The Immune System - Chapter 2 PDF

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 pathog...

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)