INNATE IMMUNITY WHAT YOU NEED TO KNOW. Players in the immune response OVERVIEW OF THE IMMUNE SYSTEM 2011 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE

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1 2011 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE INNATE IMMUNITY Our Non-Specific Defenses References: 1. Immunology by Kuby 2. Microbiology by Tortora 3. Essentials of Immunology by Roitt Marilen M. Parungao-Balolong The 2011 Nobel Prize in Physiology or Medicine was awarded to Bruce Beutler at the Scripps Research Institute in California, Jules Hoffmann at the French National Center for Scientific Research and Ralph Steinman at The Rockefeller University in New York City. Beutler and Hoffman helped to elucidate innate immunity, the non-specific array of initial responses by the body s immune system that can recognize invading microorganisms as being foreign and try to destroy them. DR.T.V.RAO MD 2 THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE 2011 The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" and the other half to Ralph M. Steinman "for his discovery of the dendritic cell and its role in adaptive immunity". OVERVIEW OF THE IMMUNE SYSTEM We are constantly being exposed to infectious agents and yet, in most cases, we are able to resist these infections. It is our immune system that enables us to resist infections. The immune system is composed of two major subdivisions, the innate or non-specific immune system and the adaptive or specific immune system DR.T.V.RAO MD 3 DR.T.V.RAO MD 5 WHAT YOU NEED TO KNOW Players in the immune response Differentiate innate from adaptive immunity Define important terms related to innate immunity Be familiar with the 4 types of defense/ barriers in innate immunity First line of defense Intact skin Mucous membranes and their secretions Normal microbiota Second line of defense Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages Inflammation Fever Antimicrobial substances Third line of defense Specialized lymphocytes: T cells and B cells Antibodies Be familiar with cells of the innate immunity and their important roles

2 Recall: the Lymphatic System 4 Types of Defensive Barriers in Innate Immunity Anatomic/Physical Phagocytic Q: Why do you think your lymph nodes swell when there is infection? Physiologic Inflammatory Anatomic: Skin Serves as a Physical Barrier Epidermis consists of tightly packed cells with KERATIN, a protective protein Normal Microbiota: Microbial antagonism/ competitive exclusion: Normal microbiota compete with pathogens Anatomic: Mucous Membranes Ciliary escalator: Microbes trapped in mucus are transported away from the lungs Lacrimal apparatus: Washes eye Saliva: Washes microbes off Urine: Flows out Vaginal secretions: Flow out SUMMARY: Skin & Mucous Membranes physiologic: low ph & Chemicals Fungistatic fatty acid in sebum Low ph ( ) of gastric juice Low ph (3-5) of skin Lysozyme in perspiration, tears, saliva, and tissue fluids Transferrins in blood find iron (Bind Serum iron) NO inhibits ATP production

3 Physiologic: Temperature (FEVER) Increased in Body Temperature Hypothalamus normally set at 37 C Hypothalamus releases prostaglandins that reset the hypothalamus to a high temperature Physiologic: Temperature (FEVER) Advantages Increase transferrins Disadvantages Tachycardia Gram-negative endotoxin cause phagocytes to release interleukin 1 (IL 1) Body increases rate of metabolism and shivering which raise temperature When IL 1 is eliminated, body temperature falls (crisis) Increase IL 1 activity Acidosis Dehydration CELLS OF INNATE IMMUNITY Neutrophils Eosinophil's Basophils/Mast Cells Monocytes Macrophages Natural Killer Cells Platelets Nice to KNow: Sickle Cell Gene & Malaria Resistance DR.T.V.RAO MD 19 Differential White Cell Count 1. Neutrophils: Phagocytic 2. Basophils: Produce histamine 3. Eosinophils: Toxic to parasites and some phagocytosis 4. Dendritic cells: Initiate adaptive immune response 5. Monocytes: Phagocytic as mature macrophages a. Fixed macrophages in lungs, liver, and bronchi b. Wandering macrophages roam tissues 6. Lymphocytes: Involved in specific immunity To Be Discussed Fully in the next Lecture : Adaptive Immunity

4 Phagocytosis Greek: Phagos (eat), cyte (cell) Ingestion of a substance/ microbe by a cell Phagocytes Cells that perform phagocytosis Leukocytes and/or derivatives Macrophage Bacterium Pseudopods SEM of a neutrophil phagocytosing Aspergillus spores Phagocytes Neutrophils: early during infection First phagocytes at site of infection Monocytes Morph into Macrophages when infection progresses Fixed v/s Wandering Macrophages Non-motile; Specifically present in tissues/ organs Lymph nodes, bone marrow, spleen, liver Roaming through tissue, gather at site of inflammation Blood - Called monocytes (1-6% WBC) Tissues - Called macrophages mature form of monocytes normally found in tissues such as gastrointestinal tract, lung, liver and spleen Functions: Phagocytose and kills after bactericidal mechanisms are activated (T cells) Produce cytokines/chemokines (initiates inflammation) Is an antigen presenting cell (co-stim. Molecules) MACROPHAGES (MQ) DR.T.V.RAO MD 27 Present in blood (55-60% of WBC) Not normally present in tissues Short lifespan - 12 hours Functions: First at the site of infection/injury Ingest and kill microbes after bactericidal mechanisms are activated (binding to pathogen) NEUTROPHILS (PMN) DR.T.V.RAO MD 28 Granulocytic Leukocyte Most Abundant White Blood Cell Very Short Lifetime 2-6 x 10 3 cells/μl % of leukocytes t 1/2 = 6 hours 55 % of Bone Marrow Weight Devoted to Neutrophil Production HUMAN NEUTROPHIL DR.T.V.RAO MD 29

