dependent diabetes where the insulin producting beta cells of the pancreas are the target of the cytotoxic T cells Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Rheumatoid arthritis – Is an autoimmune disease that leads to damage and painful inflammation of the cartilage and bone of joints Figure 43.21 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Immunodeficiency Diseases • An inborn or primary immunodeficiency – Results from hereditary or congenital defects that prevent proper functioning of innate, humoral, and/or cell-mediated defenses – Defects of IgA and complement system leads to such a disorder. – People with this disease are susceptible to infectious disease and cancers . – Some people will have defected humoral and cellular immune systems leading to severe combined immunodeficiency disease (SCID). Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • In one type of SCID, a deficency of the enzyme adenosine deaminase leads to accumulation of substances that are toxic to both B and T cells. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • An acquired or secondary immunodeficiency – Range from temporary states to chronic diseases – Results from exposure to various chemical and biological agents – Drugs used to suppress immune system after tissue transplantation – Certain cancers such as Hodgkin’s disease damages the lymphatic system thus suppress the immune system. – Viruses such as HIV suppresses the immune system Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Stress and the Immune System • Growing evidence shows – That physical and emotional stress can harm immunity – Nearly 2000 years ago Greek physician Galen recorded that people suffering from depression are more likely to develop cancer…How? – Hormones secreted during stress affect the numbers of WBC and may sppress the immune system in other ways. – Some neurotransmitters secreted when we are happy may enhance immunity. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Acquired Immunodeficiency Syndrome (AIDS) • People with AIDS – Are highly susceptible to opportunistic infections and cancers that take advantage of their collapsed immune system. – Example Pneumocystis carinii a ubiquitous fungus cause severe pneumonia in people with AIDS but cant cause any disease in healthy. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Because AIDS arises from the loss of helper T cells – Both humoral and cell-mediated immune responses are impaired. – HIV inters cells by using three proteins that participate in normal immune response. – The main receptor is the CD4 molecules, virus also infects other cells such as macrophages and brain cells. – In addition to CD4, HIV requires a second protein a coreceptor. One of these is called fusin that present on all cells infected by HIV. – Other co-receptor is found only on macrophages and helper T cell. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • A T cell infected with HIV; newly made virus particles (gray) are seen budingfrom the surface of the T cell in this colorized SEM. Figure 43.22 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 1µm • The spread of HIV – Has become a worldwide problem – Transfer of HIV requires the transfer of body fluids containing infected cells. • The best approach for slowing the spread of HIV – Is educating people about the practices that transmit the virus. – Illegal sex and drugs are among the issues that need to be stressed upon in this context. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings End Of Chapter Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings