Innate Immunity Lecture 1 PDF

Innate Immunity Lecture 1 1  The Front line Each day, we swallow and digest about 1 litre of mucus, which may contain trapped pathogens and pollutants Each day, we breath the equivalent of a small room of air-may contain dust, smoke, viruses, sand,...

Innate Immunity Lecture 1 1  The Front line Each day, we swallow and digest about 1 litre of mucus, which may contain trapped pathogens and pollutants Each day, we breath the equivalent of a small room of air-may contain dust, smoke, viruses, sand, soot, bacteria, pollen, fungi Nasal mucus clumps around microbes and pollutants Infectious agents can grow in all body compartments 2 Infectious agents can grow in all body compartments 3  The immune response Innate system Adaptive system specificity speed 4  Innate Immunity Innate immunity consists of 4 types of defense: 1. Anatomical barriers 2. Physiological defences 3. Phagocytes & other innate cells 4. The inflammatory response 5  Innate Immunity “In-born” First line of defence against invading pathogens provides a rapid first line of defense Is highly effective against the majority of microbes Does not adapt (improve) Does not remember 6  Innate Immunity Innate immunity consists of 4 types of defense: 1. Anatomical barriers 2. Physiological defenses 3. Phagocytes & other innate cells 4. The inflammatory response 7  1. Anatomical Barriers External epithelia Skin - physical contact, e.g. athlete’s foot Wounds and abrasions - puncturing of skin, e.g. tetanus Insect bites - e.g. malaria Mucosal epithelia Airways - inhaled droplets. e.g. influenza Gastrointestinal tract - contaminated water or food, e.g. typhoid fever and cholera Urinogenital tract - physical contact, e.g. UTI infection Stages of an infection Adherence to epithelia Penetration of epithelium Infection of tissues 8  Anatomical Barriers 1. External Epithelia-the skin Skin is impermeable to most microbes because Epidermis a mechanical barrier of dead cells rich in keratin (waterproof) Dead epidermal cells are shed along with associated pathogens Dermis contains collagen-tough fibre that gives skin strength/pliability- prevent pathogen penetration 9  Chemical substances-sweat and sebaceous glands. Sweat-contains salt and lysozyme. Salt draws water away from invading pathogens. Lysozyme destroys cell wall of bacteria Sebum is rich in lactic acid and fatty acids, making skin a very acidic (pH3 to pH 5) environment, unfavourable to most microbes. 10  Anatomical Barriers 2. Mucosal epithelia Line all body cavities-respiratory, urinary, digestive, reproductive tracts. Act non-specifically to limit infection Washing action of tears, saliva, urine, mucus, (vomiting) & mechanical action of cilia, coughing, sneezing, peristalsis (gut) SMOKERS-damaged cilia Microbial antagonism by the normal flora: Normal microbiota make environment less favourable to pathogenic microbes e.g. change pH, consume nutrients, stimulate production of antimicrobial peptides by epithelial cells 11 Anatomical Barriers and Diseases 12  2. Physiological defenses Temperature Normal body temperature inhibits some pathogens, enhanced by “fever” Low pH Acidity of stomach (pH 1) kills most organisms in food, Skin, urine. Chemical defenses Milk: Lactoperoxidase, defensins Tears, Saliva, Sputum: Lysozyme (Gram +ve bacteria) Ear wax: (cerumen) bacteriostatic waxes & fatty acids 13  Physiological defenses Chemical defenses (continued) Type 1 Interferon: induces an antiviral state in uninfected cells Antimicrobial peptides: Defensins (in airway mucus, insects, plants) & Cryptidins (Paneth cells of gut) lyse microbes The Complement cascade (multienzyme system) lyses microorganisms & aids phagocytosis. Defensins, produced by epithelia cells and phagocytes, disrupt the cell membrane of bacteria, fungi, and some viruses 14  The Second line of defense! Non-specific (similar to first line of defense) It does not contain barriers, but uses cells phagocytes antimicrobial chemicals (interferons, complement) and processes (inflammation and fever) 15 Stages of an infection 16  3. Phagocytes Specialised cells can engulf and digest microorganisms: Phagocytosis. This was first recognised by the Russian Zoologist Elie Metchnikoff in the 1880s. Led to Nobel Prize Using a light microscope, and transparent Daphnia or starfish larvae, he showed that “foreign matter” (spores etc) were engulfed and destroyed by special cells that looked like Amoeba. Hypothesis: Cells moved like Amoeba and therefore, they may eat like amoeba. In mammals he identified 2 types of special cell, a large cell and a small cell. 17  Phagocytes Professional Phagocytes Neutrophil and Macrophage Microbe crosses epithelial barrier, recognised by macrophage (large cell) Macrophage- mononuclear phagocytes Large, Long-lived cell, may exist as blood monocyte or tissue macrophages (lung =alveolar Mo., Liver =Kupffer cell, brain=microglia), single regular nucleus, abundant mitochondria House keeping & anti-microbial functions. 18  Phagocytes The Polymorphonuclear Neutrophil (PMN): The small cell Non-dividing, short lived cell (3d) Multi-lobed nucleus Abundant Glycogen stores (can function in anaerobic wounds) not present in normal healthy tissue Major defence against pyogenic (pus-forming) bacteria 19  Phagocytosis Chemotaxis (chemicals from complement; cytokines) Adherence (binding of phagocyte to Microbe (MO)) Ingestion (MO becomes attached to pseudopodia of cell to surround cell and form a sac called a phagosome) Digestion (lysosome fuses with phagosome to form phagolysosome; NOTE: Lysosomes contains enzymes, proteins and peptides that destroy the pathogen) Phagocytes also produce toxic molecules - hydrogen peroxide, nitric oxide and superoxide which kill bacteria Elimination (undigested remnants of MO released via exocytosis) Phagocytes also release cytokines and inflammatory mediators 20  The front line of immune defense - phagocytes Phagocytes are cells that can recognise, ingest and destroy pathogens Types of phagocytes: Pathogen Neutrophils - Internalization released into blood and die within hours Macrophages & dendritic cells - mature from blood Destruction monocytes and move into the tissues 21 Macrophages and dendritic cells also activate other immune responses Pathogen Recognition Internalization Receptor Destruction Activate adaptive immune system Gene expression Release of inflammatory mediators such as CYTOKINES 22 Phagocytes express receptors for many bacterial products Bind various components of pathogens Toll-like receptors CD14 Mannose Binds to receptor mannose on surface of Bind bacterial microorganism lipopolysaccharides Glucan receptors Bind bacterial carbohydrates 23 Macrophages express receptors that bind microbes and their components 24 How do Phagocytes kill microbes? There are 3 mechanisms of killing: 1. Killing by reactive oxygen intermediates (ROI) (Oxygen radicals etc). Potent against microbes retained in phagosome. Break down MO cell wall. Aerobic 2. Killing by reactive Nitrogen intermediates (RNI) (Nitrogen radicals etc) Potent against microbes which escape into the cytosol. Aerobic 3. Killing by preformed antimicrobials. (eg lactoferrin, lysozyme, defensins, Cathepsin G) Aerobic or anerobic. 25 Summary: stages of an infection 26  Why do phagocytes fail? Doesn’t locate target Doesn’t bind microbe Doesn’t engulf….etc One solution is…….Complement 27