Immune System - IMMUNITY ntact skin Intact Mucous Membrane...

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Unformatted text preview: IMMUNITY ntact skin Intact Mucous Membrane Immunity: Two Intrinsic Defense Systems • Innate (nonspecific) system responds quickly and consists of: – First line of defense – Intact skin and mucosae prevent entry of microorganisms Immunity: Two Intrinsic Defense Systems • Innate (nonspecific) system responds quickly and consists of: – First line of defense – Intact skin and mucosae prevent entry of microorganisms ESOPHAGUS GASTROESOPHAGEAL JUNCTION STOMACH Immunity: Two Intrinsic Defense Systems • Innate (nonspecific) system responds quickly and consists of: – Second line of defense – antimicrobial proteins, phagocytes, and other cells • Inhibit spread of invaders throughout the body Red color is the color of Inflammation Immunity: Two Intrinsic Defense Systems • Innate (nonspecific) system responds quickly and consists of: – Second line of defense – antimicrobial proteins, phagocytes, and other cells • Inflammation is its hallmark and most important mechanism A hallmark of inflammation is “ Redness” Immunity: Two Intrinsic Defense Systems • Adaptive (specific) defense system – Third line of defense – mounts attack against particular foreign substances • Takes longer to react than the innate system • Skin, mucous membranes, and their secretions make up the first line of defense • Keratin in the skin: – Presents a formidable physical barrier to most microorganisms Epithelial Chemical Barriers • Epithelial membranes produce protective chemicals that destroy microorganisms – Skin acidity (pH of 3 to 5) inhibits bacterial growth Epithelial Chemical Barriers • Epithelial membranes produce protective chemicals that destroy microorganisms – Saliva and lacrimal fluid contain lysozyme Epithelial Chemical Barriers • Epithelial membranes produce protective chemicals that destroy microorganisms – Stomach mucosae secrete concentrated HCl and protein-digesting enzymes Epithelial Chemical Barriers • Epithelial membranes produce protective chemicals that destroy microorganisms – Mucus traps microorganisms that enter the digestive and respiratory systems Respiratory Tract Mucosae • Mucus-coated hairs in the nose trap inhaled particles Respiratory Tract Mucosae • Mucosa of the upper respiratory tract is ciliated – Cilia sweep dust- and bacteria-laden mucus away from lower respiratory passages – Pseudostratified ciliated columnar epithelium + Mucus = mucociliary escalator Internal Defenses: Cells and Chemicals • The body uses nonspecific cellular and chemical devices to protect itself – Phagocytes and natural killer (NK) cells Internal Defenses: Cells and Chemicals • The body uses nonspecific cellular and chemical devices to protect itself – Inflammatory response enlists macrophages, mast cells, WBCs, and chemicals Phagocytes • Macrophages are the chief phagocytic cells • Free macrophages wander throughout a region in search of cellular debris Phagocytes • Kupffer cells (liver) and microglia (brain) are fixed macrophages Phagocytes • Neutrophils become phagocytic when encountering infectious material • Eosinophils are weakly phagocytic against parasitic worms Phagocytes • Mast cells bind and ingest a wide range of bacteria Mechanism of Phagocytosis Natural Killer (NK) Cells • Cells that can lyse and kill cancer cells and virus-infected cells • Natural killer cells: – Are a small, distinct group of large granular lymphocytes Inflammation: Tissue Response to Injury • The inflammatory response is triggered whenever body tissues are injured – Prevents the spread of damaging agents to nearby tissues Inflammation: Tissue Response to Injury • The inflammatory response is triggered whenever body tissues are injured – Disposes of cell debris and pathogens Inflammation: Tissue Response to Injury • The inflammatory response is triggered whenever body tissues are injured – Sets the stage for repair processes Inflammation: Tissue Response to Injury • The four cardinal signs of acute inflammation are redness Inflammation: Tissue Response to Injury • The four cardinal signs of acute inflammation are heat Inflammation: Tissue Response to Injury • The four cardinal signs of acute inflammation are swelling Inflammation: Tissue Response to Injury • The four cardinal signs of acute inflammation are pain Inflammation Response • Begins with a flood of inflammatory chemicals released into the extracellular fluid Toll-like Receptors (TLRs) • Macrophages and cells lining the gastrointestinal and respiratory tracts bear TLRs (release cytokines) Inflammatory Response: Vascular Permeability Vascular • Chemicals increase the Chemicals permeability of local capillaries permeability Inflammatory Response: Vascular Permeability • Exudate (fluid containing proteins, clotting factors, and antibodies): – Seeps into tissue spaces causing local edema (swelling), which contributes to the sensation of pain Inflammatory Response: Edema • The surge of protein-rich fluids into tissue spaces (edema): Ascites Inflammatory Response: Phagocytic Mobilization • Occurs in four main phases: – Leukocytosis – neutrophils are released from the bone