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Innate immune response Notes
Innate immune response Notes
Innate immune response Notes
Innate immune response Notes
Innate immune response Notes
Innate immune response Notes
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Innate immune response Notes


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  • 1. PHCL 582 Innate Immune System Jan 18, 2006 INNATE (NON-SPECIFIC) IMMUNITY Mechanisms of protection against infection and disease are diverse. Primarily they can be divided into two major categories: Non-specific or innate immunity. This consists of the pre-existing defenses of an animal such as barrier layers (skin etc) and secretions Specific or adaptive immunity. This is a response to a specific immune stimulus (antigen) that involves cells of the immune system and frequently leads to a state of immune memory. In adaptive immunity, which occurs after a lag period during which immune B and T cells become activated, invading organisms are destroyed. The differences between the two types of immunity are shown in Table 1. Table 1 INNATE ADAPTIVE Non-specific Immunity Specific Immunity Response is antigen- Response is antigen- independent dependent There is immediate There is a lag time maximal response between exposure and maximal response Not antigen-specific Antigen-specific Exposure results in no Exposure results in immunologic memory immunologic memory NON-SPECIFIC IMMUNITY The elements of the non-specific (innate) immune system (Table 2) include: Anatomical barriers Secretory molecules Cellular components Anatomical barriers Skin Intestinal movement Oscillation of broncho-pulmonary cilia Secretory molecules These include organic acids in skin secretions, thiocyanate in saliva, low molecular weight fatty acids in the lower bowel; bile acids and low molecular weight fatty acids in lower GI tract; transferrin, lactoferrin, lysozyme, interferons, fibronectin, complement, acute phase proteins, etc. in serum; Interferons and tumor necrosis factor (TNF) at the site of inflammation. Transferrin and lactoferrin deprive organisms of iron. Interferon inhibits viral replication and activates other cells which kill pathogens Lysozyme, in serum and tears, breaks down the bacterial cell wall (peptidoglycan) Fibronectin coats (opsonizes) bacteria and promotes their rapid phagocytosis. Complement components and their products cause destruction of microorganism directly or with the help of phagocytic cells. Acute phase proteins (such as CRP) interact with the complement system proteins to combat infections (pp 326 – 342 Abbas) TNF-alpha suppresses viral replication and activates phagocytes. 1
  • 2. PHCL 582 Innate Immune System Jan 18, 2006 Table 2. Physico-chemical barriers to infections System/Organ Active Effector Mechanism component Skin Squamous Desquamation; flushing, organic cells; Sweat acids GI tract Columnar Peristalsis, low pH, bile acid, cells flushing, thiocyanate Lung Tracheal cilia Mucocialiary elevator, surfactant Nasopharynx Mucus, Flushing, lysozyme and eye saliva, tears Circulation and Phagocytic Phagocytosis and intracellular killing lymphoid cells Direct and antibody dependent organs NK cells and cytolysis K-cell IL2-activated cytolysis LAK Serum Lactoferrin Iron binding and Transferrin Interferons Antiviral proteins TNF-alpha antiviral, phagocyte activation Lysozyme Peptidoglycan hydrolysis Fibronectin Opsonization and phagocytosis Complement Opsonization, enhanced phagocytosis, inflammation Cellular Components Phagocytic cells Neutrophils (PMN) and macrophages and monocytes are the most important cellular components of the non-specific immune system. Neutrophils (polymorphonuclear: PMN) are most important cellular components in bacterial destruction. They are relatively large and most abundant white blood cells with lobed nucleus and cytoplasmic granules (lysosomes). They are identified by their characteristic morphology although monoclonal antibodies against cell surface cluster differentiation (CD) markers are becoming available to identify these cells. PMN granules are of two kinds: primary (azurophilic) and secondary (specific). Primary azurophilic granules are characteristic of immature and very young neutrophils. They contain cationic proteins, defensins (small molecular weight proteins), 2
  • 3. PHCL 582 Innate Immune System Jan 18, 2006 proteases (elastase, cathepsin G, etc.), lysozyme and, characteristic for them, myeloperoxidase. Secondary granules are more characteristic of (specific for) mature granulocytes. They contain lysozyme and NADPH oxidase cofactors, lactoferrin and B-12 binding protein, the last two are characteristic of secondary granules. Mononuclear phagocytes are the other population of phagocytic cells and include monocytes in circulation, histiocytes in tissues, microglilal cells in the brain, Kupffer cells in the liver and macrophages in serous cavities and lymphoid organs. They also have granules similar to those in neutrophils, although not as abundant. They are recognized by their morphology, ability to adhere on glass/plastic surface, phagocytic property and CD14 (mac-2) marker. All phagocytic cells have receptors for a variety of molecules (Above figure ). Most pertinent to non-specific immunity are receptors for IgG Fc, complement, interferon, TNF and certain bacterial components. Receptor interactions with these ligands promote phagocytosis and activation for efficient killing of pathogens. PHAGOCYTE RESPONSE TO INFECTION Chemotaxis Bacteria produce N-formyl-methionine-containing peptides which are powerful attractants (chemotactic) for phagocytic cells. Many bacteria also act on proteins of the complement and clotting systems to produce peptides. These peptides cause vasodialation and vascular permeability, expression of adherence molecules on vascular endothelial cells. They induce expression of proteins on phagocytic cells which promote binding to endothelial cells. Phagocytic cells respond to chemotactic peptides of bacterial and host origin and migrate across the capillary wall (diapedesis) to the site of infection/inflammation (Figure below). 3
