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PowerPoint® Lecture Slides prepared by Janice Meeking, Mount Royal College CHAPTER 21 The Immune System: Innate and Adaptive Body Defenses: Part B Copyright © 2010 Pearson Education, Inc. Antibodies • Immunoglobulins—gamma globulin portion of blood • Proteins secreted by plasma cells • Capable of binding specifically with antigen detected by B cells Copyright © 2010 Pearson Education, Inc. Basic Antibody Structure • T-or Y-shaped monomer of four looping linked polypeptide chains • Two identical heavy (H) chains and two identical light (L) chains • Variable (V) regions of each arm combine to form two identical antigen-binding sites Copyright © 2010 Pearson Education, Inc. Basic Antibody Structure • Constant (C) region of stem determines • The antibody class (IgM, IgA, IgD, IgG, or IgE) • The cells and chemicals that the antibody can bind to • How the antibody class functions in antigen elimination Copyright © 2010 Pearson Education, Inc. Antigen-binding site Heavy chain variable region Heavy chain constant region Light chain variable region Light chain constant region Disulfide bond Copyright © 2010 Pearson Education, Inc. Hinge region Stem region (a) Figure 21.14a Classes of Antibodies • IgM • A pentamer; first antibody released • Potent agglutinating agent • Readily fixes and activates complement • IgA (secretory IgA) • Monomer or dimer; in mucus and other secretions • Helps prevent entry of pathogens Copyright © 2010 Pearson Education, Inc. Copyright © 2010 Pearson Education, Inc. Table 21.3 Classes of Antibodies • IgD • Monomer attached to the surface of B cells • Functions as a B cell receptor • IgG • Monomer; 75–85% of antibodies in plasma • From secondary and late primary responses • Crosses the placental barrier Copyright © 2010 Pearson Education, Inc. Classes of Antibodies • IgE • Monomer active in some allergies and parasitic infections • Causes mast cells and basophils to release histamine Copyright © 2010 Pearson Education, Inc. Copyright © 2010 Pearson Education, Inc. Table 21.3 Generating Antibody Diversity • Billions of antibodies result from somatic recombination of gene segments • Hypervariable regions of some genes increase antibody variation through somatic mutations • Each plasma cell can switch the type of H chain produced, making an antibody of a different class Copyright © 2010 Pearson Education, Inc. Antibody Targets • Antibodies inactivate and tag antigens • Form antigen-antibody (immune) complexes • Defensive mechanisms used by antibodies • Neutralization and agglutination (the two most important) • Precipitation and complement fixation Copyright © 2010 Pearson Education, Inc. Neutralization • Simplest mechanism • Antibodies block specific sites on viruses or bacterial exotoxins • Prevent these antigens from binding to receptors on tissue cells • Antigen-antibody complexes undergo phagocytosis Copyright © 2010 Pearson Education, Inc. Agglutination • Antibodies bind the same determinant on more than one cell-bound antigen • Cross-linked antigen-antibody complexes agglutinate • Example: clumping of mismatched blood cells Copyright © 2010 Pearson Education, Inc. Precipitation • Soluble molecules are cross-linked • Complexes precipitate and are subject to phagocytosis Copyright © 2010 Pearson Education, Inc. Complement Fixation and Activation • Main antibody defense against cellular antigens • Several antibodies bind close together on a cellular antigen • Their complement-binding sites trigger complement fixation into the cell’s surface • Complement triggers cell lysis Copyright © 2010 Pearson Education, Inc. Complement Fixation and Activation • Activated complement functions • Amplifies the inflammatory response • Opsonization • Enlists more and more defensive elements Copyright © 2010 Pearson Education, Inc. Adaptive defenses Humoral immunity Antigen Antigen-antibody complex Antibody Inactivates by Neutralization (masks dangerous parts of bacterial exotoxins; viruses) Agglutination (cell-bound antigens) Enhances Phagocytosis Fixes and activates Precipitation (soluble antigens) Enhances Complement Leads to Inflammation Cell lysis Chemotaxis Histamine release Copyright © 2010 Pearson Education, Inc. Figure 21.15 Monoclonal Antibodies • Commercially prepared pure antibody • Produced by hybridomas • Cell hybrids: fusion of a tumor cell and a B cell • Proliferate indefinitely and have the ability to produce a single type of antibody • Used in research, clinical testing, and cancer treatment Copyright © 2010 Pearson Education, Inc. Cell-Mediated Immune Response • T cells provide defense against intracellular antigens • Two types of surface receptors of T cells • T cell antigen receptors • Cell differentiation glycoproteins • CD4 or CD8 • Play a role in T cell interactions with other cells Copyright © 2010 Pearson Education, Inc. Cell-Mediated Immune Response • Major types of T cells • CD4 cells become helper T cells (TH) when activated • CD8 cells become cytotoxic T cells (TC) that destroy cells harboring foreign antigens • Other types of T cells • Regulatory T cells (TREG) • Memory T cells Copyright © 2010 Pearson Education, Inc. Adaptive defenses Cellular immunity Immature lymphocyte Red bone marrow T cell receptor Class II MHC protein T cell receptor Maturation CD4 cell Thymus Activation APC (dendritic cell) Activation Memory cells CD4 Class I MHC protein CD8 cell APC (dendritic cell) CD8 Lymphoid tissues and organs Helper T cells (or regulatory T cells) Copyright © 2010 Pearson Education, Inc. Effector cells Blood plasma Cytotoxic T cells Figure 21.16 Comparison of Humoral and Cell-Mediated Response • Antibodies of the humoral response • The simplest ammunition of the immune response • Targets • Bacteria and molecules in extracellular environments (body secretions, tissue fluid, blood, and lymph) Copyright © 2010 Pearson Education, Inc. Comparison of Humoral and Cell-Mediated Response • T cells of the cell-mediated response • Recognize and respond only to processed fragments of antigen displayed on the surface of body cells • Targets • Body cells infected by viruses or bacteria • Abnormal or cancerous cells • Cells of infused or transplanted foreign tissue Copyright © 2010 Pearson Education, Inc. Antigen Recognition • Immunocompetent T cells are activated when their surface receptors bind to a recognized antigen (nonself) • T cells must simultaneously recognize • Nonself (the antigen) • Self (an MHC protein of a body cell) Copyright © 2010 Pearson Education, Inc. MHC Proteins • Two types of MHC proteins are important to T cell activation • Class I MHC proteins - displayed by all cells except RBCs • Class II MHC proteins – displayed by APCs (dendritic cells, macrophages and B cells) • Both types are synthesized at the ER and bind to peptide fragments Copyright © 2010 Pearson Education, Inc. Class I MHC Proteins • Bind with fragment of a protein synthesized in the cell (endogenous antigen) • Endogenous antigen is a self-antigen in a normal cell; a nonself antigen in an infected or abnormal cell • Informs cytotoxic T cells of the presence of microorganisms hiding in cells (cytotoxic T cells ignore displayed self-antigens) Copyright © 2010 Pearson Education, Inc. Cytoplasm of any tissue cell 2 Endogenous antigen 1 Endogenous peptides enter ER via antigen is degraded transport protein. by protease. Endogenous antigen— self-protein or foreign (viral or cancer) protein Cisternae of endoplasmic reticulum (ER) 3 Endogenous antigen peptide is loaded onto class I MHC protein. 