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blood and immune system.docx

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University of Toronto Scarborough
Biological Sciences
Kenneth Welch

The Immune System: Innate and Adaptive Body Defenses 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 • Second line of defense – antimicrobial proteins, phagocytes, and other cells • Inhibit invaders spread throughout the body • Inflammation is its hallmark and most important mechanism 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 • Works in conjunction with the innate system Surface Barriers • 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 • Is resistant to weak acids and bases, bacterial enzymes, and toxins • Mucosae provide similar mechanical barriers Epithelial Chemical Barriers • Epithelial membranes produce protective chemicals that destroy microorganisms • Skin acidity (pH of 3 to 5) inhibits bacterial growth • Sebum contains chemicals toxic to bacteria • Stomach mucosae secrete concentrated HCl and protein-digesting enzymes • Saliva and lacrimal fluid contain lysozyme • Mucus traps microorganisms that enter the digestive and respiratory systems Respiratory Tract Mucosae • Mucus-coated hairs in the nose trap inhaled particles • Mucosa of the upper respiratory tract is ciliated • Cilia sweep dust- and bacteria-laden mucus away from lower respiratory passages Internal Defenses: Cells and Chemicals • The body uses nonspecific cellular and chemical devices to protect itself • Phagocytes and natural killer (NK) cells • Antimicrobial proteins in blood and tissue fluid • Inflammatory response enlists macrophages, mast cells, WBCs, and chemicals • Harmful substances are identified by surface carbohydrates unique to infectious organisms Phagocytes • Macrophages are the chief phagocytic cells • Free macrophages wander throughout a region, in search of cellular debris • Kupffer cells (liver) and microglia (brain) are fixed macrophages • Neutrophils become phagocytic when encountering infectious material • Eosinophils are weakly phagocytic against parasitic worms • Mast cells bind and ingest a wide range of bacteria Mechanism of Phagocytosis • Microbes adhere to the phagocyte • Pseudopods engulf the particle (antigen) into a phagosome • Phagosomes fuse with a lysosome to form a phagolysosome • Microbes in the phagolysosome are enzymatically digested • Indigestible and residual material is removed by exocytosis 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 • React nonspecifically and eliminate cancerous and virus-infected cells • Kill their target cells by releasing cytolytic chemicals • Secrete potent chemicals that enhance the inflammatory response Inflammation: Tissue Response to Injury • The inflammatory response is triggered whenever body tissues are injured • Prevents the spread of damaging agents to nearby tissues • Disposes of cell debris and pathogens • Sets the stage for repair processes • The four cardinal signs of acute inflammation are redness, heat, swelling, and pain Inflammatory Response • Begins with a flood of inflammatory chemicals released into the extracellular fluid • Inflammatory mediators: • Include kinins, prostaglandins (PGs), complement, and cytokines • Are released by injured tissue, phagocytes, lymphocytes, and mast cells • Cause local small blood vessels to dilate, resulting in hyperemia Inflammatory Response: Vascular Permeability • Chemicals liberated by the inflammatory response • Increase the permeability of local capillaries • Exudate (fluid containing proteins, clotting factors, and antibodies): • Seeps into tissue spaces causing local edema (swelling) • The edema contributes to the sensation of pain Inflammatory Response: Edema • The surge of protein-rich fluids into tissue spaces (edema): • Helps to dilute harmful substances • Brings in large quantities of oxygen and nutrients needed for repair • Allows entry of clotting proteins, which prevent the spread of bacteria 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 • Margination – neutrophils cling to the walls of capillaries in the injured area • Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis • Chemotaxis – inflammatory chemicals attract neutrophils to the injury site Antimicrobial Proteins • Enhance the innate defenses by: • Attacking microorganisms directly • Hindering microorganisms’ ability to reproduce • The most important antimicrobial proteins are: • Interferon • 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 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 • Lymphocytes secrete gamma () interferon, but most other WBCs secrete alpha () interferon • Fibroblasts secrete beta () interferon • Interferons also activate macrophages and mobilize NKs • FDA-approve alpha IFN is used: • As an antiviral drug against hepatitis C virus • To treat genital warts caused by a herpes virus Complement • 20 or so proteins that circulate in the blood in an inactive form • Proteins include C1 through C9, factors B, D, and P, and regulatory proteins • Provides a major mechanism for destroying foreign substances in the body • Amplifies all aspects of the inflammatory response • Kills bacteria and certain other cell types (our cells are immune to complement) • Enhances the effectiveness of both nonspecific and specific defenses Complement Pathways • Complement can be activated by two pathways: classical and alternative • Classical pathway is linked to the immune system • Depends upon the binding of antibodies to invading organisms • Subsequent binding of C1 to the antigen-antibody complexes (complement fixation) • Alternative pathway is triggered by interaction among factors B, D, and P, and polysaccharide molecules present on microorganisms • Each pathway involves a cascade in which complement proteins are activated in an orderly sequence and where each step catalyzes the next • Both pathways converge on C3, which cleaves into C3a and C3b • C3b initiates formation