5 Phagocytosis: Mechanism Mechanism of Phagocytosis Chemotaxis: attracted to site of infection Cytokines (released from other WBCs) Cell damage Microbial products Adherence: attachment to microbial surface Toll-like receptors (TLRs) Pathogen associated Molecular Patterns (PAMPs) Opsonins: proteins that coat microbe Ingestion: pseudopodia engulf microbe into phagosome Digestion: fusion of phagosome with lysosome Enzymes digest microbe Residual body excreted Who Can Evade This Process... Antimicrobial Substances Complement system = defensive system of >30 proteins produced in the liver that circulate the blood & tissues Complements the action of immune cells Destroy microbes by: 1. Cytolysis 2. Inflammation 3. Phagocytosis Act in a cascade with one reaction triggering another Activated by one of 3 possible pathways The Complement Cascade Complement-induced cytolysis 1. C3 splits into C3a and C3b 2. C3b coats the microbe to promote phagocyte attachment (opsonization) 3. C3b initiates formation of membrane attack complex (MAC) on invading cell 4. MAC causes cytolysis = bursting of invading cell due to inflow of extracellular fluid 5. C3a and C5a bind mast cells stimulate release of histamine increase blood vessel permeability C5a also attracts phagocytes before cytolysis after cytolysis

6 Complement activation: classical pathway 1. Antibodies bind antigens antigen-antibody complexes activate C1 2. Active C1 splits (activates) C2 and C4 into C2a, C2b, C4a, C4b 3. C2a and C4b combine and split C3 into fragments C3a and C3b Active fragments initiate the complement cascade Complement activation: alternative pathway No antibodies involved Direct contact between complement proteins and pathogen Steps: 1. C3 combines with factor B, D and P (complement proteins) on the surface of a microbe 2. C3 splits into C3a and C3b complement cascade Complement activation: The lectin pathway Lectins = proteins produced by the liver that bind carbohydrates Mannose binding lectin (MBL) = binds mannose (in bacterial cell walls and some viruses) Steps: 1. MBL binds an invader 2. Activates C2 and C4 3. C2a and C4b combine and activate C3 complement cascade Some Bacteria Can Evade This Process... How? Capsules Prevent C Activation Surface lipid-carbohydrates prevent MAC formation Enzymatic digestion of C5a Interferons Interferons = class of cytokines produced by certain animal cells after viral stimulation Interfere with viral multiplication Three types in humans: Alpha and Beta interferon = produced by infected host to induce antiviral protein synthesis in neighboring cells Oligoadenylate synthetase = degrades viral mrna Protein kinase = inhibits viral protein synthesis Gamma interferon = produced by lymphocytes; induces neutrophils and macrophages to kill invaders; suppresses tumor cell proliferation Interferons Interferon complications: Stable for only short time periods Side effects of injection: - Nausea, fatigue, vomiting, fever Toxic in high concentrations - heart, kidneys, liver, red bone marrow Medical usage: Limited or no effect on tumors in clinical trials Alpha interferon some virus-associated disorders Kaposi s sarcoma Chronic Hepatitis B and C

7 Interferons Iron-binding proteins Humans use iron in many ways: component of cytochromes in the ETC cofactor of many enzymes component of hemoglobin Iron-binding proteins = transport and store iron Transferrin = blood and tissue fluids Lactoferrin = milk, saliva, mucus Ferritin = liver, spleen, red blood marrow Hemoglobin = red blood cells deprives pathogens of available iron! Iron-binding proteins Siderophores = proteins released into the medium by bacteria to capture iron from transport proteins Forms iron-siderophore complex, recognized by bacterial receptors and taken into cell Splits iron from siderophore and utilizes it Other mechanisms of obtaining iron: Release toxins when iron is low Kills host cells, releasing their iron Ex) Strep pyogenes Hemolysins lysis of red blood cells Hemoglobin broken down to capture iron Antimicrobial Peptides Antimicrobial peptides (AMPs) = short chains of amino acids synthesized on ribosomes Synthesized by neutrophils when TLRs contact PAMPs - Broad spectrum killing of bacteria, viruses, fungi - Attract other phagocytes - Sequester endotoxins What makes them interesting? Work together with other antimicrobials (synergy) Stable over a wide range of ph Microbes don t develop resistance To Summarize...