Kinds of Resistance. Defense Mechanisms. Lec 7 (17): Innate Nonspecific Immunity Host Defenses. 2 Major divisions: 3 Lines of Defense

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1 Lec 7 (17): Innate Nonspecific Immunity Host Defenses Topics - Defense Mechanisms (innate, acquired) - Systems (anatomic, immunological) - Non-specific immunity (general response) 1 Kinds of Resistance 2 Major divisions: Nonspecific Specific 3 Lines of Defense Exterior General response Specialized response 2 Defense Mechanisms Innate and nonspecific First line of defense (barriers) Second line of defense (phagocytes, inflammation, fever, antimicrobials) Acquired and specific Third line of defense (specific resistance, B&T lymphocytes, Abs 3 1

2 Major Components of Host Defenses 4 First line of defense (mechanical, chemical, normal flora) Barriers Anatomical Chemical Normal Flora Genetic 5 Anatomical barriers Skin Outermost layer Hair follicles Skin glands Mucous membrane Digestive Urinary Respiratory Eye 6 2

3 The trachea contain cilia that entrap and propel particles out of the respiratory tract. F 7 Example Skin Barrier Breach Rose Gardener s Disease Skin invasion through the skin by Sporothrix schenkii (fungus) via small cuts, such as those inflicted by thorns. 8 Chemical barriers Antimicrobial peptides: Sebaceous secretions Eyelid glands meibomian gland Tears and saliva lysozyme Acidic ph Sweat Stomach Skin Semen Vagina 9 3

4 1st Line Nonspecific Chemical Defenses Toll-like receptors (TLRs) Integral membrane proteins produced by phagocytic cells Bind pathogen-associated molecular patterns (PAMPs) Initiate defensive responses Apoptosis Secretion of inflammatory mediators Production of stimulants of adaptive immune response NOD proteins Cytosolic proteins that bind PAMPs 10 Primary anatomical and chemical defense barriers 11 Normal Flora as 1 st Line Microbial antagonism Normal flora compete against potential pathogens: Nutrients Environment Stimulate second line of defense Promote health (provide vitamins) 12 4

5 Genetic barriers Different level of sensitivity and resistance to infectious agents Malaria Tuberculosis Leprosy Fungal infections 13 2 nd Line of Defense 14 Second Line of Defense (non-specific) Phagocytosis Inflammation Interferon Complement 15 5

6 2 nd line of Defense What is it? Response to pathogen penetration (skin or mucous membranes) Cells, antimicrobial chemicals Blood Chemistry: Plasma Serum Erythrocytes (O2) Leucocytes (white cells) (5 kinds) Platelets (blood clotting) Immunology Protective cells 16 What is Immunology? Study of the development of resistance to infectious agents by the body Surveillance of the body Recognition of foreign material Destruction of foreign material or agent Involve nonspecific and specific immune defense systems White blood cells (wbc) or leukocytes are involved 17 Non-specific Phagocytosis Phagocytes (white cells) Migration of roaming cells also histiocytes - Kupffer s cells, alveolar, microglial etc. 18 6

7 WBC WBC recognize self markers on the host cell Do not attack or do not respond to host cell WBC recognize non-self markers on the invading microbe Attack or respond to microbe 19 WBC must recognize and destroy non-self cells 20 Systems - connections All systems are integrated Recticuloendothelial system (RES) Extracellular fluids system (ECF) Blood or circulatory Lymphatic 21 7

8 Reticuloendothelial (RES) Network of connective tissue fibers (Reticulum) Interconnects cells Allows immune cells to bind and move outside the blood and lymphatic system 22 Extracellular fluid (ECF) The spaces surrounding tissue cells and RES Enable immune cells to move 23 Blood Stem cells precursors Hemopoiesis Components : (Blood Chemistry) Plasma Serum Erythrocytes (O2) Leucocytes (white cells) (5 kinds) Platelets (blood clotting) 24 8

9 Stem cells From blood cells RBC platelets Hematopoietic stem cells (yolk sack and liver, then bone marrow) Neutraphils, basophils, eosinophils, monocytes Lymphoid stem cells T cells B cells 25 Hematopoiesis Family Tree! Responsible for many other cells! 26 The three types of stem cells - differentiate into: Blood platelets Granulocytes agranulocytes 27 9