marrow in response to leukocytosis-inducing factors released by injured cells Inflammatory Response: Phagocytic Mobilization • Occurs in four main phases: – Margination – neutrophils cling to the walls of capillaries in the injured area Inflammatory Response: Phagocytic Mobilization • Occurs in four main phases: – Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis Betty Lou drops her handkerchief, and Cyrus picks it up to return it to her. However, she's disappointed because he doesn't even look at her. This time induced chemotaxis appears not to have worked… Inflammatory Response: Phagocytic Mobilization • Occurs in four main phases: – Chemotaxis – inflammatory chemicals attract neutrophils to the injury site 4 Positive chemotaxis Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents 1 Neutrophils enter blood from bone marrow Capillary wall 2 Endothelium Basal lamina Margination 3 Diapedesis Flowchart of Events in Inflammation Antimicrobial Proteins • Important antimicrobial proteins are: – Interferon Antimicrobial Proteins • Important antimicrobial proteins are: – Complement proteins Interferon (IFN) • Genes that synthesize IFN are activated when a host cell is invaded by a virus • Interferon molecules leave the infected cell and enter neighboring cells Interferon (IFN) • Interferon stimulates the neighboring cells to activate genes for PKR (an antiviral protein) • PKR nonspecifically blocks viral reproduction in the neighboring cell Interferon Family • Interferons are a family of related proteins each with slightly different physiological effects Interferon Family • Lymphocytes secrete gamma (γ ) interferon, Interferon Family • Most other WBCs secrete alpha (α) interferon Do you remember me? I am your friend MR Fibroblast whom you met for the first time in A&P 1 Interferon Family • Fibroblasts secrete beta (β) interferon Interferon Family • Interferons also activate macrophages and mobilize NKs Interferon Family • Interferons also activate macrophages and mobilize NKs Interferon Family • FDA-approved alpha IFN is used: – As an antiviral drug against hepatitis C virus – To treat genital warts caused by the Human Papillomavirus Complement • 20 or so proteins that circulate in the blood in an inactive form Complement • Proteins include C1 through C9, factors B, D, and P, and regulatory proteins Complement • Amplifies all aspects of the inflammatory response Complement • Kills bacteria and certain other cell types (our cells are immune to complement) Complement Pathways • Complement can be activated by two pathways: classical and alternative Complement Pathways • Classical pathway is linked to the immune system – Depends on the binding of antibodies to invading organisms – Subsequent binding of C1 to the antigen-antibody complexes (complement fixation) Complement Pathways • Alternative pathway is triggered by interaction among factors B, D, and P, and polysaccharide molecules present on microorganisms Complement Pathways • Alternative pathway is triggered by interaction among factors B, D, and P, and polysaccharide molecules present on microorganisms Complement Pathways Each pathway involves a cascade in which complement proteins are activated in an orderly sequence and where each step catalyzes the next Complement Pathways • Both pathways converge on C3, which cleaves into C3a and C3b Complement Pathways • Both pathways converge on C3, which cleaves into C3a and C3b She has been opsonized by sunflowers Complement Pathways • C3b also causes opsonization, and C3a causes inflammation Complement Pathways • C3b initiates formation of a membrane attack complex (MAC) C-reactive Protein (CRP) • CRP is produced by the liver in response to inflammatory molecules • Increased levels 1. Allograft vasculopathy and graft occlusion 2. Malignancy 3. Connective tissue disease (e.g. , lupus erythematosus, Wegener's granulomatosis) 4. Coronary artery disease 5. Obesity 6. Sepsis 7. Smoking 8. Vasculitis C-reactive Protein (CRP) • Positive CRP results also occur during the last half of pregnancy or with the use of oral contraceptives. C-reactive Protein (CRP) • Positive CRP results also occur during the last half of pregnancy or with the use of oral contraceptives. C-reactive Protein (CRP) CRP is a clinical marker used to assess for: – The presence of an acute infection – An inflammatory condition and its response to treatment Functions of C-reactive Protein • Binds to PC receptor of pathogens and exposed self-antigens • Plays a surveillance role in targeting damaged cells for disposal • Activates complement Fever • Abnormally high body temperature in response to invading microorganisms Fever • The body’s thermostat is reset upwards in response to pyrogens, chemicals secreted by leukocytes and macrophages exposed to bacteria and other foreign substances Fever • High fevers are dangerous as they can denature enzymes Graph showing effect of temperature on enzyme activity the temperature at which the enzyme activity activity enzyme is the highest is called the optimum temperature declines when temperature enzyme enzyme activity increases activity as temperature increases is high than the optimum because enzyme is low temperature – denatured low enzyme activity temperature Fever • Moderate fever can be beneficial, as it causes: – The liver and spleen to sequester iron and zinc (needed by microorganisms) – An increase in the metabolic rate, which speeds up tissue repair Adaptive (Specific) Defenses • The adaptive immune system is a functional system that: – Recognizes specific foreign substances – Acts to immobilize, neutralize, or destroy foreign substances – Amplifies inflammatory response and activates complement Adaptive Immune Defenses • The adaptive immune system is antigen-specific, systemic, and has memory Adaptive Immune Defenses • The adaptive immune system is antigen-specific, systemic, and has memory Adaptive Immune Defenses • The adaptive immune system is antigen-specific, systemic, and has memory Adaptive Immune Defenses • It has two separate but overlapping arms – Humoral, or antibody-mediated immunity PLASMA CELLS Adaptive Immune Defenses • It has two separate but overlapping arms – Cellular, or cell-mediated immunity Antigens are like art, they will create a response in you……. Antigens • Substances that can mobilize the immune system and provoke an immune response Antigens • The ultimate targets of all immune responses are mostly large, complex molecules not normally found in the body (nonself) Complete Antigens • Important functional properties: – Immunogenicity – the ability to stimulate proliferation of specific lymphocytes and antibody production Flower Reaction Complete Antigens • Important functional properties: – Reactivity – the ability to react with the products of the activated lymphocytes and the antibodies released in response to them Complete Antigens • Complete antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides What am I wearing here? I am wearing Haptens Haptens (Incomplete Antigens) • Small molecules, such as peptides, nucleotides, and many hormones, that are not immunogenic but are reactive when attached to protein carriers Haptens (Incomplete Antigens) If they link up with the body’s proteins, the adaptive immune system may recognize them as foreign and mount a harmful attack (allergy) Haptens (Incomplete Antigens) • Haptens are found in poison ivy, dander, some detergents, and cosmetics Haptens (Incomplete Antigens) • Haptens are found in poison ivy, dander, some detergents, and cosmetics Antigenic Determinants • Only certain parts of an entire antigen are immunogenic • Antibodies and activated lymphocytes bind to these 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) have little or no immunogenicity Self-Antigens: MHC Proteins • Our cells are dotted with protein molecules (self-antigens) that are not antigenic to us but are strongly antigenic to others Self-Antigens: MHC Proteins • One type of these, MHC proteins, mark a cell as self • The two classes of MHC proteins are: – Class I MHC proteins – found on virtually all body cells (nucleated cells only) Self-Antigens: MHC Proteins • The two classes of MHC proteins are: – Class II MHC proteins – found on certain cells (IMMUNE SYSTEM) in the immune response Groove MHC Proteins • Are coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual • Each MHC molecule has a deep groove that displays a peptide, which is a normal cellular product of protein recycling MHC Proteins • In infected cells, MHC proteins bind to fragments of foreign antigens, which play a crucial role in mobilizing the immune system Cells of the Adaptive Immune System • Two types of lymphocytes – B lymphocytes – oversee humoral immunity Cells of the Adaptive Immune System • Two types of lymphocytes – T lymphocytes – non-antibody-producing cells that constitute the cell-mediated arm of immunity Cells of the Adaptive Immune System • Antigen-presenting cells (APCs): – Do not respond to specific antigens – Play essential auxiliary roles in immunity Lymphocytes • Immature lymphocytes released from bone marrow are essentially identical Lymphocytes • Whether a lymphocyte matures into a Whether B cell or a T cell depends on where in the body it becomes immunocompetent immunocompetent – B cells mature in the bone marrow Lymphocytes • T cells mature in the thymus T Cell Selection in the Thymus Thymus plays elimiDATE….with the T Lymphocytes T Cells • T cells mature in the thymus under negative and positive selection pressures – Negative selection – eliminates T cells that are strongly anti-self T Cells • T cells mature in the thymus under negative and positive selection pressures – Positive selection – selects T cells with a weak response to self-antigens, which thus become both immunocompetent and self-tolerant Buster Keaton B Cells • B cells become immunocompetent and self-tolerant in bone marrow • Some self-reactive B cells are inactivated (anergy) while others are killed B Cells • Other B cells undergo receptor editing in which there is a rearrangement of their receptors Immunocompetent B or T cells • Display a unique type of receptor that responds to a distinct antigen Immunocompetent B or T cells • Are exported to secondary lymphoid tissue where encounters with antigens occur Immunocompetent B or T cells • It is genes, not antigens, that determine which foreign substances our immune system will recognize and resist Immunocompetent B or T cells Key: Red bone marrow = Site of development of immunocompetence as B or T cells; primary lymphoid organs = Site of antigen challenge and final differentiation to activated B and T cells Immature lymphocytes Circulation in blood = Site of lymphocyte origin 1 1 Lymphocytes destined to become T 1 Thymus Bone marrow cells migrate to the thymus and develop immunocompetence there. B cells develop immunocompetence in red bone marrow. 