PL1003 Innate Immunity UPDATED PDF

The innate immune system Dr. 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 p...

The innate immune system Dr. 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. 20 November 2 2024 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. 20 November 6 2024 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 Great video, but far more molecular detail than you need!!! The complement system A family of proteins involved in detection and destruction of pathogens. Named C1, C2, C3 etc. Present in blood at all times. Form a cascade, or pathway. Activation of the first component in the pathway initiates a cascade of reactions, activating protein after protein. The complement system 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 Leads to a proteolytic cascade resulting in the generation of opsonins and pro-inflammatory molecules, as well as direct microbial lysis. Activation of the complement pathway Alternative pathway: Amplification loop for classical and lectin pathways OR spontaneous hydrolysis of C3. Why don’t we get spontaneous activation of the alternative pathway on the surface of our own cells? 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: Cleavage of C5 A C5 convertase is formed (containing C3 convertase + C3b), which cleaves C5 to C5a and C5b C5a is an anaphylatoxin (increased vascular permeability and expression of adhesion molecules on blood vessel endothelium) and 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 to cell death. Formowanie_MAC.svg derivative work: Beao, CC BY-SA 3.0 , via Wikimedia Commons The complement system: C5a and the membrane attack complex  Complement for Pharmacists Inherited complement deficiencies  recurrent infection (Neisseria meningitidis), SLE, angioedema Complement also has a role in  MS, RA, IBD, atherosclerosis, vasculitis, macular degeneration, mood disorders, asthma, sepsis, osteoarthritis, dementia, myocardial infarction, stroke, trauma. Anti-complement therapy? Lots of pre-clinical and early clinical trials. Eculizumab  humanised monoclonal antibody that binds to C5 and stops it being cleaved. Used for paroxysmal nocturnal hemoglobinuria. 2024 What do people taking Eculizumab have an increased risk 20 November Inherited Deficiency of the Complement System (brainkart.com) 20  Complement for Pharmacists Accidental activation of the complement system: Complement Activation-Related Pseudoallergy (CARPA) rituximab, doxorubicin. Important consideration in the development of new drugs. 20 November Inherited Deficiency of the Complement System (brainkart.com) 21 2024 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 improve recognition by Cytotoxic T cells Recombinant Type 1 interferon given therapeutically  viral infection, cancers, SLE. 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 20 November 25 2024