L4 Innate Immunity: First Line of Defense PDF

Innate Immunity: The First Line of Defense Dr Allison Imrie Learning Outcomes You should understand and be able to describe: The role of innate immune responses in relation to the overall immune response The cells and tissues involved in innate immune responses The major features of innate immunity...

Innate Immunity: The First Line of Defense Dr Allison Imrie Learning Outcomes You should understand and be able to describe: The role of innate immune responses in relation to the overall immune response The cells and tissues involved in innate immune responses The major features of innate immunity as compared to adaptive immunity The features of immediate innate immunity Antigen recognition and the events which occur following ligation of microbial elements The Complement System in innate immune responses Phases of immune response Innate phase: immediate immune responses mediated by preformed, non-specific effectors Early induced innate responses: responses initiated by recognition of pathogens/microbes, leads to inflammatory response Adaptive immune response: mediated by B and T cells specific for the pathogen/microbe, occurs late because cells must first undergo clonal expansion in lymphoid tissues then migrate to sites of infection Defense against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity The innate immune system consists of many cell types and soluble molecules in tissues and the blood that constantly prevent microbes from invading and establishing infections Innate immunity serves three essential functions that protect us against microbes and tissue injury: Innate immunity is the initial response to microbes that prevents, controls, or eliminates infection of the host by many pathogens Innate immune mechanisms eliminate damaged cells and initiate the process of tissue repair Innate immunity stimulates adaptive immune responses and can influence the nature of the adaptive responses to make them optimally effective against different types of microbes The major types of innate immune responses that protect against microbes are inflammation and antiviral defences Features of Innate and Adaptive Immunity Innate immune responses to a microbe are immediate and do not require prior exposure to the microbe. In contrast, effective adaptive immune responses to a newly introduced microbe develop over several days as clones of lymphocytes undergo expansion and differentiate into functional effector cells There is no appreciable change in the quality or magnitude of the innate immune response to a microbe upon repeated exposure. In contrast, repeated exposure to a microbe enhances the rapidity, magnitude, and effectiveness of adaptive immune responses The innate immune response is activated by recognition of a relatively limited set of molecular structures (~1000) that are either products of microbes or are expressed by injured or dead host cells. By contrast, the adaptive immune system potentially can recognize millions of different molecular structures of microbes, and can also recognize nonmicrobial environmental antigens as well as self antigens that are normally present in healthy tissues Many barriers prevent pathogens from crossing epithelia and colonizing tissues Epithelial Barriers Intact epithelial surfaces form physical barriers between microbes in the external environment and host tissue, and epithelial cells produce antimicrobial chemicals that further impede the entry of microbes Defensins Defensins are produced by cells including epithelial cells of mucosal surfaces and by granule-containing leukocytes, including neutrophils, natural killer cells, and cytotoxic T lymphocytes Epithelial cells as well as some leukocytes produce peptides that have antimicrobial properties The protective actions of the defensins include both direct toxicity to microbes, including bacteria, fungi, and enveloped viruses, and the activation of cells involved in the inflammatory response to microbes Defensins kill microbes by a variety of mechanisms, many of which depend on their ability to insert into and disrupt functions of microbial membranes Defensins are amphipathic peptides that disrupt the cell membranes of microbes Human β-defensin is composed of a short segment of ⍺-helix (yellow) resting against three strands of anti-parallel β-sheet (green): an amphipathic peptide with a positively charged region separated from a hydrophobic region Defensins insert the hydrophobic region into the membrane bilayer; the formation of a pore makes the membrane leaky Made by epithelial cells mostly in respiratory and urogenital tracts, skin and tongue Packaged into lamellar bodies Microbial membranes have negatively charged phospholipid headgroups and hydrophobic fatty acid chains Antimicrobial effects of innate immune responses: Lysozyme Lysozyme digests the cell walls of Grampositive and Gram-negative bacteria Peptidoglycan forms the outer layer of Gram positive bacteria In Gram negative bacteria a thin layer of peptidoglycan is covered by an outer lipid membrane that contains proteins and lipopolysaccharide (LPS) Peptodoglycan is a polymer of Nacetylglucosamine (GlcNAc) and Nacetylmuramic acid (MurNAc) Lysozyme cleaves linkages between GlcNAc and MurNAc creating a defect in the peptidoglycan layer and exposing the underlying cell membrane to other antimicrobial agents Epithelia form specialized physical and chemical barriers that provide innate immune defenses in different locations: Epidermis of skin Multiple layers of keratinocytes arising from basal layer of stem cells Keratinocytes in the stratum spinosum produce β-defensins and cathelicidins which are incorporated into lamellar bodies – and secreted into the intercellular space to form a waterproof lipid layer containing antimicrobial activity Epithelia form specialized physical and chemical barriers that provide innate immune defenses in different locations: Bronchial ciliated epithelium In the lung the airways are lined by ciliated epithelium. Beating of the cilia moves a continuous stream of mucous secreted by goblet cells outward, trapping and ejecting potential pathogens Type II pneumocytes in the lungs (not shown here) also produce and secrete antimicrobial defensins Epithelia form specialized physical and chemical barriers that provide innate immune defenses in different locations: Gut epithelium In the intestine, Paneth cells (specialized cells deep in the epithelial crypts) produce several kinds of antimicrobial proteins: ⍺-defensins and the antimicrobial lectin RegIII Commensal microorganisms at different mucosal surfaces of the body live in symbiosis with the host Composition of the commensal microbiota at different mucosal surfaces in healthy humans Large intestine is colonized by at least 1000 species of bacteria that live in symbiosis with host At least 1012 microorganisms/ml of colon contents – the most numerous cells in the body In most circumstances do no harm Other mucosal populations have similar populations of resident commensal organisms Immune responses to food and microbiota antigens are tolerized Disruptions to this tolerance are the basis of some relatively common diseases – eg. Coeliac disease (response to wheat gluten) and Crohn’s disease (response to commensal bacteria) The receptors of the innate immune system are encoded by inherited genes that are identical in all cells The pattern recognition receptors of the innate immune system are nonclonally distributed; that is, identical receptors are expressed on all the cells of a particular type, such as macrophages. Therefore, many cells of innate immunity may recognize and respond to the same microbe. In contrast, antigen receptors of the adaptive immune system are encoded by genes formed by rearrangement of gene segments during lymphocyte development, resulting in many clones of B and T lymphocytes, each expressing a unique receptor. It is estimated that there are about 100 types of innate immune receptors that are capable of recognizing about 1000 pathogen associated molecular patters (PAMPs) and damage associated molecular patters (DAMPs). In striking contrast, there are only two kinds of specific receptors in the adaptive immune system (immunoglobulin [Ig] and T cell receptors [TCRs]), but because of their diversity they are able to recognize millions of different antigens. An infection and the response to it can be divided into a series of stages Infectious agent is delivered to lymph node inside dendritic cell to activate adaptive immune response