2 Immunocompetent , but still naive, lymphocyte migrates via blood 2 Lymph nodes, spleen, and other lymphoid tissues 2 After leaving the thymus or bone marrow as naive immunocompetent cells, lymphocytes “seed” the lymph nodes, spleen, and other lymphoid tissues where the antigen challenge occurs. 3 Mature (antigen-activated) 3 Activated immunocompeten t B and T cells recirculate in blood and lymph 3 immunocompetent lymphocytes circulate continuously in the bloodstream and lymph and throughout the lymphoid organs of the body. Antigen Presenting Cells Antigen-Presenting Cells (APCs) • Major rolls in immunity are: – To engulf foreign particles – To present fragments of antigens on their own surfaces, to be recognized by T cells Antigen-Presenting Cells (APCs) • Major APCs are dendritic cells (DCs), macrophages, and activated B cells Antigen-Presenting Cells (APCs) • The major initiators of adaptive immunity are DCs, which actively migrate to the lymph nodes and secondary lymphoid organs and present antigens to T and B cells Macrophages and Dendritic Cells • Secrete soluble proteins that activate T cells Macrophages and Dendritic Cells • Activated T cells in turn release chemicals that: – Rev up the maturation and mobilization of DCs Ah, if only life could be so easy... It is impossible to pet this cat too much... he is insatiable and has the sweetest purr... Macrophages and Dendritic Cells • Activated T cells in turn release chemicals that: – Prod macrophages to become activated macrophages, which are insatiable phagocytes that secrete bactericidal chemicals Adaptive Immunity: Summary • Two-fisted defensive system that uses lymphocytes, APCs, and specific molecules to identify and destroy nonself particles Adaptive Immunity: Summary • Its response depends upon the ability of its cells to: – Recognize foreign substances (antigens) by binding to them – Communicate with one another so that the whole system mounts a response specific to those antigens Humoral Immunity Response • • Antigen challenge – first encounter between an antigen and a naive immunocompetent cell Takes place in the spleen/lymph node or other lymphoid organ Humoral Immunity Response • If the lymphocyte is a B cell: – The challenging antigen provokes a humoral immune response • Antibodies are produced against the challenger Clonal Selection • Stimulated B cell growth forms clones bearing the same antigen-specific receptors Clonal Selection Fate of the Clones • Most clone cells become antibodysecreting plasma cells • Plasma cells secrete specific antibody at the rate of 2000 molecules per second Fate of the Clones • Most clone cells become antibodysecreting plasma cells Fate of the Clones • Clones that do not become plasma cells become memory cells that can mount an immediate response to subsequent exposures of the same antigen Immunological Memory • Primary immune response – cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen – Lag period: 3 to 6 days after antigen challenge – Peak levels of plasma antibody are achieved in 10 days – Antibody levels then decline Secondary Response Immunological Memory • Secondary immune response – re-exposure to the same antigen – Sensitized memory cells respond within hours – Antibody levels peak in 2 to 3 days at much higher levels than in the primary response – Antibodies bind with greater affinity, and their levels in the blood can remain high for weeks to months Active Humoral Immunity • B cells encounter antigens and produce antibodies against them – Naturally acquired – response to a bacterial or viral infection Active Humoral Immunity • B cells encounter antigens and produce antibodies against them – Artificially acquired – response to a vaccine of dead or attenuated pathogens Active Humoral Immunity • Vaccines – spare us the symptoms of disease, and their weakened antigens provide antigenic determinants that are immunogenic and reactive Passive Humoral Immunity • Differs from active immunity in the antibody source and the degree of protection – B cells are not challenged by antigens – Immunological memory does not occur – Protection ends when antigens naturally degrade in the body • Naturally acquired – from the mother to her fetus via the placenta Can you wait for the Acquired Immunity to start its work here? Passive Humoral Immunity • Differs from active immunity in the antibody source and the degree of protection – B cells are not challenged by antigens – Immunological memory does not occur – Protection ends when antigens naturally degrade in the body • Artificially acquired – from the injection of serum, such as gamma globulin Types of Acquired Immunity Antibodies • Also called immunoglobulins – Constitute the gamma globulin