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Why do we need innate immunity? 

  • The adaptive immune system is too slow to protect us from new pathogens 
    • The activation of cytotoxic T cells takes 3-4 days to kick in, antibody response takes about 5 days 
  • If the pathogen replicates relatively slowly you'll be fine as the adaptive system will kick in before the number gets too high 
  • However if a pathogen replicates at a high level they will overwhelm you if you dont have a rapid immune response 
  • The innate immune system buys you time long enough for the immune system to respond to the pathogen 


What is the specificity of the innate immune response compared to the adaptive immune response? 

Adaptive Immunity = Involves specific recognition of infectious agents (usually sees a protein = antigen) 

Innate Immunity = Involves no specific antigen recognition. (They will recognise broadly conserved features of different classes of pathogens e.g.  features of bacterial cell walls)


What does Innate Immunity consist of? 

  • Phagocytosis 
  • The inflammatory response 
  • Cytokines, Interferons, Antimicrobial Peptides 
  • Complement → enhancing the way that antobodies work 
  • Intrinsic Defences - 'The Hostile Cell' 
    • Cells have evolved to be in environments that are hostile to the replication of the pathogen 
  • NK Cells (Natural Killer) 


What is phagocytosis? 

What what cells carry this out in vertebrates? 

  • Phagocytosis is a way of clearing pathogens by engulfing foreign bodies. 
  • It is carried out by macrophages, neutrophils and dendritic cells 
    • Phagocytosis clears pathogens but will also presents peptides on MHC which will promote development or reactivation of the adaptive immune response 


Describe the difference between dendritic cells, macrophages and neutrophils? `

  • Dendritic cells = Detect a pathogen, take it up and traffic to lymph nodes where they will break down the pathogen. They will then present its peptides through MHC Class II (Class I) and our lymph nodes will educate the adaptive immune response, they will select and stimulate division of naive T and B cells  (constitute an important bridge between innate and adaptive immunity) 
  • Macrophages = Found in most tissues (most are tissue resident), present antigens, reactivate memory, clear + repair damage. 
  • Neutrophils = Rarely tissue resident, circulate around the body. When an infection is triggered you will get recruitment to infection site and there will be a massive surge in neutrophils. 
    • Neutrophils will carry out most of the phagocytosis but disadvantageous as they can cause a lot of tissue damage (chronic inflammation) 


What are the two roles of macrophages in innate immunity? 

  • Phagocytosis - Material is destroyed in lysosomes 
  • Captured material can trigger macrophage activation → activated macrophages will produce cytokines and chemokines to stimulate both innate and progression towards an adaptive immune response, this will trigger the inflammatory response and can promote a local anti-microbial state


Describe the inflammatory response? 

Generic defence mechanism whose purpose is to localise and eliminate injurious agents and remove damaged tissue components 

It will 

  • Enhance permeability and extravasation 
  • Recruits neutrophils 
  • Enhanced cell adhesion 
  • Enhance clotting 



Briefly recap the inflammatory response by a macrophage 

  • Macrophage will become infected and release signals such as cytokines and chemokines 
  • The chemicals increase permeability of the surrounding blood vessels allowing extravasation of neutrophils and macrophages which will help and deal with clearing up the remaining infection


What is the difference between cytokines and chemokines? 

  • They are both glycoprotein hormones which will affect the immune response 
      • Act to modify the behaviour of cells in the immune response 
        • Most of these are called interleukins
          • (all interleukins are cytokines but not all cytokines are interleukins e.g TNF, interferons, CXCL8)
      • Act as chemotactic factors = create concentration gradients which will attract or occasionally repel specific cell types to a site of production/ infection 


How do phagocytes know what to eat/ engulf? 

  • When there is an infection there will be a lot of uninfected tissue, a macrophage will need to know what material it can engulf by 
    • Detecting phosphatidylserine on exterior membrane surface (cells undergoing apoptosis 
    • Scavenger receptors (mainly target bacterial cell walls) 
    • Some Toll-like Receptors (TLRs) (pattern recognition receptor) 
    • By passive sampling 


What is passive sampling? 

This is a way in which neutrophils will take up stuff at random and destroy it, this can cause a lot of tissue damage 


What are PAMPs? 

  • PAMPs are Pathogen Associated Molecular Patterns 
  • They are molecules present only on pathogens and not host cells 
  • They are essential for the survival of pathogens
  • It is an invariant structure shared by the entire class of pathogens 
  • They are recognised through receptors called pattern recognition receptors (PRRs) on host cells 



What are some examples of PAMPs? 

  • Gram negative bacteria - Lipopolysaccharides (LPS) found in outer membrane 
  • Gram posotive bacteria - Lipoteichoic acid, teichoic acid, peptidoglycan foud in outer membrane 
  • Bacterial flagellin (conserved throughout bacteria) 
  • Abnormal protein glycosylation 
    • The type of glycosylation will differ between eukaryotes, prokaryotes and high eukaryotes, this means that the presence or absence of a certain type of sugar will signal that it is foreign

  • Abnormal nucleic acids 
    • The host cell can recognise subtle differences in our genome compared to the viral genome 


What are PAMPs recognised by? 

Describe them? 