4 Loaded MHC protein migrates in vesicle to the plasma membrane, where it displays the antigenic peptide. Transport protein (ATPase) Plasma membrane of a tissue cell Antigenic peptide Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Copyright © 2010 Pearson Education, Inc. Figure 21.17a Cytoplasm of any tissue cell 1 Endogenous antigen is degraded by protease. Endogenous antigen— self-protein or foreign (viral or cancer) protein Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Copyright © 2010 Pearson Education, Inc. Figure 21.17a, step 1 Cytoplasm of any tissue cell 2 Endogenous antigen 1 Endogenous peptides enter ER via antigen is degraded transport protein. by protease. Endogenous antigen— self-protein or foreign (viral or cancer) protein Cisternae of endoplasmic reticulum (ER) Transport protein (ATPase) Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Copyright © 2010 Pearson Education, Inc. Figure 21.17a, step 2 Cytoplasm of any tissue cell 2 Endogenous antigen 1 Endogenous peptides enter ER via antigen is degraded transport protein. by protease. Endogenous antigen— self-protein or foreign (viral or cancer) protein Cisternae of endoplasmic reticulum (ER) 3 Endogenous antigen peptide is loaded onto class I MHC protein. Transport protein (ATPase) Plasma membrane of a tissue cell Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Copyright © 2010 Pearson Education, Inc. Figure 21.17a, step 3 Cytoplasm of any tissue cell 2 Endogenous antigen 1 Endogenous peptides enter ER via antigen is degraded transport protein. by protease. Endogenous antigen— self-protein or foreign (viral or cancer) protein Cisternae of endoplasmic reticulum (ER) 3 Endogenous antigen peptide is loaded onto class I MHC protein. 4 Loaded MHC protein migrates in vesicle to the plasma membrane, where it displays the antigenic peptide. Transport protein (ATPase) Plasma membrane of a tissue cell Antigenic peptide Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Copyright © 2010 Pearson Education, Inc. Figure 21.17a, step 4 Class II MHC Proteins • Bind with fragments of exogenous antigens that have been engulfed and broken down in a phagolysosome • Recognized by helper T cells Copyright © 2010 Pearson Education, Inc. Cytoplasm of APC 1a Class II MHC is synthesized in ER. Invariant chain prevents class II MHC from binding to peptides in the ER. 3 Vesicle fuses with phagolysosome. Invariant chain is removed, and antigen is loaded. 2a Cisternae of endoplasmic Phagosome reticulum (ER) 1b Extracellular antigen (bacterium) is phagocytized. Class II MHC is exported from ER in a vesicle. 4 Vesicle with loaded MHC migrates to the plasma membrane. 2b Phagosome merges with lysosome, forming a phagolysosome; antigen is degraded. Extracellular antigen Extracellular fluid Lysosome Plasma membrane of APC Antigenic peptide (b) Exogenous antigens are processed and displayed on class II MHC of antigen-presenting cells (APCs). Copyright © 2010 Pearson Education, Inc. Figure 21.17b 1a Invariant chain prevents class II MHC from binding to peptides in the ER. Class II MHC is synthesized in ER. Cytoplasm of APC Cisternae of endoplasmic reticulum (ER) Plasma membrane of APC Extracellular fluid (b) Exogenous antigens are processed and displayed on class II MHC of antigen-presenting cells (APCs). Copyright © 2010 Pearson Education, Inc. Figure 21.17b, step 1a 1a Invariant chain prevents class II MHC from binding to peptides in the ER. Class II MHC is synthesized in ER. Cytoplasm of APC Cisternae of endoplasmic reticulum (ER) 1b Extracellular antigen (bacterium) is phagocytized. Extracellular antigen Extracellular fluid Plasma membrane of APC (b) Exogenous antigens are processed and displayed on class II MHC of antigen-presenting cells (APCs). Copyright © 2010 Pearson Education, Inc. Figure 21.17b, step 1b 1a Invariant chain prevents class II MHC from binding to peptides in the ER. Class II MHC is synthesized in ER. Cytoplasm of APC 2a Cisternae of endoplasmic reticulum (ER) 1b Extracellular antigen (bacterium) is phagocytized. Extracellular antigen Extracellular fluid Class II MHC is exported from ER in a vesicle. Plasma membrane of APC (b) Exogenous antigens are processed and displayed on class II MHC of antigen-presenting cells (APCs). Copyright © 2010 Pearson Education, Inc. Figure 21.17b, step 2a Cytoplasm of APC 1a Class II MHC is synthesized in ER. Invariant chain prevents class II MHC from binding to peptides in the ER. 2a Cisternae of endoplasmic Phagosome reticulum (ER) 1b Extracellular antigen (bacterium) is phagocytized. Class II MHC is exported from ER in a vesicle. 