portion of blood proteins – Are soluble proteins secreted by activated B cells and plasma cells in response to an antigen – Are capable of binding specifically with that antigen • There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE Classes of Antibodies • IgD – monomer attached to the surface of B cells, important in B cell activation Classes of Antibodies • IgM – pentamer released by plasma cells during the primary immune response Classes of Antibodies • IgG – monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity Classes of Antibodies • IgA – dimer that helps prevent attachment of pathogens to epithelial cell surfaces Classes of Antibodies • IgE – monomer that binds to mast cells and basophils, causing histamine release when activated Basic Antibody Structure • Consists of four looping polypeptide chains linked together with disulfide bonds – Two identical heavy (H) chains and two identical light (L) chains Basic Antibody Structure • The four chains bound together form an antibody monomer Basic Antibody Structure • Each chain has a variable (V) region at one end and a constant (C) region at the other Basic Antibody Structure • Variable regions of the heavy and light chains combine to form the antigen-binding site Basic Antibody Structure Figure 21.12a, b Antibody Structure • Antibodies responding to different antigens have different V regions but the C region is the same for all antibodies in a given class • C regions form the stem of the Y-shaped antibody and: – Determine the class of the antibody – Serve common functions in all antibodies – Dictate the cells and chemicals that the antibody can bind to – Determine how the antibody class will function in elimination of antigens Mechanisms of Antibody Diversity • Plasma cells make over a billion different types of antibodies • Each cell, however, only contains 100,000 genes that code for these polypeptides • To code for this many antibodies, somatic recombination takes place – Gene segments are shuffled and combined in different ways by each B cell as it becomes immunocompetent – Information of the newly assembled genes is expressed as B cell receptors and as antibodies Antibody Diversity • Random mixing of gene segments makes unique antibody genes that: – Code for H and L chains – Account for part of the variability in antibodies • V gene segments, called hypervariable regions, mutate and increase antibody variation • Plasma cells can switch H chains, making two or more classes with the same V region Mechanisms of Antibody Action Figure 21.13 Antibody Targets • Antibodies themselves do not destroy antigen; they inactivate and tag it for destruction • All antibodies form an antigenantibody (immune) complex • Defensive mechanisms used by antibodies are neutralization, agglutination, precipitation, and complement fixation Complement Fixation and Activation • Complement fixation is the main mechanism used against cellular antigens • Antibodies bound to cells change shape and expose complement binding sites • This triggers complement fixation and cell lysis • Complement activation: – Enhances the inflammatory response – Uses a positive feedback cycle to promote phagocytosis – Enlists more and more defensive elements Other Mechanisms of Antibody Action • Neutralization – antibodies bind to and block specific sites on viruses or exotoxins, thus preventing these antigens from binding to receptors on tissue cells Other Mechanisms of Antibody Action • Agglutination – antibodies bind the same determinant on more than one antigen – Makes antigen-antibody complexes that are cross-linked into large lattices – Cell-bound antigens are cross-linked, causing clumping (agglutination) • Precipitation – soluble molecules are cross-linked into large insoluble complexes Monoclonal Antibodies • Commercially prepared antibodies are used: – To provide passive immunity – In research, clinical testing, and treatment of certain cancers Monoclonal Antibodies • Monoclonal antibodies are pure antibody preparations – Specific for a single antigenic determinant – Produced from descendents of a single cell Monoclonal Antibodies • Hybridomas – cell hybrids made from a fusion of a tumor cell and a B cell – Have desirable properties of both parent cells – indefinite proliferation as well as the ability to produce a single type of antibody Cell-Mediated Immune Response • Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed Cell-Mediated Immune Response • Two major populations of T cells mediate cellular immunity – CD4 cells (T4 cells) are primarily helper T cells (TH) – CD8 cells (T8 cells) are cytotoxic T cells (TC) that destroy cells harboring foreign antigens Cell-Mediated Immune Response • Other types of T cells are: – Suppressor T cells (TS) – Memory T cells Major Types of T Cells Figure 21.14 Importance of Humoral Response • Soluble antibodies – The simplest ammunition of the immune response – Interact in extracellular environments such as body secretions, tissue fluid, blood, and lymph Importance of Cellular Response • T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells • T cells are best suited for cell-to-cell interactions, and target: – Cells infected with viruses, bacteria, or