  • PAMPs are recognised by PRRs (pattern recognition receptors) 
  • They are host factors which will recognise a particular type of PAMP 
  • They are germ-line endcoded (encoded by inherited genes that are identical in all cells, PRRs are non-clonally distributed and identical receptors are expressed on all the cells of a particular type e.g macrophages) 
    • There are several classes of PRRs but they can be classified into broad function of 
      • EXTRACELLULAR = Will recognise PAMPs outside a cell and trigger a co-ordinated response to the pathogen 
      • INTRACELLULAR (cytoplasmic) = Recognise PAMPs inside the cell and act to co-ordinate a response to the pathogen 
      • SECRETED - act to tag circulating pathogens for elimination 
        • Complement proteins do this 


What are some examples of pattern recognition receptors (PRRs) ?

  • Lectin receptors - PAMP ligand (Terminal mannose and fucose) = Phagocytosis 
  • Scavenger receptors - PAMP ligand (bacterial cell walls, modified LDLs) = Phagocytosis 
  • Toll-like receptors (TLRs) - PAMP ligand (LPS, Lipoproteins, flagellin) 


What is the function of pattern recognition receptors RIG-like receptors and MDA5 receptors? 

  • They are cytoplasmic anti-viral receptors and will recognise dsRNA structures 
    • As we only have dsDNA (nucleus) and ssRNA (cytoplasm) dsRNA molecules are completely foreign
    • 5’-triphospho-RNA is RNA which hasn’t been capped, we make very little of it



Describe the complement system? 

  • Originally described as a heat-sensitive component which could augument the abillity of antibodies to inactivate antigens 
    • Originally thought to be a biochemically complex antibody-dependant effector mechanism which leads to 
      • Opsonisation, recruitment of phagocytic cells, vasoactive function, punches holes in target membranes 
    • However it actually predates the development of the adaptive immune system and is evolutionary ancient 
      • In the innate immune system complement proteins will act as PRRs (pattern recognition receptors) and are activated by a number of PAMPs but can also be activated by self 


Describe the main role of the complement system in innate immunity? 

A group of serum proteins which enhances the abillity of antibodies and phagocytic cells to clear microbes and damaged cells from an organism by

  • inducing an inflammatory response (C5a)
  • promote chemotaxis
  • increase phagocytosis through opsonisation (C3b)
  • Increase vascular permeability
  • Cell lysis (formation of MAC (membrane attack complex)) 
  • Mast cell granulation 


What is the role of the complement system in innate immunity? 

In the innate immune system complement proteins will act as pattern recognition receptors (PRRs) and can be activated by a range of PAMPs and also be activated by ‘altered self’


What are the three pathways of complement? 

CLASSICAL = The antigen-antibody pathway. The triggering protein is C1q which will recognise LPS and decorate those with C1q allowing for opsonisation and phagocytosis 

LECTIN PATHWAY = Recognises abnormal glycosylation of proteins and activate complement

ALTERNATIVE PATHWAY = Any pathogen surface that is not of host origin will lack complement control proteins and complement will be activated 


Describe interferons and how they play an important role in innate immunity? 

  • Interferons will play a major role in innate immunity 
    • (Without them we would be killed by many viruses) 
  • They are secreted glycoproteins (type I and type III) 
  • They are not expressed in tissues so they require the thing that they are going to eliminate to turn them on 
    • E.g. Activate the cell through PAMPs causing interferon secretion 
  • These are induced through viral infections 
  • Offer cross-protection 


Describe how interferons are released from infected cells. 

  • The virus will enter the primary infected cell and multiply rapidly, in the primary infected cell there is no antiviral response 
  • These cells will die and release lots more virus, which will attempt to invade neighbouring cells 
  • However the primary infected cell will have released interferon which will bind to neighbouring cells and trigger an antiviral state through transcriptional activation of antiviral response genes 


Briefly describe the molecular mechanism how interferons can induce an antiviral state

  1. Interferons will arrive from an infected cell and bind to a cell receptor 
  2. Cause signal transduction and genes to be switched on e.g procaspases, PKRi
  3. E.g PKRi is inactive form of PKR (protein kinase R) which requires dsRNA (co-factor) converting it to active form PKRa which will switch off ribosome function = make no more protein and viruses are unable to utillise host machinery 


Describe AMPs (anti-microbial peptides) 

  • They are short peptides (18-45 amino acids)
  • Work by disrupting the cell wall = lysis 
  • Some are induced by bacterial infection 
  • Offer broad protection 


What is an example of a Anti-microbial peptide? 

Defensin is an example of an AMP 


Describe the hostile cells intrinsic defences 

This is the concept that cells themselves will have biochemical mechanisms within them which will discourage viral replication

  • Apoptosis
  • Restriction factors/ Intrinsic immunity
  • Epigenetic silencing
  • RNA silencing
  • Autophagy/ Xenophagy


Describe natural killer cells

  • Make up 4% of WBCs 
  • Similar to lymphocytes but are larer with granular cytoplasm 
  • Have the abillity to kill certain tumour and viral infected cells 
  • Target cell destruction caused by cytotoxic molecules called granzymes and perforins

  • Also secrete interferon gamma which activates macrophages to become more effective at killing phagocytosed microbes 


Describe how NK cells are activated. 

  • NK cells will recognise and lyse virally infected cells and tumour cells 
  • Selectivity will be conferred through LOSS of 'self' MHC molecules on target cell surfaces AND up-regulation of activating ligands 
    • Some pathogens down-regulate the production of MHC Class I in an attempt to avoid immune recognition. However NK cells will recognise the absence of MHC class I signal and destroy the cell 


Compare innate and adaptive immunity

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