10 Leucocytes (white blood cells) Leukocytes Granulocytes (large cytoplasmic granules) Neutrophils phagocytes, digestive enzyme, 1 st to arrive Basophils histamine, like eosinophils, localized ones called mast cells Eosinophils phagocytosis, eukaryotic pathogens, inflammation & allergy Agranulocytes (very small granules) T cells cell-mediated B cells Ab production Monocytes mature into macrophage 28 Leukocytes (Blood Smear) See Fig Lymphocytes Specific immunity T cells (cell-mediated) B cells (Ab-mediated) Present throughout the body: Phagocytes (white cells) Migration of roaming cells also histiocytes Kupffer s cells, alveolar, microglial etc

11 Phagocytosis Chemotaxis Adherence (opsins can increase this) Ingestion via phagocytic vesicle phagosome ph to 4.0, enzymes kick in Lysosomes fuse w/ phagosome phagolysosome 30 minutes bacteria dead 31 Phagocytosis the artist s rendition 32 How to evade phagocytosis! (run away run away!) Adherence inhibition via M protein or capsule Toxins (Staph produces leukocidins, Streps produce streptolysin) Membrane attack proteins Special adaptive factors and tolerances 33 11

12 Non-phagocytic Killing Eosinophils: Attack parasitic helminths (surface attachment) Secrete toxins (weaken or kill helminths) Eosinophilia (elevated) often = helminthic infestation Eosinophil mitochondrial DNA and proteins form structure that kills some bacteria Natural Killer Cells (lymphocytes): Secrete toxins onto surface of virally infected cells and tumors Differentiate normal body cells because they have membrane proteins similar to the NK cells 34 Non-phagocytic Killing (cont.) Neutraphils: Produce chemicals that kill nearby invaders Generate extracellular fibers [neutrophil extracellular traps (NETs)] that bind to and kill bacteria 35 Lymphatic system Network of vessels that extend to most body areas Includes nodes, spleen, thymus Connected to the blood system Provides an auxiliary route for the return of extracellular fluid to the circulatory system Drain off system for inflammatory response Contains lymphocytes, phagocytes and antibodies 36 12

13 Artist s rendition- Lymphatic System 37 Lymphatic Fluids Plasma-like fluid (lymph) Water Dissolved salts Proteins (antibodies, albumin) White blood cells No red blood cells Formed from blood components Diffuse into the lymphatic capillaries 38 Lymphatic Vessels (carry lymphatic fluid ) Parallels the blood system Returns lymph to the blood system Movement of lymph depends on muscle contractions Permeates the body except the cns, bone, placenta, and thymus

14 Human Lymph System/Nodes Exist in clusters Located along the lymphatic channels and blood vessels in the thoracic and abdominal cavity regions, armpit, groin and neck Filter for the lymph Provide environment for immune reactions 40 Spleen Located in the upper left portion of the abdominal cavity Filter for blood traps pathogens and phagocytizes pathogens Adults can survive without spleen Asplenic children are severely immunocompromised 41 Thymus Embryo two lobes in the pharyngeal region Differentiate immature T-cells into mature t-cells High activity (releases mature T cells) until puberty Adult Gradually shrinks Lymph node and spleen supply mature T cells 42 14

15 Gut-Associated Lymphoid Tissue (GALT) Recognized incoming microbes from food Supply lymphocytes for antibody response Ex. Appendix, lacteals, Peyer s patches, isolated lymphoid follicles (ILF) 43 Non-specific Immunity Inflammation Phagocytosis Interferon Complement 44 Inflammation Triggered by damage Five (4 major) symptoms 1. Redness 2. Warmth 3. Swelling 4. Pain 5. *Loss of function Acute vs. Chronic 45 15

16 Inflammation Causes: Trauma Tissue injury due to physical or chemical agents Specific immune reactions 3 Functions: Destroy agent (and remove or destroy) Limit wall or confine Repair or replace Stages: vascular edema fever Results in: Mobilization and attraction of immune components to the site of injury Aid in repair of tissue damage Localized, remove of harmful substances Destroy microbes and block their invasion 46 The major events in inflammation: injury, vascular reactions, edema, resolution 47 3 Stages of Inflammation 1. Vascular changes (vasodilation = increased permeability) 2. Edema (phagocytic migration and phagocytosis) 3. Fever (followed by tissue repair) 48 16

17 1-Vascular changes Blood cells, tissue cells, and platelets release chemical mediators and cytokines Chemical mediators (Cause fever, stimulate lymphocytes, prevent virus spread, cause allergic reactions) Vasoactive Affect endothelial cells, smooth muscles of blood vessels histamines permeability rise = edema nerve damage, toxin irritation, pressure etc.) Chemotactic (chemokines) Affect WBC 49 Cytokines 3 major types (messengers) 50 Effects of chemical mediators during inflammation 51 17

