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Nonspecific Defenses of the Host Innate Immunity Nonspecific Host Defense Resistance: ability to ward off disease through our defenses Susceptibility: vulnerability, lack of resistance to disease Innate Immunity: non-specific defense, protect us from pathogens in general; natural, born with defense Adaptive immunity: protects from specific MO, develops after exposure to specific MO Innate vs. Adaptive Immunity Innate and Adaptive immune systems do not operate independently of each other Very inner-connected in activities First Line of Defense Intact skin and mucous membrane Mechanical factors provides formidable physical barrier to MOs Chemical factors Intact Skin: Mechanical Factors - Keratin Continuous sheet of closely packed epithelial cells Consists of connective tissue, inner dermis and outer epidermis Top layer has waterproofing protein called keratin When epithelial surface broken subcutaneous infection may develop, frequently by Staphylococcus aureus Mucous Membranes – Mucous Outer epithelial and inner connective tissue layers; line digestive, respiratory, urinary, and reproductive tracts Goblet cells in epithelial layers secrete mucous to prevent drying out, act to trap MOs Some pathogens (T. pallidum, M. tuberculosis, S. pneumoniae), survive in these moist secretions; if present in sufficient numbers able to penetrate membrane Mucous Membranes - Cilia Cells of RT mucous membranes contain cilia Move synchronously to propel inhaled dust and MOs trapped in mucous, upward toward the throat away from LRT Eye Lacrimal Apparatus Washing Manufacture and drain away tear secretion By continual washing action, helps keep MOs from settling on surface of eye If something irritates eye, the lacrimal glands secrete heavily to wash away irritating substance Cleansing Mechanisms Similar cleansing action of saliva washes MOs from teeth, mucous membranes in mouth Nose has mucous coated hairs that filter air; trap MOs, dust, pollutants Epiglottis covers larynx during swallowing, prevent MOs from entering LRT Flow of urine through urethra provides mechanical cleansing of urinary tract Intact Skin: Chemical Factors Sebum - produced by oil glands provides protective film over skin; unsaturated fatty acids inhibit growth of bacteria and fungi due to low pH of skin Perspiration - produced by sweat glands contributes to high salt content of skin, make it osmotically unfavorable for MOs Lysozyme – in perspiration, tears, saliva, nasal secretions and tissue. What is the activity of lysozyme? Chemical Factors Gastric juice - produced by stomach, very acidic and destroy most bacteria and bacterial toxins; food particles may protect enteric pathogens from acid Defensins - cysteine rich antimicrobial peptides produced by skin Cryptocidins – antimicrobial peptides produced by epithelium of intestine Normal flora - protect colonization by potentially pathogenic bacteria. How? Second Line of Defense: Phagocytosis Process of engulfing and ingesting foreign particles by WBCs Blood – plasma, formed elements: RBCs - erythrocytes Platlets - thrombocytes WBCs - leukocytes WBCs Divided into two basic types: Granulocytes Agranulocytes Both may be phagocytic Complete Blood Cell (CBC) Count Determine – RBC, WBC, Differential Count Leukocytosis increase leukocytes, often in bacteria infection Leukopenia - some diseases cause decrease leukocytes Differential WBC Count -percentage of each type by counting 100 WBCs WBC Function Neutrophils (PMNs) - highly phagocytic, leave blood, enter infected tissue, destroy foreign substances Basophils - release histamine and heparin, inflammatory response, hypersensitivity reaction Eosinophils – somewhat phagocytic, ingest antigenantibody complexes, increased during parasitic infection, hypersensitivity reaction Lymphocytes - mainly in lymphoid tissue, some in circulating blood, important in antibody production (B cell) and modulating immune response (T cell) Monocytes - poorly phagocytic until stimulated by infection; then move into tissue and differentiate into macrophages (highly phagocytic) WBC Function During infection both neutrophils (PMNs) and monocytes (become macrophages) migrate to infected area Neutrophils - first cell arrive at infected site and predominant cell found during initial stage of infection In latter stages of infection monocytes predominate Phagocytosis Migration to infection site; chemotaxis (1) Attachment of MO to phagocyte (1) Ingestion of MO (2) Killing of MO (3-7) Phagocytosis: Chemotaxis The process of adherence facilitated by chemotaxis Attraction of phagocytes to MOs via chemical factors (cytokines) released by certain WBCs, damaged tissues, microbial products or peptides derived from the complement cascade Cell Cytokine Activated macrophages serve many other functions against infections including leukocyte recruitment and tissue remodeling These functions mediated by cytokines Cytokines - chemicals produced by innate immunity, mainly by PMNs, macrophages and NK cells Endothelial cells and epithelial cells may also produce cytokines Cytokines serve to communicate (via signal transduction) information among inflammatory cells, responsive tissue cells Phagocytosis: Attachment Adherence of MO via receptor on phagocyte Cell receptor called Pattern Recognition Receptor Recognizes MO structure - PAMP (Pathogen Associated Molecular Pattern not present on host Toll Receptor and Signal Transduction Pathways Pattern recognition receptor also called tolllike receptor originally ID in Drosophila innate immune response Binding of PAMP to tolllike receptor triggers a signaling cascade (signal transduction) in which transcription factors translocated into nucleus leads to gene expression involved innate response Activates phagocytic cell LPS Activation of Innate Immunity Example of LPS (PAMP) which binds to toll-like receptor to trigger a subsequent signal transduction pathway Leads to expression of genes involved in innate immune response Attachment of Encapsulated MOs MO capsule protects against phagocytosis MO adherence difficult, occur by two mechanisms: 1. Non-immune or surface phagocytosis – phagocyte traps MO against a rough surface, cannot slide away 2. Opsonization – MO coated by opsonin (antibody or complement) Phagocytic cell