The Immune System - Chapter 1 PDF

Peter Parham The Immune System Fourth Edition Chapter 1 Elements of the Immune System and their Roles in Defense Copyright © Garland Science 2015  Edward Jenner (late 18th C.) Inoculation with cowpox could protect against smallpox....

Peter Parham The Immune System Fourth Edition Chapter 1 Elements of the Immune System and their Roles in Defense Copyright © Garland Science 2015  Edward Jenner (late 18th C.) Inoculation with cowpox could protect against smallpox. Vaccination discovery!  Figure 1-2 Robert Koch proved that infectious diseases are caused by microorganisms  Part I – Check list Commensal microorganisms Pathogens Body barriers against infection Inflammation Adaptive immunity Hematopoietic stem cells 1-1 Numerous commensal microorganisms inhabit healthy human bodies: More than 1000 different microbial species live in the healthy adult human gut. They are called “commensal”: i.e. they “eat at the same table”. Animals are both tolerant to their commensal species and dependent upon them. Figure 1.2 Antibiotic treatments disrupt the natural ecology of the colon. When antibiotics are taken orally to counter a bacterial infection, beneficial populations of commensal bacteria in the colon are also destroyed. This provides an opportunity for pathogenic strains of bacteria to populate the colon and cause further disease. 1-2 Pathogens are infectious organisms that cause disease: Pathogen: any organism with the potential to cause disease. Four kinds: bacteria, viruses, fungi, and internal parasites. Have evolved special adaptations to invade their hosts, replicate in them, and be transmitted. 1-2 Pathogens are infectious organisms that cause disease 1-3 The skin and mucosal surfaces form barriers against infection: Skin: tough, impenetrable barrier of epithelium protected by layers of keratinized cells. - Is the body’s first defense against infection. - Can be violated by physical damage, such as wounds, burn, or surgical procedures. Other epithelia: mucosae lining the respiratory, gastrointestinal, and urogenital tracts. 1-4 The innate immune response causes inflammation at sites of infection: The innate immune response consists of two parts: Recognition via soluble or surface-bound receptor proteins (primitive non-specific recognition: mainly phagocytes) Recruitment of effector mechanisms to kill and eliminate the pathogen Almost all components of the IS contribute to mechanisms for either recognizing or destroying pathogens, or to mechanisms for communicating between these two activities. Figure 1.6 The recognition of pathogens followed by their destruction is illustrated here by a fundamental process used to get rid of pathogens. Serum proteins of the complement system (turquoise) are activated in the presence of a pathogen (red): A piece of complement tags the pathogen as dangerous. The soluble complement fragment binds to a receptor on the surface of a phagocytic WBC, and summons it to the site of complement activation. The receptor and its bound ligand are taken up into the cell by phagocytosis. Figure 1.7 Innate immune mechanisms establish a state of inflammation at sites of infection. Inflammation, which is characterized by heat, pain, redness, and swelling (calor, dolor, rubor, and tumor, respectively) is not due to the infection itself, but to the immune system’s response to the pathogen. It enables cells and molecules of the IS to be brought rapidly and in large numbers into the infected tissue. 1-5 The adaptive immune response adds to an ongoing innate immune response: In normal individuals, a primary infection is cleared from the body by the combined effects of innate and adaptive immunity. 1-6 Adaptive immunity is better understood than innate immunity: Figure 1.10 The benefits of having both innate and adaptive immunity. Red line: uncontrolled infection occurs because the adaptive immune response cannot be deployed without the preceding innate response. Green line: the infection is initially contained by innate immunity but cannot be cleared from the body. Much of medical practice is concerned with the small proportion of infections that innate immunity fails to terminate. 1-7 Immune system cells with different functions all derive from hematopoietic stem cells Figure 1.12 The site of human hematopoiesis changes during development. Blood cells are first made in the yolk sac of the embryo, and later in the embryonic liver and spleen. They also start to be made in the bone marrow before birth By the time of birth, the BM is the only tissue in which hematopoiesis occurs. Types of hematopoietic cells: Figure 1.14 The relative abundance of the leukocyte cell types in human peripheral blood. Figure 1.15 Neutrophils are stored in the bone marrow and move in large numbers to sites of infection, where they act and then die. After one round of ingestion and killing of bacteria, a neutrophil dies. The creamy material known as pus is composed of dead neutrophils. Figure 1.16 Macrophages respond to pathogens by using different receptors to stimulate phagocytosis and cytokine secretion.  