intracellular parasites – Abnormal or cancerous cells – Cells of infused or transplanted foreign tissue Antigen Recognition and MHC Restriction • Immunocompetent T cells are activated when the V regions of their surface receptors bind to a recognized antigen • T cells must simultaneously recognize: – Nonself (the antigen) – Self (a MHC protein of a body cell) MHC Proteins • Both types of MHC proteins are important to T cell activation • Class I MHC proteins – Always recognized by CD8 T cells – Display peptides from endogenous antigens Class I MHC Proteins • Endogenous antigens are: – Degraded by proteases and enter the endoplasmic reticulum – Transported via TAP (transporter associated with antigen processing) – Loaded onto class I MHC molecules – Displayed on the cell surface in association with a class I MHC molecule Class I MHC Proteins Figure 21.15a Class II MHC Proteins • Class II MHC proteins are found only on mature B cells, some T cells, and antigen-presenting cells • A phagosome containing pathogens (with exogenous antigens) merges with a lysosome • Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum Class II MHC Proteins • Class II MHC proteins migrate into the phagosomes where the antigen is degraded and the invariant chain is removed for peptide loading • Loaded Class II MHC molecules then migrate to the cell membrane and display antigenic peptide for recognition by CD4 cells Class II MHC Proteins Figure 21.15b Antigen Recognition • Provides the key for the immune system to recognize the presence of intracellular microorganisms • MHC proteins are ignored by T cells if they are complexed with self protein fragments Antigen Recognition • If MHC proteins are complexed with endogenous or exogenous antigenic peptides, they: – Indicate the presence of intracellular infectious microorganisms – Act as antigen holders – Form the self part of the self-antiself complexes recognized by T cells T Cell Activation: Step One – Antigen Binding • T cell antigen receptors (TCRs): – Bind to an antigen-MHC protein complex – Have variable and constant regions consisting of two chains (alpha and beta) T Cell Activation: Step One – Antigen Binding • MHC restriction – TH and TC bind to different classes of MHC proteins • TH cells bind to antigen linked to class II MHC proteins • Mobile APCs (Langerhans’ cells) quickly alert the body to the presence of antigen by migrating to the lymph nodes and presenting antigen T Cell Activation: Step One – Antigen Binding • TC cells are activated by antigen fragments complexed with class I MHC proteins • APCs produce co-stimulatory molecules that are required for TC activation T Cell Activation: Step One – Antigen Binding • TCR that acts to recognize the selfantiself complex is linked to multiple intracellular signaling pathways • Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition) T Cell Activation: Step One – Antigen Binding Figure 21.16 T Cell Activation: Step Two – Costimulation • Before a T cell can undergo clonal expansion, it must recognize one or more co-stimulatory signals T Cell Activation: Step Two – Costimulation • This recognition may require binding to other surface receptors on an APC – Macrophages produce surface B7 proteins when nonspecific defenses are mobilized – B7 binding with the CD28 receptor on the surface of T cells is a crucial costimulatory signal T Cell Activation: Step Two – Costimulation • Other co-stimulatory signals include cytokines and interleukin 1 and 2 T Cell Activation: Step Two – Costimulation • Depending on receptor type, costimulators can cause T cells to complete their activation or abort activation • Without co-stimulation, T cells: – Become tolerant to that antigen – Are unable to divide – Do not secrete cytokines T Cell Activation: Step Two – Costimulation • T cells that are activated: – Enlarge, proliferate, and form clones – Differentiate and perform functions according to their T cell class T Cell Activation: Step Two – Costimulation • Primary T cell response peaks within a week after signal exposure • T cells then undergo apoptosis between days 7 and 30 • Effector activity wanes as the amount of antigen declines • The disposal of activated effector cells is a protective mechanism for the body • Memory T cells remain and mediate secondary responses to the same antigen Cytokines • Mediators involved in cellular immunity, including hormonelike glycoproteins released by activated T cells and macrophages • Some are co-stimulators of T cells and T cell proliferation • Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to: – Release interleukin 2 (IL-2) – Synthesize more IL-2 receptors Cytokines • IL-2 is a key growth factor, which sets up a positive feedback cycle that encourages activated T cells to divide – It is used therapeutically to enhance the body’s defenses against cancer • Other cytokines amplify and regulate immune and nonspecific responses Cytokines • Examples include: – Perforin and lymphotoxin – cell toxins – Gamma interferon – enhances the killing power of macrophages – Inflammatory factors Helper T Cells (TH) • Regulatory cells that play a central role in the immune response • Once primed by APC presentation of