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Lymphatic System and Immunity: Slide 2 Lymphatic System Lymph Lymphatic vessels Lymphatic tissue Lymphatic nodules Lymph nodes Tonsils Spleen Thymus Slide 3 Lymphatic Vessels Carry lymph away from tissues Lymphatic capillaries More permeable than blood capillaries Epithelium functions as series of one-way valves Slide 4 Functions of the Lymphatic System Fluid balance Fluid balance Excess interstitial fluid enters lymphatic capillaries and becomes lymph Excess interstitial fluid enters lymphatic capillaries and becomes lymph Fat absorption Fat absorption Absorption of fat and other substances from digestive tract Absorption of fat and other substances from digestive tract Defense Defense Microorganisms and other foreign substances are filtered from lymph by lymph nodes and from blood by spleen Microorganisms and other foreign substances are filtered from lymph by lymph nodes and from blood by spleen Slide 5 Lymphatic Vessels Carry lymph away from tissues Lymphatic capillaries More permeable than blood capillaries Epithelium functions as series of one-way valves Slide 6 Lymphatic Vessels Lymphatic capillaries join to form Lymphatic capillaries join to form Lymphatic vessels Lymphatic vessels Have valves that ensure one-way flow Have valves that ensure one-way flow Lymph nodes: Distributed along vessels and filter lymph Lymph nodes: Distributed along vessels and filter lymph Lymphatic trunks: Jugular, subclavian, bronchomediastinal, intestinal, lumbar Lymphatic trunks: Jugular, subclavian, bronchomediastinal, intestinal, lumbar Lymphatic ducts: Right and thoracic which connect to large veins Lymphatic ducts: Right and thoracic which connect to large veins Slide 7 Lymph Drainage Slide 8 Lymphatic Tissue and Nodules Lymphatic tissue Consists mainly of lymphocytes Encapsulated or not Lymphatic nodules Numerous in loose connective tissue of digestive (Peyers patches), respiratory, urinary, reproductive systems Slide 9 Tonsils Large groups of lymphatic nodules in nasopharynx and oral cavity Provide protection against bacteria and other harmful material Groups Palatine Pharyngeal Lingual Slide 10 Lymph Nodes Organized in cortex and medulla Substances removed by phagocytosis or stimulate lymphocytes or both Only structures to filter lymph Afferent and efferent vessels Slide 11 Figure 25-16 Molecular Biology of the Cell ( Garland Science 2008) Slide 12 Slide 13 Slide 14 Spleen Located in left superior side of abdomen Located in left superior side of abdomen Can be ruptured in traumatic abdominal injuries resulting in bleeding, shock, death Can be ruptured in traumatic abdominal injuries resulting in bleeding, shock, death Blood flows through at 3 different rates Blood flows through at 3 different rates Fast (most), slow, intermediate Fast (most), slow, intermediate Functions Functions Destroys defective RBCs Destroys defective RBCs Detects and responds to foreign substances Detects and responds to foreign substances Limited reservoir for blood Limited reservoir for blood Slide 15 Spleen Slide 16 Thymus Located in superior mediastinum Divisions: Cortex and medulla Site of maturation of T cells Slide 17 Slide 18 Hassall's corpuscle Found in the central region of each thymic lobule Found in the central region of each thymic lobule Sometimes referred to as a thymic corpuscle Sometimes referred to as a thymic corpuscle Function is unknown Function is unknown Known source of Thymic Stromal Lymphopoietin (TSLP) Known source of Thymic Stromal Lymphopoietin (TSLP) TSLP is a Cytokine which activates Antigen Presenting Cells (APCs), which in turn play a strong role in T-lymphocyte selection. TSLP is a Cytokine which activates Antigen Presenting Cells (APCs), which in turn play a strong role in T-lymphocyte selection. Slide 19 Immunity Ability to resist damage from foreign substances as microorganisms and harmful chemicals Ability to resist damage from foreign substances as microorganisms and harmful chemicals Categories Categories Innate or nonspecific resistance Innate or nonspecific resistance Mechanical mechanisms: Prevent entry or remove microbes Mechanical mechanisms: Prevent entry or remove microbes Chemical mediators: Promote phagocytosis and inflammation Chemical mediators: Promote phagocytosis and inflammation Cells: Involved in phagocytosis and production of chemicals Cells: Involved in phagocytosis and production of chemicals Adaptive or specific immunity Adaptive or specific immunity Specificity: Ability to recognize a particular substance Specificity: Ability to recognize a particular substance Memory: Ability to remember previous encounters with a particular substance and respond rapidly Memory: Ability to remember previous encounters with a particular substance and respond rapidly Slide 20 An Overview of the Immune Response Slide 21 Innate immune Responses Innate immune Responses Innate immune responses provide the first line of defense Innate immune responses provide the first line of defense The response lack specificity. The response lack specificity. An invading agent first encounters a phagocytic cell. An invading agent first encounters a phagocytic cell. Phagocytes have receptor proteins such as the Toll-like receptors (TLRs). Phagocytes have receptor proteins such as the Toll-like receptors (TLRs). Activation of such receptors play a role in promoting immunity, by initiating secretion of inflammatory mediators (such as cytokines). Activation of such receptors play a role in promoting immunity, by initiating secretion of inflammatory mediators (such as cytokines). Slide 22 Model of a TLR3 bound to a dsRNA molecule Slide 23 Innate responses are typically accompanied by the concentration of defensive agents at the site of infectioninflammation. Innate responses are typically accompanied by the concentration of defensive agents at the site of infectioninflammation. Another mechanism produces proteins called complement that bind to pathogens and initiate their lysis. Another mechanism produces proteins called complement that bind to pathogens and initiate their lysis. Innate responses against viruses include natural killer (NK) cell to induce apoptosis in the infected cell. Innate responses against viruses include natural killer (NK) cell to induce apoptosis in the infected cell. Slide 24 Inflammatory Response Tissue injury regardless of type can cause inflammation Tissue injury regardless of type can cause inflammation Response initiated by chemical mediators that produce vasodilation, chemotactic attraction, increased vascular permeability Response initiated by chemical mediators that produce vasodilation, chemotactic attraction, increased vascular permeability Types Types Local: Symptoms are redness, heat, swelling, pain, loss of function Local: Symptoms are redness, heat, swelling, pain, loss of function Systemic: Symptoms are increase in neutrophil numbers, fever and shock Systemic: Symptoms are increase in neutrophil numbers, fever and shock Slide 25 Inflammatory Response Slide 26 C3a stimulates mast cells and basophils, which then secrete inflammatory mediators Slide 27 Innate Immunity: Cells White blood cells White blood cells Most important cellular components of immune system Most important cellular components of immune system Methods Methods Chemotaxis Chemotaxis Phagocytosis Phagocytosis Neutrophils Neutrophils Phagocytic and first cells to enter infected tissue Phagocytic and first cells to enter infected tissue Macrophages Monocytes that leave blood, enter tissues Large phagocytic cells Basophils and mast cells Promote inflammation Eosinophils Reduce inflammation Natural killer cells Lyse tumor and virus- infected cells Slide 28 Slide 29 Innate immunity Slide 30 Antigenic Determinants Antigenic determinants Specific regions of a given antigen recognized by a lymphocyte Antigenic receptors Surface of lymphocyte that combines with antigenic determinant Slide 31 An Overview of the Immune Response Slide 32 Another innate antiviral response is initiated by virus-infected cells that produce interferon. Another innate antiviral response is initiated by virus-infected cells that produce interferon. Interferon binds to the surface of non-infected cells making them resistant to infection. Interferon binds to the surface of non-infected cells making them resistant to infection. A type of interferon may induce synthesis of miRNAs that target viral RNA genomes. A type of interferon may induce synthesis of miRNAs that target viral RNA genomes. Slide 33 Adaptive Immune Responses Adaptive Immune Responses Adaptive (or acquired) immune responses require a lag period for an attack against a foreign agent. Adaptive (or acquired) immune responses require a lag period for an attack against a foreign agent. This response is specific and occurs only in vertebrates. This response is specific and occurs only in vertebrates. There are two broad categories of adaptive immunity: There are two broad categories of adaptive immunity: Humoral immunity Humoral immunity Cell-mediated immunity Cell-mediated immunity Slide 34 Humoral immunity is carried out by