CHAPTER CONTENTS 1-8 Immunoglobulins and T-cell receptors are the diverse lymphocyte receptors of adaptive immunity 1-9 On encountering their specific antigen, B cells and T cells differentiate into effector cells 1-10 Antibodies bind to pathogens and cause their inactivation or destruction 1-11 Most lymphocytes are present in specialized lymphoid tissues 1-12 Adaptive immunity is initiated in secondary lymphoid tissues 1-13 The spleen provides adaptive immunity to blood infections 1-14 Most secondary lymphoid tissue is associated with the gut 1-8 Immunoglobulins and T-cell receptors are the diverse lymphocyte receptors of adaptive immunity: B-cell receptor: Y-shaped immunoglobulin (glycoprotein) Membrane-bound: anchored by a transmembrane tail 2 identical Ag-binding sites Plasma cell receptor: Secreted soluble Ab: lacks the transmembrane tail Otherwise identical to BCR T-cell receptor: Membrane-bound protein (no secreted form) Only one Ag-binding site 1-9 On encountering their specific antigen, B cells and T cells differentiate into effector cells: Two main kinds of activated T-cells: Cytotoxic T cells: TC Helper T cells: TH A subset of TH cells activate B cells Ab-secreting plasma cells. Figure 1.9 Effector cells are selected Against specific antigens. 1-10 Antibodies bind to pathogens and cause their inactivation or destruction: Ab main function: facilitate the engulfment and destruction of foreign bodies by phagocytes. Mechanisms by which Abs combat infection: Neutralization of toxins: Ab binds to toxins and prevents their interaction with receptors on human cells. Opsonization of bacteria: IgG can coat the bacterium through binding with its variable region. In both cases, the constant region of the Ab is recognized by receptors on a macrophage phagocytosis 1-11 Most lymphocytes are present in specialized lymphoid tissues: Primary lymphoid tissues: sites of development and maturation of lymphocytes – BM and thymus Secondary lymphoid tissues: sites of stimulation in response to pathogens – All other lymphoid tissues  left subclavian vein Figure 1.20 Lymphocyte recirculation. 1-12 Adaptive immunity is initiated in secondary lymphoid tissues Figure 1.22 Architecture of the lymph node, the site where blood- borne lymphocytes respond to lymphborne pathogens. Small kidney-shaped organs Composed of a cortex and a medulla. Packed with lymphocytes, macrophages, and other cells of the IS, between which the lymph percolates.  Free pathogens and debris are removed by macrophages. Dendritic cells become resident in the lymph node and move to the T-cell areas, where they specifically stimulate the division and differentiation of small lymphocytes into effector lymphocytes. Some helper T cells and cytotoxic T cells leave in the efferent lymph and travel to the infected tissue via the lymph and blood. Some helper T cells remain in the lymph node and stimulate the division and differentiation of B cells into plasma cells. Plasma cells move to the medulla of the lymph node, where they secrete pathogen-specific antibodies. Antibodies are taken to the site of infection by the efferent lymph and subsequently the blood. Some plasma cells leave the lymph node and travel via the efferent lymph and the blood to the BM, where they continue to secrete antibodies. 1-13 The spleen provides adaptive immunity to blood infections: Large lymphoid organ in the upper left part of the abdomen Weighs about 150 grams Serves as a filter for the blood Two main functions: - Removes damaged or senescent RBCs (red pulp) - Works as a secondary lymphoid organ by defending the body against blood-borne pathogens (white pulp) Asplenia: case of being born without a spleen Figure 1.24 Nodule of white pulp in transverse section. Central arteriole surrounded by sheath of lymphocytes: periarteriolar lymphoid sheath (PALS). The lymphocytes close to the arteriole are mostly T cells (blue region); B cells are placed more peripherally (yellow regions). Lymphoid follicles comprise a germinal center, a B-cell corona, and a marginal zone containing macrophages and differentiating B cells. Both follicle and PALS are surrounded by a perifollicular zone abutting the red pulp and containing a variety of cells, including erythrocytes, macrophages, T cells, and B cells. 