Innate Immunity Lecture Slides PDF

The innate immune system Janine Coombes, [email protected]  Learning outcomes Explain how the complement system is activated, and its key defensive functions. Define the role of opsonins in host defence against pathogens. Explain, with examples, the role of acute phase...

The innate immune system Janine Coombes, [email protected]  Learning outcomes Explain how the complement system is activated, and its key defensive functions. Define the role of opsonins in host defence against pathogens. Explain, with examples, the role of acute phase proteins in host defence. Explain how Natural Killer cells defend against tumour or virus-infected cells. 5 December 2 2 024 Host Barriers to Infection Extra-cellular or Cellular mediators soluble mediators Physical /Chemical mucus Barriers epithelium antimicrobial factors macrophages cytokines neutrophils complement Innate Immunity dendritic cells acute phase proteins mast cells antimicrobial factors Adaptive Immunity T cells cytokines, antibodies B cells Properties and Functions of Extra-cellular Innate Mediators A wide variety of soluble mediators Some are constitutive, some inducible: e.g. acute phase proteins Bind to pathogens and kill them directly Bind to pathogens and enhance their uptake by phagocytic cells (opsonisation) Recruit immune cells (chemotaxis) Activate immune cells and systemic inflammatory responses (cytokines)  Innate Immunity Opsonins and Opsonisation Opsonisation = Coating of an Fc receptor infectious agent with host protein which makes it more easily antibody recognised by phagocytes. Opsonins are the proteins that decorate the surface of the pathogen. Phagocytes have specific pathogen receptors for the opsonins , allowing Adapted from: Maher33, CC BY-SA 4.0 them to attach to the pathogen, and , via Wikimedia Commons engulf and destroy it. Opsonins include antibodies and complement proteins. Cytokines Stimulus (e.g bacterial ligand) Effect Cytokines are a family of small proteins used for communication in the immune system. They play diverse roles in the regulation of an immune Cytokine producing cell Target cell response: type, magnitude, location. 5 December 2 6 024 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)  CHEMOTAXIS The ability of a cell to respond to a particular chemokine gradient depends on the expression of chemokine receptors on the cell surface. Direction of migration  Acute Phase Proteins Produced in the liver in response to inflammation (inducible). Sentinel cells  cytokines (IL-6)  acute phase proteins Slaats et al. (2016) PLoS Pathog 12(12): e1005973. Acute Phase Proteins Functions include: Recruitment of immune cells. Pattern recognition (bind to bacterial and fungal polysaccharides and glycolipids) and activation of complement cascade. Binding to, and killing pathogens. Binding to pathogens and enhancing uptake by phagocytic cells = opsonisation. Acute Phase Proteins Complement proteins Opsonins, chemoattractants, proteins with direct microbe killing function Used as a non-specific C-reactive protein Opsonin, activation of complement blood marker of infection or Mannose Binding Lectin Activation of complement inflammation Serum amyloid A Degradation of extracellular matrix (indirect), immune cell recruitment Fibrinogen, prothrombin, Coagulation factors. Physical restraint of factor VIII, pathogens in blood clots, immune cell von Willebrand factor recruitment  The Complement System https://www.youtube.com/watch?v=BSypUV6QUNw https://www.youtube.com/watch?v=2-57bqFSJ1E The complement system Family of abundant serum proteins involved in detection and destruction of pathogens. Key proteins of the complement pathway are named C1, C2, C3 etc. May be activated in three different 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 Complement Activation May be activated in three different 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 Ma YJ and Garred P (2018) Pentraxins in Complement Activation and Regulation. Front. Immunol. 9:3046. doi: 10.3389/fimmu.2018.03046 Complement Activation May be activated in three different 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 Ma YJ and Garred P (2018) Pentraxins in Complement Activation and Regulation. Front. Immunol. 9:3046. doi: 10.3389/fimmu.2018.03046 Complement Activation May be activated in three different 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 Ma YJ and Garred P (2018) Pentraxins in Complement Activation and Regulation. Front. Immunol. 9:3046. doi: 10.3389/fimmu.2018.03046 Complement Activation May be activated in three different 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 Ma YJ and Garred P (2018) Pentraxins in Complement Activation and Regulation. Front. Immunol. 9:3046. doi: 10.3389/fimmu.2018.03046 The Complement System: Cleavage of C3 C3 All pathways initiate a proteolytic cascade which results in the generation of a C3 convertase. Cleaves complement component C3 to generate C3b the opsonin C3b and the anaphylatoxin C3a: increases vasodilation and vascular permeability, C3a plays a role in recruitment of innate immune cells, bacterium enhances degradation of pathogens by phagocytes. The complement system: C5a and the membrane attack complex A C5 convertase is formed, which cleaves C5 to C5a and C5b C5a is an anaphylatoxin (increased vascular permeability and expression of adhesion molecules on blood vessel endothelium) and chemoattractant Formowanie_MAC.svg derivative work: Beao, CC BY-SA 3.0 , via Wikimedia Commons The complement system: C5a and the membrane attack complex C5b, together with C6,7,8,9 form the membrane attack complex (MAC). The MAC binds to the outer surface of microbes, and multiple copies of C9 form a pore in the membrane. This allow for free diffusion of molecules into and out of the pathogen. This leads toderivative Formowanie_MAC.svg cellwork: death. Beao, CC BY-SA 3.0 , via Wikimedia Commons Anti-viral defences Type 1 interferons Produced by virus-infected cells very early after infection Acts on neighbouring cells to increase resistance to viral infection Increases MHC-I expression and antigen presentation – infected cells can be identified by Cytotoxic (CD8+) T cells Activates NK cells Natural Killer (NK) Cells Bone marrow derived lymphocytes lacking the antigen specific receptors of T or B cells Around 10% of peripheral lymphocytes Important in protection against viral infection, and cancerous cells  recognise and kill stressed cells. Specialised NK cells found in placenta – important role in pregnancy.  Next…. The adaptive immune system 5 December 2 23 024