antibodies, which are globular proteins of the immunoglobulin superfamily (IgSF). Humoral immunity is carried out by antibodies, which are globular proteins of the immunoglobulin superfamily (IgSF). Cell-mediated immunity is carried out by cells. Cell-mediated immunity is carried out by cells. Both types of immunity are mediated by lymphocytes, which are leukocytes that circulate between the blood and lymphoid organs. Both types of immunity are mediated by lymphocytes, which are leukocytes that circulate between the blood and lymphoid organs. Slide 35 Humoral immunity is mediated by B lymphocytes, which differentiate into antibody- secreting plasma cells when activated. Humoral immunity is mediated by B lymphocytes, which differentiate into antibody- secreting plasma cells when activated. Cell-mediated immunity is carried out by T lymphocytes (or T cells), which recognize and kill infected cells when activated. Cell-mediated immunity is carried out by T lymphocytes (or T cells), which recognize and kill infected cells when activated. B and T cells arise from hematopoietic stem cells. B and T cells arise from hematopoietic stem cells. Slide 36 Origin and Development of Lymphocytes B and T cells Originate in red bone marrow Move to lymphatic tissue from processing sites and continually circulate Clones are small groups of identical lymphocytes Slide 37 Adaptive immunity involves the ability to recognize, respond to, and remember a particular substance (stimulant). Stimulants Stimulants Antigens: Large molecules Antigens: Large molecules Foreign: Not produced by body, introduced from outside Foreign: Not produced by body, introduced from outside Self-antigens: Produced by body Self-antigens: Produced by body Haptens: Small molecules and capable of combining Haptens: Small molecules and capable of combining Types Types Humoral or Antibody-mediated: B cells Humoral or Antibody-mediated: B cells Cell-mediated: T cells Cell-mediated: T cells Slide 38 Normal Microcirculation Flow Slide 39 Exudate Formation Slide 40 Leukocyte Margination and Migration Slide 41 Diapedesis Slide 42 Chemotaxis Slide 43 Slide 44 Major Histocompatability Complex (MHC) Most lymphocyte activation involves glycoproteins of cell surfaces called MHC molecules Most lymphocyte activation involves glycoproteins of cell surfaces called MHC molecules Class I molecules display antigens on surface of nucleated cells, resulting in destruction of cells Class I molecules display antigens on surface of nucleated cells, resulting in destruction of cells Class II molecules display antigens on surface of antigen-presenting cells (APCs), resulting in activation of immune cells Class II molecules display antigens on surface of antigen-presenting cells (APCs), resulting in activation of immune cells Slide 45 The MHC proteins hold fragments of antigen in place on APCs. The MHC proteins hold fragments of antigen in place on APCs. The TCR interacts with an APC when it docks with MHC proteins. The TCR interacts with an APC when it docks with MHC proteins. Cytotoxic T cells recognize their antigen in association with MHC I molecules. Cytotoxic T cells recognize their antigen in association with MHC I molecules. Helper T cells recognize their antigen in association with MHC II molecules. Helper T cells recognize their antigen in association with MHC II molecules. Slide 46 Peptides produced by antigen processing bind within a groove of the MHC protein molecule Slide 47 MHC class I Slide 48 Origin and Development of Lymphocytes Positive selection Positive selection Ensures survival of lymphocytes that react against antigens Ensures survival of lymphocytes that react against antigens Negative selection Negative selection Eliminates lymphocytes that react against self-antigens Eliminates lymphocytes that react against self-antigens Primary lymphatic organs (red bone marrow, thymus) Primary lymphatic organs (red bone marrow, thymus) Where lymphocytes mature into functional cells Where lymphocytes mature into functional cells Secondary lymphatic organs Secondary lymphatic organs Where lymphocytes produce an immune response Where lymphocytes produce an immune response Slide 49 Thymus Located in superior mediastinum Divisions: Cortex and medulla Site of maturation of T cells Slide 50 T-cells, activated by clonal selection, interact with antigens through a surface protein called a T-cell receptor. T-cells, activated by clonal selection, interact with antigens through a surface protein called a T-cell receptor. T cells are activated by fragments of antigens that are