18 2 - Edema Leakage of vascular fluid (exudate) into tissue Exudate - plasma proteins, blood cells (wbc), debris, and pus Migration of wbc is called diapedesis or transmigration Chemotaxis 52 Transmigration (diapedesis) of WBCs is followed by chemotaxis Fever Caused by pyrogens Endogenous (cytokines, IL-6, tumor-necrosis factor) OR Exogenous (Microbes and their products, ex. Endotoxins, LPS, superantigens) Reset hypothalamic thermostat (increase temperature) Vasoconstriction Phagocytes release IL-1 increase t-cells Increases interferon effect (Fe++) Speed up metabolism Inhibits microbe and viral multiplication ( reduces nutrient availability, increases immune reactions ) 54 18

19 Hypothalamus in Inflammation Macrophages recognize pathogens in an area and release cytokines that trigger inflammation. The cytokines send a signal up the vagus nerve to the hypothalamus. Fig Neutrophils and eosinophils Early responders to inflammation Neutrophils are primary components of pus Eosinophils are primary responders to parasitic infections 56 Phagocytosis - Macrophages Monocytes transform into macrophages Scavengers Histiocytes reside in one location (ex. Alveolar, Kupffer, Langerhans) Drift throughout the RES Undergo phagocytosis, Interact with B and T cells 57 19

20 Histiocytes Macrophages can become histiocytes by taking up permanent residence in the lung (alveolar), liver (Kupffer) and skin (Langerhans). 58 Macrophage mechanism Chemotaxis Ingestion Phagolysosome Destruction 59 Chemotaxis & PAMPS Directed by Phagocytic cells with pattern recognition receptors (PRRs) that recognize: Pathogen-associated molecular patterns (PAMPs ex. Peptidoglycan, LPS) Foreign debris 60 20

21 Ingestion Pseudopods enclose the pathogen or foreign material Form a phagosome Fig Phagolysosome Lysosomes fuse with the phagosome Other antimicrobials chemicals are released into the phagolysosome 62 Destruction Within the phagolysosome Oxygen-dependent system Oxidative burst (oxidizing agents) Enzymes Nitric oxide Undigestible debris released 63 21

22 Phagocytosis Example (a) (b) Cutaneous leishmaniasis is a disfiguring disease caused by the intracellular flagellate Leishmania tropica, transmitted by the bite of a sand fly. LM of sample from skin lesion shows a macrophage infected with L. tropica amastigotes (arrows). The amastigotes have lost their flagella but their nuclei are visible. Soon the amastigotes will lyse the macrophage and be engulfed by other phagocytes, spreading the infection. (credit a: modification of work by Otis Historical Archives of National Museum of Health & Medicine ; credit b: modification of work by Centers for Disease Control and Prevention) Fig nd Line includes: Nonspecific Chemical Defenses Interferons Interferons Protein molecules released by host cells to nonspecifically inhibit the spread of viral infections Cause many symptoms associated with viral infections Two types Types I (alpha and beta) Type II (gamma) 65 Produced in response to: viral infections microbe infections RNA immune products antigens Interferon Synthesis: WBCs,Tissue cells Classes: 1. Alpha = prod of lymphocytes and macrophages 2. Beta = prod of fibroblasts and epithelial cells 3. Gamma = prod of T-cells Fig

23 Interferon activity Ex. Virus - binds to host cell A signal is sent to the nucleus to synthesized (transcription and translation) interferon Interferon is secreted Binds to other host cells Host cells produce antiviral proteins inhibit viral multiplication or translation Not virus-specific 67 Interferon mechanism: produced, released, and taken-up by a near-by cell, original cell is not protected but recipient cell is protected 68 Other Interferon roles Activates and instructs T and B cell development Inhibits cancer cells Activates macrophages 69 23

24 Complement What is it? Causes cell lysis Consist of 26 blood proteins Produced by liver hepatocytes, lymphocytes, and monocytes 3 major Pathways Cascade reaction What are the stages? 70 Complement pathways Classical activated by antibody bound to microbes Lectin activated by host serum protein binding a sugar (mannan) in the wall of fungi and other microbes Alternative activated when complement proteins bind to cell wall or surface components of microbes 71 The complement pathways, activators, and involved proteins 72 24

25 4 Stage of Complement Activation 1. Initiation 2. Amplification and cascade 3. Polymerization 4. Membrane attack!! 73 The Attack Complex Holes! The cell cannot survive! (why not?) 74 Onward! to Specific Immunity The 3 rd Line of Defense Graphic from: Oat Willie s Logo, Austin Texas 75 25

26 Some additional Info 76 26