2b Phagosome merges with lysosome, forming a phagolysosome; antigen is degraded. Extracellular antigen Extracellular fluid Lysosome Plasma membrane of APC (b) Exogenous antigens are processed and displayed on class II MHC of antigen-presenting cells (APCs). Copyright © 2010 Pearson Education, Inc. Figure 21.17b, step 2b Cytoplasm of APC 1a Class II MHC is synthesized in ER. Invariant chain prevents class II MHC from binding to peptides in the ER. 3 Vesicle fuses with phagolysosome. Invariant chain is removed, and antigen is loaded. 2a Cisternae of endoplasmic Phagosome reticulum (ER) 1b Extracellular antigen (bacterium) is phagocytized. Class II MHC is exported from ER in a vesicle. 2b Phagosome merges with lysosome, forming a phagolysosome; antigen is degraded. Extracellular antigen Extracellular fluid Lysosome Plasma membrane of APC (b) Exogenous antigens are processed and displayed on class II MHC of antigen-presenting cells (APCs). Copyright © 2010 Pearson Education, Inc. Figure 21.17b, step 3 Cytoplasm of APC 1a Class II MHC is synthesized in ER. Invariant chain prevents class II MHC from binding to peptides in the ER. 3 Vesicle fuses with phagolysosome. Invariant chain is removed, and antigen is loaded. 2a Cisternae of endoplasmic Phagosome reticulum (ER) 1b Extracellular antigen (bacterium) is phagocytized. Class II MHC is exported from ER in a vesicle. 4 2b Phagosome merges with lysosome, forming a phagolysosome; antigen is degraded. Extracellular antigen Extracellular fluid Lysosome Plasma membrane of APC Vesicle with loaded MHC migrates to the plasma membrane. Antigenic peptide (b) Exogenous antigens are processed and displayed on class II MHC of antigen-presenting cells (APCs). Copyright © 2010 Pearson Education, Inc. Figure 21.17b, step 4 T Cell Activation • APCs (most often a dendritic cell) migrate to lymph nodes and other lymphoid tissues to present their antigens to T cells • T cell activation is a two-step process 1. Antigen binding 2. Co-stimulation Copyright © 2010 Pearson Education, Inc. T Cell Activation: Antigen Binding • CD4 and CD8 cells bind to different classes of MHC proteins (MHC restriction) • CD4 cells bind to antigen linked to class II MHC proteins of APCs • CD8 cells are activated by antigen fragments linked to class I MHC of APCs Copyright © 2010 Pearson Education, Inc. T Cell Activation: Antigen Binding • Dendritic cells are able to obtain other cells’ endogenous antigens by • Engulfing dying virus-infected or tumor cells • Importing antigens through temporary gap junctions with infected cells • Dendritic cells then display the endogenous antigens on both class I and class II MHCs Copyright © 2010 Pearson Education, Inc. T Cell Activation: Antigen Binding • TCR that recognizes the nonself-self 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) • Antigen binding stimulates the T cell, but costimulation is required before proliferation can occur Copyright © 2010 Pearson Education, Inc. Adaptive defenses Cellular immunity 1 Dendritic cell Viral antigen Dendritic cell T cell receptor (TCR) Clone formation Class lI MHC protein displaying processed viral antigen CD4 protein engulfs an exogenous antigen, processes it, and displays its fragments on class II MHC protein. 2 Immunocompetent CD4 cell recognizes antigen-MHC complex. Both TCR and CD4 protein bind Immunocom- to antigen-MHC complex. petent CD4 T cell 3 CD4 cells are activated, proliferate (clone), and become memory and effector cells. Helper T memory cell Copyright © 2010 Pearson Education, Inc. Activated helper T cells Figure 21.18 T Cell Activation: Co-Stimulation • Requires T cell binding to other surface receptors on an APC • Dendritic cells and macrophages produce surface B7 proteins when innate defenses are mobilized • B7 binding with a CD28 receptor on a T cell is a crucial co-stimulatory signal • Cytokines (interleukin 1 