  • 4. PHCL 582 Innate Immune System Jan 18, 2006 Attachment Once at the site of infection, phagocytes can attach to bacteria via receptors for bacterial polysaccharides (scavenger receptor) or host proteins that act as opsonins (proteins which aid phagocytosis: fibronectin, complement and IgG antibody). This attachment triggers the activation of respiratory burst (hexose monophosphate shunt), internalization of the organisms (phagosome formation), phagosome lysosome fusion etc (Figure below). Table 3 Reaction Enzyme H2O2 + Cl- --> OCl- + H2O Myeloperoxidase OCl- + H2O --> 1O2 +Cl- + H2O 2O2 + 2H+ --> O2- + H2O2 Superoxide dismutatse H2O2 --> H2O + O2 Catalase Fusion of phagosome with primary granules exposes its content to myeloperoxidase which catalyzes production of toxic oxidants, halogenation of bacterial proteins and microbial death (Table 3). 4
  • 5. PHCL 582 Innate Immune System Jan 18, 2006 Three modes of intracellular killing It should be apparent from the preceding discussion that there are three pathways of intracellular killing (Tables 3 and 4): (1) by lysosomal antibacterial substances (lactoferrin, cationic proteins, lysozyme, defensins, proteases, etc.) without the requirement of respiratory burst (oxygen-independent killing: Table 4) Table 4. Oxygen-independent mechanisms of intracellular killing Effector Molecule Function Cationic proteins (including cathepsin) Damage to microbial membranes Lysozyme Splits mucopeptide in bacterial cell wall Lactoferrin Deprives proliferating bacteria of iron Proteolytic and hydrolytic enzymes Digestion of killed organisms 2) by products of the respiratory burst (super-oxide, singlet oxygen, hydroxyl radical, hydrogen peroxide, etc.) without the need for myeloperoxidase (oxygen-dependent, myeloperoxidase-independent killing) (3) by hydrogen peroxide metabolites halogenation of bacterial proteins catalyzed by myeloperoxidase (oxygen-dependent, myeloperoxidase-dependent killing: Figure 5B). A defect in any of these pathways, for example, due to absence of NADPH oxidase (cytochrome b558: p91-, p22, 947- & p61-phox), myeloperoxidase, etc. may predispose the individual to increased susceptibility to pyogenic infections. Neutrophils also contain catalase and glutathione (GS) which detoxify excess H2O2. GS, in its reduced form (GSH), also recycles NADP to NADPH. Interaction of phagocytic cells with certain humoral factors (e.g. interferons, TNF, C5a, IL-2, etc.) can increase their phagocytic function, respiratory burst and intra-cellular killing. Some cytokines can also induce phagocytic cells, particularly macrophages, to produce nitric oxide (NO), which is toxic to microorganisms and malignant cells. 5
  • 6. PHCL 582 Innate Immune System Jan 18, 2006 OTHER CELLS A number of other cells are also involved in non-specific resistance: they include natural killer (NK), killer (K) and lymphokine activated killer (LAK) cells and eosinophils. NK cells are important in defense against viral infections and malignancies. They resemble lymphocytes in morphology but are larger and granular, hence also known as large granular lymphocytes (LGL). The granules contain cytolytic proteins such as perforin. NK cells recognize the difference between normal and malignant or virus-infected cells in a nonspecific manner via sugar-lectin interaction and kill them following intimate contact. They also have low affinity Fc (gammaIII) receptor (CD16) by which they can interact with antibody coated cells and cause their death. NK cells also have receptors for interleukin-2 (IL-2) and interferon-gamma and interaction with these cytokines leads to their activation. The presence of CD56 and CD16 and the absence of CD3 is currently used as characteristic markers for NK cells. Interaction with IL-2 (or interferon-gamma) causes activation of NK cells. These activated cells are referred to as LAK (lymphokine-activated killer) cells. LAK cells function the same way as NK cells except that they are more active and also can kill transformed (even nonmalignant) cells. K-cells are morphologically undefined cells which attach to target cells coated with IgG antibody via the Fc receptor and cause their lysis; thus, they require interaction of specific antibody with target. Macrophages can also function as K cells since they also have Fc receptors, and, when activated, they can kill malignant cells without the aid of antibody. Eosinophils have Fc receptor for IgE and cause cytotoxicity to large multicellular parasites coated with specific IgE antibody, analogous to K cells. Table 5. Characteristics of cells involved in non-specific resistance Identifying marker(s) and/or function Effector cell CD3 Ig Fc CD Phagocytosis Neutrophil - - IgG CD67 + Macrophage - - IgG CD14 + NK cell - - IgG CD56 & 16 - K-cells - - IgG ? - LAK cell - - ? ? ? Eosinophil - - IgE CD67 - 6