antigen, they: – Chemically or directly stimulate proliferation of other T cells – Stimulate B cells that have already become bound to antigen • Without TH, there is no immune response Helper T Cells (TH) Figure 21.17a Helper T Cell • TH cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors • TH cells stimulate B cells to divide more rapidly and begin antibody formation • B cells may be activated without TH cells by binding to T cell–independent antigens • Most antigens, however, require TH costimulation to activate B cells • Cytokines released by TH amplify nonspecific defenses Helper T Cells Figure 21.17b Cytotoxic T Cell (Tc) • TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells • They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized • Their targets include: – – – – Virus-infected cells Cells with intracellular bacteria or parasites Cancer cells Foreign cells from blood transfusions or transplants Cytotoxic T Cells • Bind to self-antiself complexes on all body cells • Infected or abnormal cells can be destroyed as long as appropriate antigen and co-stimulatory stimuli (e.g., IL-2) are present • Natural killer cells activate their killing machinery when they bind to MICA receptor • MICA receptor – MHC-related cell surface protein in cancer cells, virus-infected cells, and cells of transplanted organs Mechanisms of Tc Action • In some cases, TC cells: – Bind to the target cell and release perforin into its membrane • In the presence of Ca2+ perforin causes cell lysis by creating transmembrane pores • Other TC cells induce cell death by: – Secreting lymphotoxin, which fragments the target cell’s DNA – Secreting gamma interferon, which stimulates phagocytosis by macrophages Mechanisms of Tc Action Figure 21.18a, b Other T Cells • Suppressor T cells (TS) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells • Gamma delta T cells (Tgd) – 10% of all T cells found in the intestines that are triggered by binding to MICA receptors Summary of the Primary Immune Response Figure 21.19 Organ Transplants • The four major types of grafts are: – Autografts – graft transplanted from one site on the body to another in the same person – Isografts – grafts between identical twins – Allografts – transplants between individuals that are not identical twins, but belong to same species – Xenografts – grafts taken from another animal species Prevention of Rejection • Prevention of tissue rejection is accomplished by using immunosuppressive drugs • However, these drugs depress patient’s immune system so it cannot fight off foreign agents Immunodeficiencies • Congenital and acquired conditions in which the function or production of immune cells, phagocytes, or complement is abnormal – SCID – severe combined immunodeficiency (SCID) syndromes; genetic defects that produce: • A marked deficit in B and T cells • Abnormalities in interleukin receptors • Defective adenosine deaminase (ADA) enzyme – Metabolites lethal to T cells accumulate – SCID is fatal if untreated; treatment is with bone marrow transplants Acquired Immunodeficiencies • Hodgkin’s disease – cancer of the lymph nodes leads to immunodeficiency by depressing lymph node cells • Acquired immune deficiency syndrome (AIDS) – cripples the immune system by interfering with the activity of helper T (CD4) cells – Characterized by severe weight loss, night sweats, and swollen lymph nodes – Opportunistic infections occur, including pneumocystis pneumonia and Kaposi’s sarcoma AIDS • Caused by human immunodeficiency virus (HIV) transmitted via body fluids – blood, semen, and vaginal secretions • HIV enters the body via: – Blood transfusions – Contaminated needles – Intimate sexual contact, including oral sex • HIV: – Destroys TH cells – Depresses cell-mediated immunity AIDS • HIV multiplies in lymph nodes throughout the asymptomatic period • Symptoms appear in a few months to 10 years • Attachment – HIV’s coat protein (gp120) attaches to the CD4 receptor – A nearby protein (gp41) fuses the virus to the target cell AIDS • HIV enters the cell and uses reverse transcriptase to produce DNA from viral RNA • This DNA (provirus) directs the host cell to make viral RNA (and proteins), enabling the virus to reproduce and infect other cells AIDS • HIV reverse transcriptase is not accurate and produces frequent transcription errors – This high mutation rate causes resistance to drugs • Treatments include: – Reverse transcriptase inhibitors (AZT) – Protease inhibitors (saquinavir and ritonavir) – New drugs currently being developed that block HIV’s entry to helper T cells Autoimmune Diseases • Loss of the immune system’s ability to distinguish self from nonself • The body produces autoantibodies and sensitized TC cells that destroy its own tissues • Examples include multiple sclerosis, myasthenia gravis, Graves’ disease, Type I (juvenile) diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis Mechanisms of Autoimmune Diseases • Ineffective lymphocyte programming – selfreactive T and B cells that should have been eliminated in the thymus and bone marrow escape into the circulation • New self-antigens appear, generated by: – Gene mutations that cause new proteins to appear – Changes in