displayed on the surface of antigen-presenting cells (APCs). T cells are activated by fragments of antigens that are displayed on the surface of antigen-presenting cells (APCs). Dendritic cells ingest antigens by endocytosis. Dendritic cells ingest antigens by endocytosis. Macrophages ingest antigens by phagocytosis. Macrophages ingest antigens by phagocytosis. These cells process and present the antigen to other cells. These cells process and present the antigen to other cells. Slide 51 T cells release cytokines that alter the activity of the target cell. T cells release cytokines that alter the activity of the target cell. Slide 52 Any students interested in partaking in a directed study group led by a past graduate of the course (one of the good ones), on Fridays from 1-2:30 pm, Please email Sorouch Safa at: soroush.safa@yahoo.ca Slide 53 Structure of the antigen receptors of a B cell and a T cell Slide 54 Three classes of T cells are distinguished by the proteins on their surfaces and their biological functions: Three classes of T cells are distinguished by the proteins on their surfaces and their biological functions: Cytotoxic T lymphocytes (CTLs) kill target cells by inducing apoptosis. Cytotoxic T lymphocytes (CTLs) kill target cells by inducing apoptosis. Helper T (T H ) lymphocytes are regulatory cells activated by APCs. Helper T (T H ) lymphocytes are regulatory cells activated by APCs. Regulatory T lymphocytes (T Reg cells) suppress the activities of other immune cells. Regulatory T lymphocytes (T Reg cells) suppress the activities of other immune cells. Slide 55 T-cell receptor synthesis The ability of T cells to recognize foreign antigens is mediated by the T-cell receptor (TCR). The ability of T cells to recognize foreign antigens is mediated by the T-cell receptor (TCR). Unlike most genes, the TCR gene is made up of a series of alternative gene fragments. Unlike most genes, the TCR gene is made up of a series of alternative gene fragments. In order to create a functional T cell receptor, immature T- lymphocyte precursors use a series of DNA-interacting enzymes to bring separate gene fragments together. In order to create a functional T cell receptor, immature T- lymphocyte precursors use a series of DNA-interacting enzymes to bring separate gene fragments together. The outcome of this process is that the TCR for EACH and EVERY T-lymphocyte has a different sequence. The outcome of this process is that the TCR for EACH and EVERY T-lymphocyte has a different sequence. Slide 56 DNA rearrangements that lead to the formation of genes for an immunoglobulin (such as the T-cell receptor) Slide 57 DNA Rearrangement of Genes Encoding B- and T-Cell Antigen Receptors DNA Rearrangement of Genes Encoding B- and T-Cell Antigen Receptors Two separate genes (a C gene and V gene) are combined (with a joining segment) through rearrangement to form one continuous gene that encodes one antibody chain. Two separate genes (a C gene and V gene) are combined (with a joining segment) through rearrangement to form one continuous gene that encodes one antibody chain. Slide 58 DNA rearrangement (continued) DNA rearrangement (continued) The process is catalyzed by V(D)J recombinase which joins V and J segments of the gene, and deleting the intervening DNA. The process is catalyzed by V(D)J recombinase which joins V and J segments of the gene, and deleting the intervening DNA. Rearrangement is facilitated by signal sequences which are similar in V and J segments. Rearrangement is facilitated by signal sequences which are similar in V and J segments. Slide 59 DNA rearrangement (continued) DNA rearrangement (continued) Variability in polypeptide chains is achieved by: Variability in polypeptide chains is achieved by: The variety of V and J exons in the DNA of the germ line. The variety of V and J exons in the DNA of the germ line. Varying the site at which J and V sequences are joined. Varying the site at which J and V sequences are joined. The enzymatic insertion of nucleotides. The enzymatic insertion of nucleotides. Somatic hypermutation refers to a high mutation rate in V elements of B cells. Somatic hypermutation refers to a high mutation rate in V elements of B cells. Slide 60 T-cell receptor assembly The TCR chain is paired with the pre-T to generate the pre- TCR. The TCR chain is paired with the pre-T to generate the pre- TCR. The disadvantage in the gene-rearrangement process is that many of the combinations of the TCR gene fragments are non-functional. The disadvantage in the gene-rearrangement process is