and 2 from APCs or T cells) trigger proliferation and differentiation of activated T cell Copyright © 2010 Pearson Education, Inc. T Cell Activation: Co-Stimulation • Without co-stimulation, anergy occurs • T cells • Become tolerant to that antigen • Are unable to divide • Do not secrete cytokines Copyright © 2010 Pearson Education, Inc. T Cell Activation: Co-Stimulation • T cells that are activated • Enlarge, proliferate, and form clones • Differentiate and perform functions according to their T cell class Copyright © 2010 Pearson Education, Inc. T Cell Activation: Co-Stimulation • Primary T cell response peaks within a week • T cell apoptosis occurs between days 7 and 30 • Effector activity wanes as the amount of antigen declines • Benefit of apoptosis: activated T cells are a hazard • Memory T cells remain and mediate secondary responses Copyright © 2010 Pearson Education, Inc. Cytokines • Mediate cell development, differentiation, and responses in the immune system • Include interleukins and interferons • Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to • Release interleukin 2 (IL-2) • Synthesize more IL-2 receptors Copyright © 2010 Pearson Education, Inc. Cytokines • IL-2 is a key growth factor, acting on cells that release it and other T cells • Encourages activated T cells to divide rapidly • Used therapeutically to treat melanoma and kidney cancers • Other cytokines amplify and regulate innate and adaptive responses Copyright © 2010 Pearson Education, Inc. Roles of Helper T(TH) Cells • Play a central role in the adaptive immune response • Once primed by APC presentation of antigen, they • Help activate T and B cells • Induce T and B cell proliferation • Activate macrophages and recruit other immune cells • Without TH, there is no immune response Copyright © 2010 Pearson Education, Inc. Helper T Cells • Interact directly with B cells displaying antigen fragments bound to MHC II receptors • 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 require TH co-stimulation to activate B cells Copyright © 2010 Pearson Education, Inc. TH cell help in humoral immunity Activated helper T cell 1 TH cell binds with the Helper T cell CD4 protein self-nonself complexes of a B cell that has encountered its antigen and is displaying it on MHC II on its surface. MHC II protein of B cell displaying processed antigen 2 TH cell releases T cell receptor (TCR) IL- 4 and other cytokines interleukins as co-stimulatory signals to complete B cell activation. B cell (being activated) (a) Copyright © 2010 Pearson Education, Inc. Figure 21.19a Helper T Cells • Cause dendritic cells to express costimulatory molecules required for CD8 cell activation Copyright © 2010 Pearson Education, Inc. TH cell help in cell-mediated immunity CD4 protein Helper T cell 1 Previously activated TH cell binds dendritic cell. Class II MHC protein APC (dendritic cell) 2 TH cell stimulates IL-2 dendritic cell to express co-stimulatory molecules (not shown) needed to activate CD8 cell. 3 Dendritic cell can Class I MHC protein (b) Copyright © 2010 Pearson Education, Inc. CD8 protein CD8 T cell now activate CD8 cell with the help of interleukin 2 secreted by TH cell. Figure 21.19b Roles of Cytotoxic T(TC) Cells • Directly attack and kill other cells • Activated TC cells circulate in blood and lymph and lymphoid organs in search of body cells displaying antigen they recognize Copyright © 2010 Pearson Education, Inc. Roles of Cytotoxic T(TC) Cells • Targets • Virus-infected cells • Cells with intracellular bacteria or parasites • Cancer cells • Foreign cells (transfusions or transplants) Copyright © 2010 Pearson Education, Inc. Cytotoxic T Cells • Bind to a self-nonself complex • Can destroy all infected or abnormal cells Copyright © 2010 Pearson Education, Inc. Cytotoxic T Cells • Lethal hit • Tc cell releases perforins and granzymes by exocytosis • Perforins create pores through which granzymes enter the target cell • Granzymes stimulate apoptosis • In some cases, TC cell binds with a Fas