self-antigens by hapten attachment or as a result of infectious damage Mechanisms of Autoimmune Diseases • If the determinants on foreign antigens resemble self-antigens: – Antibodies made against foreign antigens cross-react with self-antigens Weapons of Mass Hypersensitivity Weapons of Mass Hypersensitivity Normal lung Tissue Dust Lung Tissue as seen in a Hypersensitivity reaction Hypersensitivity • Immune responses that cause tissue damage Hypersensitivity • Different types of hypersensitivity reactions are distinguished by: – Their time course Hypersensitivity • Different types of hypersensitivity reactions are distinguished by: – Whether antibodies or T cells are the principle immune elements involved Plasma cell Hypersensitivity • Antibody-mediated allergies are immediate and subacute hypersensitivities Hypersensitivity The most important cell-mediated allergic condition is delayed hypersensitivity Immediate Hypersensitivity Acute (type I) hypersensitivities begin in seconds after contact with allergen Immediate Hypersensitivity • Anaphylaxis – initial allergen contact is asymptomatic but sensitizes the person Immediate Hypersensitivity • How is the person sensitized: 1. IgE production is initiated by plasma cells Immediate Hypersensitivity How is the person sensitized: 2. IgE binds to the IgE Fc receptors on Basophils and mast cells Immediate Hypersensitivity Reexposure to the allergen will result in cross linking of IgE molecules on the surface of basophils/mast cells with resultant degranulation and release of histamine Immediate Hypersensitivity • Subsequent exposures to allergen cause: • Release of histamine and inflammatory chemicals • Systemic or local responses Immediate Hypersensitivity – The mechanism involves IL-4 secreted by T cells – IL-4 stimulates B cells to produce IgE Immediate Hypersensitivity – IgE cross links at the surface of the mast cells and basophils causing them to degranulate, resulting in a flood of histamine release and inducing the inflammatory response Acute Allergic Response Anaphylaxis • Reactions include runny nose, itching reddened skin, and watery eyes Anaphylaxis • If allergen is inhaled, asthmatic symptoms appear – constriction of bronchioles and restricted airflow Anaphylaxis • If allergen is ingested, cramping, vomiting, or diarrhea occur Anaphylaxis • Antihistamines counteract these effects Need an shot honey? Anaphylactic Shock • Response to allergen that directly enters the blood (e.g., insect bite, injection) Anaphylactic Shock • Basophils and mast cells are enlisted throughout the body Anaphylactic Shock • Systemic histamine releases may result in: – Constriction of bronchioles Anaphylactic Shock • Systemic histamine releases may result in: – Sudden vasodilation and fluid loss from the bloodstream Anaphylactic Shock • Systemic histamine releases may result in: – Hypotensive shock and death Anaphylactic Shock • Treatment – epinephrine is the drug of choice Subacute Hypersensitivities • Caused by IgM and IgG, and transferred via blood plasma or serum – Onset is slow (1–3 hours) after antigen exposure – Duration is long lasting (10–15 hours) Subacute Hypersensitivities • Cytotoxic (type II) reactions – Antibodies bind to antigens on specific body cells, stimulating phagocytosis and complement-mediated lysis of the cellular antigens – Example: mismatched blood transfusion reaction Butterfly Rash Subacute Hypersensitivities • Immune complex (type III) hypersensitivity – Antigens are widely distributed through the body or blood – Insoluble antigen-antibody complexes form – Complexes cannot be cleared from a particular area of the body – Intense inflammation, local cell lysis, and death may result – Example: systemic lupus erythematosus (SLE) 19. Mitral Stenosis - Tuberculin test Tuberculin test Tuberculin test What is another term for the Tuberculin test? What is another term for the Tuberculin test? • Mantoux test Delayed Hypersensitivities (Type IV) • Onset is slow (1–3 days) • Mediated by mechanisms involving delayed hypersensitivity T cells and cytotoxic T cells • Cytokines from activated TC are the mediators of the inflammatory response • Antihistamines are ineffective and corticosteroid drugs are used to provide relief Delayed Hypersensitivities (Type IV) • Example: allergic contact dermatitis (e.g., poison ivy) • Involved in protective reactions against viruses, bacteria, fungi, protozoa, cancer, and rejection of foreign grafts or transplants Developmental Aspects • Immune system stem cells develop in the liver and spleen by the ninth week • Later, bone marrow becomes the primary source of stem cells • Lymphocyte development continues in the bone marrow and thymus system begins to wane Developmental Aspects • TH2 lymphocytes predominate in the newborn, and the TH1 system is educated as the person encounters antigens • The immune system is impaired by stress and depression • With age, the immune system begins to wane ...
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This note was uploaded on 10/10/2011 for the course ZOO 3733 taught by Professor Sa during the Spring '07 term at University of Central Florida.

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