that many of the combinations of the TCR gene fragments are non-functional. Cells that fail to produce a functional pre-TCR are eliminated by apoptosis (-selection). Cells that fail to produce a functional pre-TCR are eliminated by apoptosis (-selection). Following -selection, the cells undergo TCR rearrangement, resulting in completely assembled TCR in its final form. Following -selection, the cells undergo TCR rearrangement, resulting in completely assembled TCR in its final form. Slide 61 T-cell receptor (general structure) Slide 62 TCR interactions with MHC I and MHC II Slide 63 Slide 64 Positive T-cell receptor selection Thymocytes which pass -selection now express a TCR which is capable of assembling on the cell surface. Thymocytes which pass -selection now express a TCR which is capable of assembling on the cell surface. However many of these TCRs will still be non-functional (unable to bind MHC I or II). However many of these TCRs will still be non-functional (unable to bind MHC I or II). Thymocytes that have a T cell receptor incapable of binding MHC class I or class II undergo apoptosis (panel b). Thymocytes that have a T cell receptor incapable of binding MHC class I or class II undergo apoptosis (panel b).apoptosis The remaining thymocytes will undergo negative selection. The remaining thymocytes will undergo negative selection. Slide 65 Negative T-cell receptor selection The key disadvantage in the process of TCR assembly is that by random chance, some arrangements will create a TCR capable of binding self-peptides presented on MHC class I or II. The key disadvantage in the process of TCR assembly is that by random chance, some arrangements will create a TCR capable of binding self-peptides presented on MHC class I or II. Such T cells would be capable of activating an immune response against self, resulting in an autoimmune disease. Such T cells would be capable of activating an immune response against self, resulting in an autoimmune disease. During negative selection, all thymocytes with a high affinity for binding self peptides presented on MHC class I or class II are induced to undergo apoptosis (panel a). During negative selection, all thymocytes with a high affinity for binding self peptides presented on MHC class I or class II are induced to undergo apoptosis (panel a). Cells which do not have a high affinity for self antigens survive negative selection (panel c). Cells which do not have a high affinity for self antigens survive negative selection (panel c). Slide 66 Determining the fate of a newly formed T cell in the thymus Slide 67 Features of the B-cell clonal selection: Features of the B-cell clonal selection: Antibody production follows selection of B cells by antigen. Antibody production follows selection of B cells by antigen. Each B cell becomes committed to produce one species of antibody. Each B cell becomes committed to produce one species of antibody. B cells become committed to antibody formation in the absence of antigen. B cells become committed to antibody formation in the absence of antigen. B-cells undergo a process of positive selection to eliminate self-recognition. Slide 68 Slide 69 Lymphocytes Are Activated by Cell-Surface Signals Lymphocytes Are Activated by Cell-Surface Signals T cell activation requires interaction between its TCR and an MHC-peptide complex. T cell activation requires interaction between its TCR and an MHC-peptide complex. Activation also requires a second signal called the costimulatory signal that is delivered by a second type of receptor. Activation also requires a second signal called the costimulatory signal that is delivered by a second type of receptor. Slide 70 Lymphocyte activation (continued) Lymphocyte activation (continued) Activation of Helper T Cells by Professional APCs Activation of Helper T Cells by Professional APCs B7 proteins on APC cells interact with CD28 proteins on helper T cells in a costimulatory signal interaction. B7 proteins on APC cells interact with CD28 proteins on helper T cells in a costimulatory signal interaction. Only professional APCs are capable of costimulatory signaling; they are the only ones that initiate a T H response. Only professional APCs are capable of costimulatory signaling; they are the only ones that initiate a T H response. T H cell activation requires two signals, which protects other cells from autoimmune attack involving T H cells. T H cell activation requires two signals, which protects other cells from autoimmune attack involving T H cells. Slide 71 T-cells interact with antigens