receptor on the target cell, and stimulates apoptosis Copyright © 2010 Pearson Education, Inc. Adaptive defenses Cytotoxic T cell (TC) Cellular immunity 1 TC binds tightly to the target cell when it identifies foreign antigen on MHC I proteins. granzyme molecules from its granules by exocytosis. Granule Perforin TC cell membrane Target cell membrane Target cell 2 TC releases perforin and Perforin pore Granzymes 5 The TC detaches and 3 Perforin molecules insert into the target cell membrane, polymerize, and form transmembrane pores (cylindrical holes) similar to those produced by complement activation. 4 Granzymes enter the target cell via the pores. Once inside, these proteases degrade cellular contents, stimulating apoptosis. searches for another prey. (a) A mechanism of target cell killing by TC cells. Copyright © 2010 Pearson Education, Inc. Figure 21.20a Natural Killer Cells • Recognize other signs of abnormality • Lack of class I MHC • Antibody coating a target cell • Different surface marker on stressed cells • Use the same key mechanisms as Tc cells for killing their target cells Copyright © 2010 Pearson Education, Inc. Regulatory T (TReg) Cells • Dampen the immune response by direct contact or by inhibitory cytokines • Important in preventing autoimmune reactions Copyright © 2010 Pearson Education, Inc. Cell-mediated immunity Antigen (Ag) intruder Humoral immunity Inhibits Inhibits Triggers Adaptive defenses Innate defenses Surface Internal barriers defenses Ag-infected body cell engulfed by dendritic cell Becomes Ag-presenting cell (APC) presents self-Ag complex Activates Free Ags may directly activate B cell Antigenactivated B cells Clone and give rise to Activates Naïve Naïve CD8 CD4 T cells T cells Activated to clone Activated to clone and give rise to Induce and give rise to co-stimulation Memory cytotoxic T cells Activated cytotoxic T cells Memory helper T cells Activated helper T cells Memory B cells Plasma cells (effector B cells) Secrete Cytokines stimulate Together the nonspecific killers and cytotoxic T cells mount a physical attack on the Ag Copyright © 2010 Pearson Education, Inc. Nonspecific killers (macrophages and NK cells of innate immunity) Antibodies (Igs) Circulating lgs along with complement mount a chemical attack on the Ag Figure 21.21 Organ Transplants • Four varieties • Autografts: from one body site to another in the same person • Isografts: between identical twins • Allografts: between individuals who are not identical twins • Xenografts: from another animal species Copyright © 2010 Pearson Education, Inc. Prevention of Rejection • Depends on the similarity of the tissues • Patient is treated with immunosuppressive therapy • Corticosteroid drugs to suppress inflammation • Antiproliferative drugs • Immunosuppressant drugs • Many of these have severe side effects Copyright © 2010 Pearson Education, Inc. Immunodeficiencies • Congenital and acquired conditions that cause immune cells, phagocytes, or complement to behave abnormally Copyright © 2010 Pearson Education, Inc. Severe Combined Immunodeficiency (SCID) Syndrome • Genetic defect • 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 Copyright © 2010 Pearson Education, Inc. Hodgkin’s Disease • An acquired immunodeficiency • Cancer of the B cells • Leads to immunodeficiency by depressing lymph node cells Copyright © 2010 Pearson Education, Inc. Acquired Immune Deficiency Syndrome (AIDS) • Cripples the immune system by interfering with the activity of helper T cells • Characterized by severe weight loss, night sweats, and swollen lymph nodes • Opportunistic infections occur, including pneumocystis pneumonia and Kaposi’s sarcoma Copyright © 2010 Pearson Education, Inc. Acquired Immune Deficiency Syndrome (AIDS) • Caused by human immunodeficiency virus (HIV) transmitted via body fluids—blood, semen, and vaginal secretions • HIV enters the body via • Blood transfusions • Blood-contaminated needles • Sexual intercourse and oral sex • HIV • Destroys TH cells • Depresses