1-14 Most secondary lymphoid tissue is associated with the gut: The gastrointestinal and respiratory tracts are particularly vulnerable to infections are heavily invested with secondary lymphoid tissue. 2 types of Mucosa-Associated Lymphoid Tissue (MALT) named according to location: Gut-Associated Lymphoid Tissue (GALT): In GI tract, includes the tonsils, adenoids, appendix, and Peyer’s patches. Bronchial-Associated Lymphoid Tissue (BALT): In respiratory tract  The GALT is organized similarly to the lymph node and the white pulp of the spleen. M cells in the gut epithelium deliver pathogens from the gut lumen to the lymphoid tissue within the gut wall.  Peter Parham The Immune System Fourth Edition Chapter 2 Innate Immunity: The Immediate Response to Infection Copyright © Garland Science 2015 2-1 Physical barriers colonized by commensal microorganisms protect against infection by pathogens: Mammalian babies have no commensal microorganisms before birth. After birth: commensals from environment (family members, pets) begin to populate the skin and mucosal surfaces. The microbiota is an integral part of a healthy human body; it influences and shapes the development of the IS. Figure 2.1Many barriers prevent pathogens from crossing epithelia and colonizing tissues. The Surface epithelia provide mechanical, chemical and microbiological barriers to infection. 2-2 Intracellular and extracellular pathogens require different types of immune response: Extracellular pathogens: Live and replicate in the spaces between human cells Accessible to soluble, secreted molecules of IS Intracellular pathogens: Live and replicate inside human cells Host cells must be killed in order to expose pathogen to the soluble IS molecules Figure 2.2 Pathogens can be present outside and inside human cells. On invading the human body, all four classes of pathogen — bacteria, viruses, fungi, and parasites — can be present in the extracellular spaces of the infected tissue (left panel). Viruses and some bacteria need to get inside human cells in order to replicate (right panel). 2-3 Complement is a system of plasma proteins that mark pathogens for destruction: Soluble proteins made by the liver, and present in the blood, lymph, and ECF Many are proteases: circulate as inactive “zymogens”, until their activation upon infection Complement proteins activate each other in cascade, by proteolytic cleavage Figure 2.3 Complement activation results in covalent attachment of C3b to a pathogen’s surface. The key event in complement activation in response to a pathogen is the proteolytic cleavage of complement fragment C3. This cleavage produces a large C3b fragment and a small C3a fragment. C3b is chemically reactive and becomes covalently attached, or fixed, to the pathogen’s surface, thereby marking the pathogen as dangerous. C3a recruits phagocytic cells to the site of infection. 2-3 Complement is a system of plasma proteins that mark pathogens for destruction 3 pathways of complement activation: Alternative: First pathway to be activated, part of innate immunity Initiated by direct interaction with pathogen Lectin: Part of innate immunity Initiated by mannose-binding lectin in plasma Classical: Initiated in the innate response by the binding of C- reactive protein to pathogen surfaces Initiated in the adaptive response by the binding of antibodies to pathogen surfaces 2-4 At the start of an infection, complement activation proceeds by the alternative pathway: Constituents of bacterial surfaces induce changes in the local physiochemical environment These changes trigger the hydrolysis of serum C3, giving C3(H2O) (also called iC3) iC3 binds to the inactive complement factor B Cleavage of the bound factor B by a protease (factor D) gives iC3Bb, a soluble C3 convertase: cleaves C3 into C3a and C3b. C3b fragments covalently attach to the pathogen surface. The alternative C3 convertase C3bBb works at the surface of the pathogen. It functions similarly to the soluble iC3Bb, but since it is pathogen-bound, it is unable to diffuse away. Once some C3bBb molecules have been assembled, they cleave more C3 and fix more C3b at the pathogen surface, leading to the assembly of even more convertase positive feedback leading to rapid coating with C3b. MOVIE 2-5 Regulatory proteins determine the extent and site of C3b deposition: Formation and stability of C3bBb on the cell surface is determined by complement control proteins: Factor P: extends lifetime on microbial surface Factor I: cleaves and inactivates C3bBb (assisted by Factor H) DAF and MCP: disrupt C3bBb on human cell surface 2-6 Phagocytosis by macrophages provides a first line of cellular defense against invading microorganisms: Macrophages are the mature forms of circulating monocytes that have left the blood