through a surface protein called a T-cell receptor. T-cells interact with antigens through a surface protein called a T-cell receptor. T cells are activated by fragments of antigens that are displayed on the surface of APCs. T cells are activated by fragments of antigens that are displayed on the surface of APCs. Dendritic cells ingest antigens by endocytosis. Dendritic cells ingest antigens by endocytosis. Macrophages ingest antigens by phagocytosis. Macrophages ingest antigens by phagocytosis. These cells process and present the antigen to other cells. These cells process and present the antigen to other cells. These cells are referred to as Professional APCs These cells are referred to as Professional APCs Slide 72 Professional APCs Slide 73 Figure 25-5 Molecular Biology of the Cell ( Garland Science 2008) Slide 74 Lymphocyte activation Slide 75 Interaction between an APC and a T cell during antigen presentation Slide 76 Lymphocyte activation (continued) Lymphocyte activation (continued) Activation of Cells by T H Cells Activation of Cells by T H Cells T H cells bind to B cells whose receptors recognize the same antigen. T H cells bind to B cells whose receptors recognize the same antigen. B cells are activated by the interaction of cell surface proteins and by cytokines. B cells are activated by the interaction of cell surface proteins and by cytokines. Slide 77 Three-dimensional model of a peptide bound with the antigen-binding pocket of a MHC I Slide 78 The Clonal Selection Theory As It Applies to B Cells (3) Features of clonal selection (continued) Features of clonal selection (continued) Immunologic memory provides long-term immunity. Immunologic memory provides long-term immunity. Immunologic tolerance prevents the production of antibodies against self. Immunologic tolerance prevents the production of antibodies against self. The body prevents production of autoantibodies, which could produce organ destruction and disease. The body prevents production of autoantibodies, which could produce organ destruction and disease. Slide 79 The Clonal Selection Theory As It Applies to B Cells (4) Vaccination Vaccination The first vaccine produced was against smallpox. The first vaccine produced was against smallpox. Most vaccines contain attenuated pathogens, which are capable of stimulating immunity but unable to cause disease. Most vaccines contain attenuated pathogens, which are capable of stimulating immunity but unable to cause disease. Some vaccines do not last a lifetime and require a booster shot. Some vaccines do not last a lifetime and require a booster shot. Slide 80 Slide 81 Antigen Processing Slide 82 Phagocytosis Phagocytosis also involves membrane invagination. This process does not involve clathrin. Pseudopods extend around a particle, forming a phagosome. Phagosome will fuse with a lysosome, containing digestive enzymes. There are smaller transport mechanisms in the wall of the secondary lysosome. Slide 83 Slide 84 Costimulation Slide 85 Proliferation of Helper T Cells Slide 86 Binding of an antigen to the B-cell receptor primes the B-cell Slide 87 Slide 88 Proliferation of B Cells Slide 89 Comparison of the structure of a B cell and a plasma cell Slide 90 Lymphocyte Inhibition Tolerance: To prevent the immune system from responding to self-antigens Tolerance: To prevent the immune system from responding to self-antigens Provoked by Provoked by Deletion of self-reactive lymphocytes Deletion of self-reactive lymphocytes Preventing activation of lymphocytes Preventing activation of lymphocytes Activation of suppressor T cells Activation of suppressor T cells Slide 91 Antibody-Mediated Immunity Antibodies or Immunoglobulins (Ig) Classes: IgG, IgM, IgA, IgE, IgD Structure Variable region: Part that combines with anitgenic determinant of antigen Constant region: Responsible for activities Slide 92 Actions of Antibodies Slide 93 Figure 25-11 Molecular Biology of the Cell ( Garland Science 2008) Slide 94 Antibody Production Slide 95 Cell-Mediated Immunity Antigen activates effector T cells and produces memory T cells Cytotoxic T cells lyse virus-infected cells, tumor cells, and tissue transplants Cytotoxic T cells produce cytokines, which promote phagocytosis and inflammation Slide 96 Interactions and Responses of Innate and Adaptive Immunity Slide 97 Ways to Acquire Adaptive Immunity Slide 98 Effects of Aging Little effect on lymphatic system Little effect on lymphatic system Decreased ability of helper T cells to proliferate in response to antigens Decreased ability of helper T cells