receptor for opsonin act as bridge to promote attachment of MO to phagocyte Phagocytosis: Ingestion MO engulfed by pseudopods Phagocytic membrane fold inward enclosing MO in phagosome (vacuole) Phagosome pinch off, enter cytoplasm to fuse with lysosome Digestive enzymes present in lysosome kill the MO But not all MO killed by lysosomal enzymes Phagocytosis: Killing Killing MO via digestive enzymes in lysosomes Other killing mechanisms - intracellular and extracellular: In plasma membrane is oxidase enzyme activated to produce reactive oxygen intermediates (ROIs) such as superoxide radical; process called respiratory or oxidative burst Nitric oxidase synthase in cytosol activated to produce nitric oxide (NO); diffuses into phagolysosome, activated by acid pH, interact with ROIs to generate a highly toxic peroxynitrite radical All these also released from activated phagocytes to kill extracellular bacteria Microbicidal Mechanisms of Phagocytes Second Line of Defense: Inflammation Damage to body tissue trigger inflammatory response Four symptoms of inflammation: redness, pain, heat, and swelling Also sometimes loss of function Inflammation has three functions: Destroy injurious agent, remove it from body If destruction not possible, wall off injurious agent Repair or replace damaged tissue Inflammation: Three Stage Process Tissue Damage causes release of histamine, prostoglandin, kinin; vasodilation, permeability of blood vessels WBC Migration of phagocyes to injury site, phagocytosis of MO Tissue Repair last stage of inflammatory process Inflammation: Tissue Damage Vasodilation - increase diameter blood vessels, increase blood flow to injured area; redness and heat Vascular permeability - permits defensive substances present in blood enter injured area; edema, swelling; pain from swelling, nerve damage, toxins Clotting elements - delivered to injured area, clots prevent spreading of MOs; result in localized collection of pus formed by breakdown of body tissue (forms abscess) Inflammation: WBC Migration Blood flow decreases, phagocytic cells stick to blood vessels (margination), cells squeeze through walls of vessels to damaged area (diapedesis) PMN’s arrive first, attracted by chemotactic factors released from damaged tissue Leokocytosis promoting factor released from inflamed tissue, production of additional PMNs from bone marrow Monocytes enter inflamed area; differentiate to macrophages, larger, more phagocytic than PMNs PMNs & macrophages engulf large number MOs and tissue, die; collection of dead cells & various tissue fluids = pus Pus formation continue until infection subsides Inflammation: Tissue Repair Process by which tissues replace dead or damaged cells Second Line of Defense: Fever Systemic response to infection Body temperature controlled by hypothalamus Antigens such as LPS cause phagocytic cells to release leukocyte pyrogen (IL-1), hypothalamus release prostoglandins that reset body thermostat at higher temperature Blood vessel constriction, increased metabolism and shivering all help to increase temperature; shivering sign body temperature rising As infection subsides, heat losing mechanisms such as vasodilation and sweating occur Fever beneficial to inhibit bacterial growth, intensify interferon, help body tissue to repair But if body temperature too high (>450 C) may damage or be lethal Second Line of Defense: Interferon IFN produced, released from virus infected cell IFN binds to receptor on neighboring cell Via signal transduction pathway, induce antiviral proteins; block virus replication, protect cell IFN host specific but not viral specific Second Line of Defense: Complement Group of proteins found in normal blood serum Important in both non-specific and specific antigen-antibody defense Function to attack and destroy invading MOs, stimulate inflammatory response Proteins act in sequence or cascade reactions In sequence of steps, proteins activate one another by cleaving next protein in series Cleaved proteins have new enzymatic or physiological function Complement: Three Pathways Three different, interconnected pathways of Complement activation 1. Classical 2. Lecitin 3. Alternative (Properdin) Complement: Classical Pathway Via antigen-antibody complex Activates Complement component C1 to activated C1 complex Activates C4, C2 to form another activated complex This complex next activates C3, cleaved into C3a and C3b Complement: Lectin Pathway The Lectin pathway initiated by binding of serum protein, mannose-binding lectin (MBL) produced during inflammation MBL binds to mannose residues on glycoproteins or carbohydrates on surface of MOs Functions like an activated C1-like complex Complement: Alternate (Properidin) Pathway Activated by bacteria cell wall polysaccharides interaction with properdin factors to activate C3 by cleavage into C3a and C3b C3b produced by all three pathways involves components C5 through C9 in a membrane attack complex that punches a hole in MO leading to cytolysis (process called complement fixation) C3a and cleavage products from C5, C6, and C7 contribute to development of acute inflammatory response Results of Complement Fixation Complement Stimulation of Inflammation Second Line of Defense: Natural Killer (NK) Cell Lymphocytes activated by: 1. Antibody coated cells 2. Cells infected by viruses, intracellular bacteria 3. Cells lacking class I MHC NK cells express inhibitory receptors that recognize class I MHC molecules (self) NK cells activated by target cells lacking class I molecules (non-self) Some viruses down regulate expression of class I molecules Activated NK cells lyse target cells by releasing granules that induce apoptosis of target cell NK Activity With Normal Cell NK Activity With Cell Lacking MHC Class I Components of Innate Immunity Innate Stimulates Adaptive Immunity Class Assignment Textbook Reading: Chapter 2 Host- Pathogen Interaction B. Pathogenesis of Infection Host Resistance Factors Key Terms Learning Assessment Questions Review, Review, Review! MICR 301 Midterm Exam Tuesday, Oct. 25, 2011; 8:30-9:40am Specimen Collection & Processing through Host Defense Lecture, Reading, Key Terms, Learning Assessment Questions Case Study: Viral 1 (WNV), Viral 2 (HBV), Bacterial 1 (M. tb) Exam Format: Objective Questions (M.C., T/F, ID) and Short Essay