to take up residence in the tissues Prevalent in connective tissues, GI and respiratory tracts, and liver (Kupffer cells) Participate in both innate and adaptive immunity Figure 2.10 Complement receptors on phagocytes trigger the uptake and breakdown of C3b-coated pathogens. CR1 on the surface of macrophages recognize C3b-coated pathogens. Upon recognition, CR1 generates intracellular signals that enhance phagocytosis, and the fusion of the phagosome with lysosomes. MOVIE  Innate Immunity: The Immediate Response to Infection 2-1 Physical barriers colonized by commensal 2-2 Intracellular and extracellular pathogens require different types of immune response 2-3 Complement is a system of plasma proteins that mark pathogens for destruction 2-4 At the start of an infection, complement activation proceeds by the alternative pathway 2-5 Regulatory proteins determine the extent and site of C3b deposition 2-6 Phagocytosis by macrophages as a first line of cellular defense against invading microorganisms  CHAPTER CONTENTS 2-7 The terminal complement proteins lyse pathogens by forming membrane pores 2-8 Small complement peptides induce local inflammation 2-9 Several classes of plasma protein limit the spread of infection 2-10 Antimicrobial peptides kill pathogens by perturbing their membranes 2-11 Pentraxins are plasma proteins of innate immunity that bind microorganisms and target them to phagocytes 2-7 The terminal complement proteins lyse pathogens by forming membrane pores:  The binding of C3b to the alternative C3 convertase produces C3b2Bb: the alternative C5 convertase. The C3b component of C3b2Bb cleaves C5 into C5a and C5b.  C5b initiates the formation of a membrane-attack complex (MAC), which can make holes in the membranes of bacterial pathogens and eukaryotic cells. Figure 2.13 The electron micrograph shows erythrocyte membranes with membrane-attack complexes seen end-on. Figure 2.14 CD59 prevents assembly of the MAC on human cells: By binding to the C5b678 complex, the human cell surface protein CD59 prevents the recruitment of C9 and its polymerization in the membrane to form a pore. Homologous Restriction Factor (HRF) works in the same way. 2-8 Small peptides released during complement activation induce local inflammation: C3a and C5a fragments induce anaphylactic shock (acute inflammatory reaction): referred to as anaphylatoxins. Have receptors on phagocytes, endothelial cells, and mast cells. Roles in inflammation: Increase blood flow Increase vascular permeability Serve as chemoattractants (C5a) 2-9 Several classes of plasma protein limit the spread of infection: Coagulation system: Plasma enzymes that form blood clots Pathogens are immobilized in clots and prevented from entering blood and lymph Kinin system: Plasma proteins that cause vasodilation (bradykinin) Increase the supply of innate immunity components to the infected site Protease inhibitors: Inhibit pathogenic cell-surface or secreted proteases eg: α2-Macroglobulins Figure 2.16 α2-Macroglobulin inhibits potentially damaging proteases. The α2-macroglobulins contain a highly reactive thioester bond (left panel) and inhibit microbial proteases. An α2-macroglobulin first traps the microbial protease with a ‘bait’ region. When the protease cleaves the bait, the α2-macroglobulin binds the protease covalently through activation of the thioester group (middle panel). It enshrouds the protease so that it cannot access other protein substrates, even though the protease is still catalytically active (right panel).  2-10 Antimicrobial peptides kill pathogens by perturbing their membranes: Figure 2.17 Defensins disrupt microbial membranes. Human β1-defensin is composed of a short segment of α-helix (yellow) resting against three strands of antiparallel β-sheet (green): it is an amphipathic peptide with separate regions having charged or hydrophobic residues.  Defensin can interact with the charged surface of a cell membrane and then insert into the lipid bilayer. This leads to the formation of pores and a loss of membrane integrity. Figure 2.18 Paneth cells are located in the crypts of the small intestine. The α-defensins HD5 and HD6 (cryptdins) are made only by Paneth cells. Paneth cells also secrete other antimicrobial factors, including lysozyme and phospholipase A2. Although they are of epithelial, not hematopoietic, origin, Paneth cells can be considered cells of the IS. Figure 2.19 Human defensins are variable antimicrobial peptides. 2-11 Pentraxins are plasma proteins of innate immunity that bind microorganisms and target them to phagocytes: Pentraxins play a role similar to the antibodies. 2 types: One of the principal members of the pentraxin family are serum C-reactive protein (CRP)