to proliferate in response to antigens Decreased primary and secondary antibody responses Decreased primary and secondary antibody responses Decreased ability of cell-mediated immunity to resist intracellular pathogens Decreased ability of cell-mediated immunity to resist intracellular pathogens Slide 99 Immune System Problems Hypersensitivity reactions Hypersensitivity reactions Autoimmune disease Autoimmune disease Severe combined immunodeficiency disease (SCID) Severe combined immunodeficiency disease (SCID) Transplantation Transplantation Acute rejection Acute rejection Chronic rejection Chronic rejection Slide 100 Slide 101 Atherosclerosis is an Inflammatory Disease Ross R. N Engl J Med 1999;340:115-126. Endothelium Vessel Lumen Intima Foam Cell Monocyte Cytokines Growth Factors Metalloproteinases Cell Proliferation Matrix Degradation Macrophage Slide 102 Lipoprotein Classes and Inflammation Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000; 149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. HDLLDL Chylomicrons, VLDL, and their catabolic remnants > 30 nm 2022 nm Potentially proinflammatory 915 nm Potentially anti- inflammatory Slide 103 LDL is composed of a core of 1500 molecules of cholesterol enclosed in layers of phospholipid and unesterified cholesterol molecules. LDL is composed of a core of 1500 molecules of cholesterol enclosed in layers of phospholipid and unesterified cholesterol molecules. A large protein called apoprotein B-100 is embedded in this hydrophilic layer. A large protein called apoprotein B-100 is embedded in this hydrophilic layer. LDL is generated by the bodies fat-transport system via two mechanisms; the exogenous and the endogenous pathways. LDL is generated by the bodies fat-transport system via two mechanisms; the exogenous and the endogenous pathways. Slide 104 Structure of LDL Murphy HC et al. Biochemistry 2000;39:9763-970. Hydrophobic Core of Triglyceride and Cholesteryl Esters apoB Surface Monolayer of Phospholipids and Free Cholesterol Slide 105 The exogenous pathway begins in the intestine, and commences as the dietary fats become packaged into lipoprotein particles called chylomicrons. The exogenous pathway begins in the intestine, and commences as the dietary fats become packaged into lipoprotein particles called chylomicrons. Chylomicrons contain phospholipid, cholesterol, apolipoproteins (apo), for example apo B48, apo A-1, apo 11, C 11 and apo-E. Chylomicrons contain phospholipid, cholesterol, apolipoproteins (apo), for example apo B48, apo A-1, apo 11, C 11 and apo-E. Slide 106 Slide 107 Role of LDL in Inflammation Steinberg D et al. N Engl J Med 1989;320:915-924. Endothelium Vessel Lumen LDL LDL Readily Enter the Artery Wall Where They May be Modified LDL Intima Modified LDL Modified LDL are Proinflammatory Hydrolysis of Phosphatidylcholine to Lysophosphatidylcholine Other Chemical Modifications Oxidation of Lipids and ApoB Aggregation Slide 108 LDL LDL Modified LDL Stimulate Expression of MCP-1 in Endothelial Cells Navab M et al. J Clin Invest 1991;88:2039-2046. Endothelium Vessel Lumen Intima Monocyte Modified LDL MCP-1 Slide 109 LDL LDL Differentiation of Monocytes into Macrophages Steinberg D et al. N Engl J Med 1989;320:915-924. Endothelium Vessel Lumen Intima Monocyte Modified LDL Modified LDL Promote Differentiation of Monocytes into Macrophages MCP-1 Macrophage Slide 110 LDL LDL Modified LDL Induces Macrophages to Release Cytokines That Stimulate Adhesion Molecule Expression in Endothelial Cells Nathan CF. J Clin Invest 1987;79:319-326. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines Intima Slide 111 LDL LDL Endothelium Vessel Lumen Monocyte Macrophage MCP-1 Adhesion Molecules Steinberg D et al. N Engl J Med 1989;320:915-924. Macrophages Express Receptors That Take up Modified LDL Foam Cell Modified LDL Taken up by Macrophage Intima Slide 112 LDL LDL Endothelium Vessel Lumen Monocyte Macrophage Adhesion Molecules Macrophages and Foam Cells Express Growth Factors and Proteinases Foam Cell Intima Modified LDL Cytokines Cell Proliferation Matrix Degradation Growth Factors Metalloproteinases Ross R. N Engl J Med 1999;340:115-126. MCP-1MCP-1 Slide 113 Endothelium Vessel Lumen Monocyte Macrophage MCP-1MCP-1 Adhesion Molecules The Remnants of VLDL and Chylomicrons are Also Proinflammatory Foam Cell Intima Modified Remnants Cytokines Cell Proliferation Matrix Degradation Doi H et al. Circulation 2000;102:670-676. Growth Factors Metalloproteinases Remnant Lipoproteins Remnants Slide 114 Structure of HDL Rye KA et al. Atherosclerosis 1999;145:227-238. Hydrophobic Core of Triglyceride and Cholesteryl Esters apoA-II Surface Monolayer of Phospholipids and Free Cholesterol apoA-I Slide 115 LDL LDL Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines HDL Prevent Formation of Foam Cells Intima HDL Promote Cholesterol Efflux Foam Cell Slide 116 LDL LDL Mackness MI et al. Biochem J 1993;294:829-834. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines HDL Inhibit the Oxidative Modification of LDL Foam Cell HDL Promote Cholesterol Efflux Intima HDL Inhibit Oxidation of LDL Slide 117 LDL LDL Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines Inhibition of Adhesion Molecules Intima HDL Inhibit Oxidation of LDL HDL Inhibit Adhesion Molecule Expression Foam Cell HDL Promote Cholesterol Efflux Slide 118 Macrophage Functions in Atherogenesis Activation Slide 119 Slide 120 Slide 121 Slide 122 Slide 123 Slide 124 Slide 125 Lp(a) in Atherogenesis: Another Culprit? Identical to LDL particle except for addition of apo(a) Identical to LDL particle except for addition of apo(a) Plasma concentration predictive of atherosclerotic disease in many, although not all, epidemiologic studies Plasma concentration predictive of atherosclerotic disease in many, although not all, epidemiologic studies Accumulates in atherosclerotic plaque Accumulates in atherosclerotic plaque Binds apo Bcontaining lipoproteins and proteoglycans Binds apo Bcontaining lipoproteins and proteoglycans Taken up by foam cell precursors Taken up by foam cell precursors May interfere with thrombolysis May interfere with thrombolysis Maher VMG et al. JAMA 1995;274:1771-1774. Stein JH et al. Arch Intern Med 1997;157:1170-1176. Slide 126 Atherosclerosis is an Inflammatory Disease Ross R. N Engl J Med 1999;340:115-126. Endothelium Vessel Lumen Intima Foam Cell Monocyte Cytokines Growth Factors Metalloproteinases Cell Proliferation Matrix Degradation Macrophage Slide 127 LDL is composed of a core of 1500 molecules of cholesterol enclosed in layers of phospholipid and unesterified cholesterol molecules. LDL is composed of a core of 1500 molecules of cholesterol enclosed in layers of phospholipid and unesterified cholesterol molecules. A large protein called apoprotein B-100 is embedded in this hydrophilic layer. A large protein called apoprotein B-100 is embedded in this hydrophilic layer. LDL is generated by the bodys fat-transport system via two mechanisms; the exogenous and the endogenous pathways. LDL is generated by the bodys fat-transport system via two mechanisms; the exogenous and the endogenous pathways. Slide 128 The exogenous pathway begins in the intestine, and commences as the dietary fats become packaged into lipoprotein particles called chylomicrons. The exogenous pathway begins in the intestine, and commences as the dietary fats become packaged into lipoprotein particles called chylomicrons. Chylomicrons contain phospholipid, cholesterol, apolipoproteins (apo), for example apo B48, apo A-1, apo 11, C 11 and apo-E. Chylomicrons contain phospholipid, cholesterol, apolipoproteins (apo), for example apo B48, apo A-1, apo 11, C 11 and apo-E. Slide 129 LDL LDL Endothelium Vessel Lumen Monocyte Macrophage MCP-1 Adhesion Molecules Steinberg D et al. N Engl J Med 1989;320:915-924. Macrophages Express Receptors That Take up Modified LDL Foam Cell Modified LDL Taken up by Macrophage Intima Slide 130 LDL LDL Endothelium Vessel Lumen Monocyte Macrophage Adhesion Molecules Macrophages and Foam Cells Express Growth Factors and Proteinases Foam Cell Intima Modified LDL Cytokines Cell Proliferation Matrix Degradation Growth Factors Metalloproteinases Ross R. N Engl J Med 1999;340:115-126. MCP-1MCP-1 Slide 131 Endothelium Vessel Lumen Monocyte Macrophage MCP-1MCP-1 Adhesion Molecules The Remnants of VLDL and Chylomicrons are Also Proinflammatory Foam Cell Intima Modified Remnants Cytokines Cell Proliferation Matrix Degradation Doi H et al. Circulation 2000;102:670-676. Growth Factors Metalloproteinases Remnant Lipoproteins Remnants Slide 132 LDL LDL Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines HDL Prevent Formation of Foam Cells Intima HDL Promote Cholesterol Efflux Foam Cell Slide 133 Macrophage Functions in Atherogenesis Activation Slide 134 Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M ) in Human Atheroma Galis ZS et al. J Clin Invest 1994;94:2493-2503. Slide 135 Role of CETP Inhibition in Cholesterol Metabolism Brewer HB et al. Am J Cardiol 2003;92:10K-16K. LCAT LCAT LPL HL Oxidation Macrophage CD36 SR-A Arterial Wall Nascent HDL ABCA1 CETP Recycling HL