Innate Immunity Lecture 12 2022 PDF

Introduction to Immunology Innate Immunity: Nonspecific Defense Mechanisms  Immunity Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells History of Immunology Louis Pasteur- demonstrating t...

Introduction to Immunology Innate Immunity: Nonspecific Defense Mechanisms  Immunity Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells History of Immunology Louis Pasteur- demonstrating that it was possible to attenuate, or weaken, a pathogen and administer the attenuated strain as a vaccine. In 1885, Pasteur administered his first vaccine to a human, a young boy who had been bitten repeatedly by a rabid dog Comparison of Innate and Adaptive Immunity Innate Immunity Adaptive Immunity No time lag A lag period Not antigen specific Antigen specific No memory Development of memory  Effects of the Immune System Beneficial: Protection from Invaders Elimination of Altered Self Detrimental: Inflammation Damage to self (hypersensitivity or autoimmunity)  Innate response Components Lysozymes Mucus a. Biochemical enzymes, C’, etc. Cilia: trachea secretions Sebaceous glands pH b. Physical Skin skin Acid in cilia stomach c. Cells Phagocytes, NK Commensal organisms in gut & vagina  Anatomical Barriers - Mechanical Factors Skin Mucociliary escalator Flushing action of saliva, tears, urine Anatomical Barriers – Chemical factors Antimicrobial HCl in stomach Lysozyme in tears /saliva Peptides in sweat  Anatomical Barriers – Biological factors Normal flora – microbes in many parts of the body Normal flora – > 1000 species of bacteria Normal flora – competes with pathogens for nutrients and space  Innate response – internal defences Cellular Extracellular Neutrophils Cytokines Monocytes /macrophages Complement NK cells Coagulation  Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Major cellular components of the Innate- Nonspecific System Erythrocyte Platelets WBCs Neutrophil Red bone marrow Eosinophil = site of origin Basophil Monocyte Macrophage Pre-T-lymphocyte B-lymphocyte Plasma cell Thymus T-lymphocyte T-lymphocyte maturation  Neutrophils Most abundant WBCs (~50-60%) Efficient phagocytes Most important cells of the innate immune system  How do neutrophils find microbes ? https://youtu.be/I_xh-bkiv_c How do neutrophils eat and digest microbes ? Granules  Basophils Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Basophil and mast cell: Proinflammatory chemical-secreting cells Arteriole Vasodilation Basophil Histamine Increases capillary Capillary permeability Heparin Anticoagulant Eicosanoids Increases inflamation Venule  Eosinophils Eosinophils: Parasite-destroying cells Peroxide ions Parasitic worm Eosino phil Eosinophils also phagocytose antigen-antibody complexes  Monocytes Monocytes (~5% of WBCs) Migrate into the tissues and become Macrophages Lung Bone Liver Brain intestine  Phagocytosis... ◻ Adherence – binding of organism to the surface of phagocytic cell. ◻ Engulfment:- is the ingestion and formation of phagosomes. ◻ Digestion – after the foreign particle is ingested, cytoplasm lysosome fuse with phagosome. The enzymes of lysosome then contribute to microbial killing and lysis.  Natural Killer cells Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. NK cell: Apoptosis-initiating cells Perforin and granzyme Perforin forms a transmembrane pore Granzymes enter NK cell pore, causing apoptosis of cell Unhealthy or unwanted cell Apoptosis Recognizes unhealthy cell (usually expressing abnormal proteins) or viral proteins – uses perforins (make a hole in the membrane) and granzymes initiate apoptosis – programmed cell death via gene expression  How does the killer kill ? Kills both host cells and microbes Release of granules with perforins and proteases MHC 1 - major histocompatibility complex  Cytokines Small proteins – secreted by cells of the immune system Affect the behaviour of other cells signalling molecules Key players in innate and acquired immunity Interferons Interleukins Tumour necrosis factor (TNF)  Interferons Binds receptors of neighboring cells: promotes macrophage function and apoptosis of infected cell triggers synthesis of enzymes destroying viral RNA or DNA triggers synthesis of enzymes that inhibit synthesis of viral proteins IFN-α and IFN-β stimulate NK cells, which produce IFN-γ  