cell-mediated immunity Copyright © 2010 Pearson Education, Inc. Acquired Immune Deficiency Syndrome (AIDS) • HIV multiplies in lymph nodes throughout the asymptomatic period • Symptoms appear in a few months to 10 years • HIV-coated glycoprotein complex attaches to the CD4 receptor • HIV enters the cell and uses reverse transcriptase to produce DNA from viral RNA • The DNA copy (a provirus) directs the host cell to make viral RNA and proteins, enabling the virus to reproduce Copyright © 2010 Pearson Education, Inc. Acquired Immune Deficiency Syndrome (AIDS) • HIV reverse transcriptase produces frequent transcription errors; high mutation rate and resistance to drugs • Treatment with antiviral drugs • Reverse transcriptase inhibitors (AZT) • Protease inhibitors (saquinavir and ritonavir) • New Fusion inhibitors that block HIV’s entry to helper T cells Copyright © 2010 Pearson Education, Inc. Autoimmune Diseases • Immune system loses the ability to distinguish self from foreign • Production of autoantibodies and sensitized TC cells that destroy body tissues • Examples include multiple sclerosis, myasthenia gravis, Graves’ disease, type I diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis Copyright © 2010 Pearson Education, Inc. Mechanisms of Autoimmune Diseases 1. Foreign antigens may resemble self-antigens • Antibodies against the foreign antigen may crossreact with self-antigen 2. New self-antigens may appear, generated by • Gene mutations • Changes in self-antigens by hapten attachment or as a result of infectious damage Copyright © 2010 Pearson Education, Inc. Mechanisms of Autoimmune Diseases 3. Release of novel self-antigens by trauma of a barrier (e.g., the blood-brain barrier) Copyright © 2010 Pearson Education, Inc. Hypersensitivities • Immune responses to a perceived (otherwise harmless) threat • Causes tissue damage • Different types are distinguished by • Their time course • Whether antibodies or T cells are involved • Antibodies cause immediate and subacute hypersensitivities • T cells cause delayed hypersensitivity Copyright © 2010 Pearson Education, Inc. Immediate Hypersensitivity • Acute (type I) hypersensitivities (allergies) begin in seconds after contact with allergen • Initial contact is asymptomatic but sensitizes the person • Reaction may be local or systemic Copyright © 2010 Pearson Education, Inc. Immediate Hypersensitivity • The mechanism involves IL-4 secreted by T cells • IL-4 stimulates B cells to produce IgE • IgE binds to mast cells and basophils, resulting in a flood of histamine release and inducing the inflammatory response Copyright © 2010 Pearson Education, Inc. Anaphylactic Shock • Systemic response to allergen that directly enters the blood • Basophils and mast cells are enlisted throughout the body • Systemic histamine releases may cause • Constriction of bronchioles • Sudden vasodilation and fluid loss from the bloodstream • Hypotensive shock and death • Treatment: epinephrine Copyright © 2010 Pearson Education, Inc. Subacute Hypersensitivities • Caused by IgM and IgG transferred via blood plasma or serum • Slow onset (1–3 hours) and long duration (10–15 hours) • 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 Copyright © 2010 Pearson Education, Inc. 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) Copyright © 2010 Pearson Education, Inc. Delayed Hypersensitivities (Type IV) • Slow onset (one to three days) • Mechanism depends on helper T cells • Cytokine-activated macrophages and cytotoxic T cells cause damage • Example: allergic contact dermatitis (e.g., poison ivy) Copyright © 2010 Pearson Education, Inc. Developmental Aspects • Immune system stem cells develop in the liver and spleen by the ninth week • Bone marrow becomes the primary source of stem cells • Lymphocyte development continues in the bone marrow and thymus Copyright © 2010 Pearson Education, Inc. 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, and incidence of cancer increases Copyright © 2010 Pearson Education, Inc.