of a membrane attack complex (MAC) 2+ • MAC causes cell lysis by interfering with a cell’s ability to eject Ca • C3b also causes opsonization, and C3a causes inflammation Fever • Abnormally high body temperature in response to invading microorganisms • The body’s thermostat is reset upwards in response to pyrogens, chemicals secreted by leukocytes and macrophages exposed to bacteria and other foreign substances • High fevers are dangerous as they can denature enzymes • 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 them • Amplifies inflammatory response and activates complement Adaptive Immune Defenses • The adaptive immune system is antigen-specific, systemic, and has memory • It has two separate but overlapping arms • Humoral, or antibody-mediated immunity • Cellular, or cell-mediated immunity Antigens (Ags) • Substances that can mobilize the immune system and provoke an immune response • 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 • Reactivity – the ability to react with the products of the activated lymphocytes and the antibodies released in response to them • Complete antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides Haptens (Incomplete Antigens) • Small molecules, such as peptides, nucleotides, and many hormones, that are not immunogenic but are reactive when attached to protein carriers • 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 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 • 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 • Class II MHC proteins – found on certain immune response 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 • 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 • T lymphocytes – non-antibody-producing cells that constitute the cell-mediated arm of immunity • 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 • Whether a lymphocyte matures into a B cell or a T cell depends on where in the body it becomes immunocompetent • B cells mature in the bone marrow • T cells mature in the thymus T Cells and B Cells • T cells mature in the thymus under negative and positive selection pressures • Negative selection – eliminates T cells that are strongly anti-self • Positive selection – selects T cells with a weak response to self-antigens, which thus become both immunocompetent and self-tolerant • B cells become immunocompetent and self-tolerant in bone marrow Immunocompetent B or T cells • Display a unique type of receptor that responds to a distinct antigen • Become immunocompetent before they encounter antigens they may later attack • Are exported to secondary lymphoid tissue where encounters with antigens occur • Mature into fully functional antigen-activated cells upon binding with their recognized antigen • It is genes, not antigen, that determine which foreign substance our immune system will recognize and resist Antigen-Presenting Cells (APCs) • Major rolls in immunity are: • To engulf foreign particles • To present fragment of antigens on their own surfaces, to be recognized by T cells • Major APCs are dendritic cells (DCs), macrophages, and activated B cells • 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 active T cells • Activated T cells in turn release chemicals that: • Rev up the maturation and mobilization of DCs • Prod macrophages to become activated macrophages, which are insatiable phagocytes and release bactericidal chemicals Adaptive Immunity: Summary • Two-fisted defensive system that uses lymphocytes, APCs, and specific molecules to identify and destroy nonself particles • 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 and antigen and a naive immunocompetent cell • Takes place in the spleen or other lymphoid organ • 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 • A naive, immunocompetent B cell is activated when antigens bind to its surface receptors and cross-link adjacent receptors • Antigen binding is followed by receptor-mediated endocytosis of the cross-linked antigen- receptor complexes • These activating events, plus T cell interactions, trigger clonal selection Fate of the Clones • Most clone cells become antibody-secreting plasma cells • Plasma cells secrete specific antibody at the rate of 2000 molecules per second • Secreted antibodies: • Bind to free antigens • Mark the antigens for destruction by specific or nonspecific mechanisms • Clones that do not become plasma cells become memory cells that can mount an immediate response to subsequent exposures to an 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 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 Immunological Memory Active Humoral Immunity • B cells encounter antigens and produce antibodies against them • Naturally acquired – response to a bacterial or viral infection • Artificially acquired – response to a vaccine of dead or attenuated pathogens • 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 antigen • 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 • Artificially acquired – from the injection of serum, such as gamma globulin Antibodies (Ab) • Also called immunoglobulins (Igs) • 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 • IgM – pentamer released by plasma cells during the primary immune response • IgG – monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity • IgA – dimer that helps prevent attachment of pathogens to epithelial cell surfaces • IgE – monomer that binds to mast cells and basophils, causing histamine release when activated Basic Antibody Structure • Consist of four looping polypeptide chains linked together with disulfide bonds • Two identical heavy (H) chains and two identical light (L) chains • The four chains bound together form an antibody monomer • Each chain has a variable (V) region at one end and a constant (C) region at the other • Variable regions of the heavy and light chains combine to form the antigen-binding site • 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
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