Fortress Body II: Innate Immune Responses (PDF)

10/11/23 Fortress Body II: innate immune responses: part 1 Learning objective: de ne the key physical and functional barriers to infection. Learning objective: understand the role and function of soluble innate mediators including complement, collectins, CRP and defensins. Learning objective: unders...

10/11/23 Fortress Body II: innate immune responses: part 1 Learning objective: de ne the key physical and functional barriers to infection. Learning objective: understand the role and function of soluble innate mediators including complement, collectins, CRP and defensins. Learning objective: understand the role and function of phagocytes and NK cells. Learning objective: understand the function of pattern recognition receptors. Learning objective: understand the link bet ween innate and adaptive immune response. recap Interfaces between the body and external environment: Major interfaces include the skin, the gastrointestinal tract, the respiratory tract and the genitourinary tract. Microbes come into contact with these interfaces via physical contact, ingestion, inhalation and sexual activity. The epithelia, consisting of tightly adherence cells, form a mechanical barrier against these microbes. Skin – defence mechanisms at epithelial services: Strati ed squamous epithelium consists of several stack layers of cells. Outermost layers are dry and inhospitable to microbes, regular shedding helps reduce microbial load. It’s also water resistant and the high salt content and low pH of sweat inhibits bacterial growth. Contains anti-microbial proteins. Mucous membranes: Gastrointestinal, respiratory and Urogenital tracts. Single layer or several layers. Mucus: adhesive barrier, which traps pathogens. In respiratory tract, pathogens trapped in the mucus can be expelled by beating of cilia. Mucus is a lubricant, which is produced by goblet cells within the epithelium and is also in the specialised submucosal glands. Defence mechanisms at epithelial services – gastrointestinal tract: Low pH of gastric secretions inhibit bacterial growth. Peristalsis moves pathogens through GI tract. microbes a may outcompete pathogens. Compete for nutrients or physical spaces that would Normal ora other wise be occupied by pathogens. Strengthen epithelial barriers, produce anti-microbial factors of their own and stimulate development of the immune system. microbes Norman Stem cells really important; they allow the epithelium of the GI tract to repair. The Paneth cells are located nearby and secrete substances to protect the stem cells from microbes. Paneth cells secrete: antimicrobial proteins, defensins, lysozymes, secretory phospholipase A2 and Reg IIIy. Epithelial cells secrete soluble mediators that contribute to host defence: Epithelial cells produce anti-microbial substances. Epithelial cells release chemotactic signals to recruit immune cells. Epithelial cells release cytokines to communicate with immune cells. Opsonins and Opsonisation: Opsonins are the proteins that decorate the surface of the pathogen. Opsonisation is the coating of an infectious agent with host protein which makes it easier for phagocytes to recognise. Phagocytes have speci c receptors for the opsonins, allowing them to attach to the pathogen and engulf and destroy it. Chemokines and cell migration: Chemokines are a family of cytokines that direct the migration of immune cells ( up a concentration gradient towards the source of the Chemokine ), this is called chemotaxis. The ability of a cell to respond to a particular chemokine gradient depends on the expression of chemokine receptors on their surface. Acute phase proteins: Produced in the liver in response to in ammation. Sentinel cells trigger cytokines ( IL-6 ) which trigger acute phase proteins. cytokines liver Functions: Recruitment of immune cells. Pattern recognition ( bind to bacterial and fungal polysaccharides and glycolipids ) and activation of complement cascade. Binding to pathogens and enhancing uptake by phagocytic cells = opsonisation. Binding to, and killing pathogens. I add Collectins: Acute phase proteins. Molecules that act as soluble pattern recognition receptors. Bind oligosaccharides or lipids on microbial surfaces. ( PAMPs ). Functions: Opsonisation and stimulation of phagocytosis. Activation of the complement pathway. Aggregation or killing of pathogens. Modulation of the immune response. a Extra-cellular innate mediators: A wide variety of soluble mediators. Some are constitutive, some are inducible. Bind to pathogens and block their cellular receptors Bind to pathogens and kill them directly. Bind to pathogens and enhanced their uptake by phagocytic cells ( opsonisation ). Recruit immune cells ( chemotaxis ). Activate immune cells and systematic in ammatory responses ( cytokines ). The complement system: Family of abundant serum proteins involved in detection and destruction of pathogens. Key proteins of the complement pathway are name, C1, C2 and C3 etc. May be activated in three ways: Classical- via antibody. Alternative- via direct contact with pathogens. Lectin- via carbohydrate binding mediators. Each pathway starts with recognition of the surface of a microbe. Cleavage of C3: C3a: anaphlatoxin increases vasodilation, and vascular permeability and plays a role in recruitment of innate immune cells. C3b: Opsonin enhances degradation of pathogens by phagocytes. Cleavage relies on generation of a C3 convertase. C3b then goes into the membrane attack pathway. Cell membrane attack pathway: The Cb5 has a receptor, which usually attaches to the cell membrane that has the activating complex attached. The Cb5 also binds to C6 and C7 and then to C8 and multiples of C9. This forms the membrane attack complex, as C8 and C9 have hydrophobic components that incorporate into the membrane and make an ion channel. The channel allows water to move but not protein this result in cell lysis. https://www.youtube.com/watch?v=BSypUV6QUNw https://www.youtube.com/watch?v=2-57bqFSJ1E videos on the complement system