Interleukins Interleukins – 1-37 Not stored inside cells Quickly synthesized and secreted in response to infection Key modulators of behaviour of immune cells Mostly secreted by T-lymphocytes & macrophages  What to interleukins do ? Proliferation of immune cells Interleukins Increase antibody production Inflammation Activation of immune cells  Tumour Necrosis Factor (TNF) TNF Killing of cancer Fever Inflammation  Antimicrobial Peptides Short peptides that consist of a chain of about 12 to 50 amino acids synthesized on ribosomes. Activity against bacteria, viruses, fungi, and eukaryotic parasites. AMPs produced by humans are dermcidin, produced by sweat glands; defensins and cathelicidins, produced by neutrophils, macrophages, and epithelium; and thrombocidin, produced by platelets. AMPs are also very stable over a wide range of pH. Microbes do not develop resistance  Antimicrobial Proteins Complement Proteins) Opsonization Inflammation Cytolysis Elimination of immune complexes Complement Complement Antigen C Mast cell Basophil Neutrophil Macrophage MAC Antibody protein Complement C Pathogen Erythrocyte Pathogen Inflammation Macrophage Complement (C) cross-links immune (antigen-antibody) Complement (C) binds to Complement activates and attracts various cells of Complement proteins create complexes to erythrocyte and pathogen; acts as opsonin innate immunity. MAC to lyse cell. transports to liver and spleen. Opsonin – coats pathogen to make appear different and thus recognizable by macrophages Inflammation - Activates mast cells, basophils, neutrophils, and macrophages to increase inflammatory response - Cytolysis – causes cell lysis (Membrane attack complex (MAC attack)) Eliminates Antigen-Antibody complexes on RBCs killed in spleen  Iron-Binding Proteins Iron-binding proteins— transferrin, lactoferrin, ferritin, and hemoglobin Some bacteria obtain iron by secreting proteins siderophores and take iron from iron-binding proteins by binding it more tightly. Neisseria meningitidis produces receptors on its surface that bind directly to human iron-binding proteins. Streptococcus pyogenes, release hemolysin, a protein that causes the lysis of red blood cells. The hemoglobin is then degraded by other bacterial proteins to capture the iron.  Coagulation Coagulation: mechanism to stop bleeding after injury to blood vessels Complex pathway involves Platelets Coagulation factors Vitamin K How does blood clot ?  Inflammation Normal blood vessel Normal blood vessel Dilated blood vessel Vascular changes Leaky blood vessel Capillary Vasodilatation permeability Heat / redness Swelling Pain Temporary Fever loss of function  Role of Inflammation in innate immunity Initiation of phagocytosis – killing of pathogen Limiting the spread of infection Initiate tissue repair Chronic inflammation - tissue damage Normal tissue Chronic inflammation - macrophages in the injured tissue. Macrophages release toxins (including reactive oxygen species or ROS) that injure Tissue : chronic inflammation tissues Chronic inflammation is almost always accompanied by tissue destruction.  Innate Immunity: Fever Fever Abnormal elevation of body temperature -- at least 1oC from normal (37oC) May accompany inflammatory response Due to excess fluid loss so requires increased fluid intake to prevent dehydration Events of fever Results from release of pyrogens such as interleukin 1, interferons toxins from infectious agents, drug reactions toxins, brain tumors Pyrogens released and circulate through the body target hypothalamus and cause release of prostaglandin E2 raises temperature set point of hypothalamus  Innate Immunity: Fever Benefits of fever Inhibits reproduction of bacteria and viruses Promotes interferon activity Increases activity of adaptive immunity Accelerates tissue repair Recommended to leave a low fever untreated Risks of a high fever High fevers potentially dangerous above 39.50C in children Changes in metabolic pathways and denaturation of proteins Possible seizures, irreversible brain damage at greater than 410C, death above 42.80C Summary of Innate Immunity Defenses Summary of Innate Immunity Defenses Summary of Innate Immunity Defenses References Gerard J. Tortora, Berdell R. Funke, Christine L. Case - Microbiology_ an introduction-Pearson (2018), Chapter 16