Innate Sensing

• Sensing


  To clear infection the immune system first needs to detect infection
• The Immune Detection Challenge

  How can you rapidly detect such a wide range of diverse pathogens, and distinguish them from self? How can you individually recognise specific pathogens? How can you remember previous pathogen encounters?
• The Immune System


  A range of cells working together as a team
• Innate Immunity


  • Broad Specificity, Recognises danger signals, Ready to go, Rapid response
• Adaptive Immunity


  • Highly specific, Recognises individual pathogens/strains, Requires time to develop, Memory (remembers pathogens)
• Innate Immunity


  Recognises generic Danger Signals, common evolutionary conserved pathogen molecules (PAMPs), molecules produced by damaged host cells (DAMPs), Limited receptor diversity, Not adaptable; receptors germline encoded, Cells of same and different innate lineages share same receptors and recognise same molecules
• Adaptive Immunity


  Can recognise almost any microbial or non-microbial molecule (antigens), Very large (almost infinite) receptor diversity, Adaptable; receptors created by somatic recombination of gene segments, Each cell has one unique receptor that is highly specific for a particular molecule
• Innate and Adaptive immunity use two very different systems to sense pathogens
• Sensing Microorganisms 1 - 3 will cover Innate sensing, Adaptive sensing, and how innate and adaptive sensing link together
• Cells of innate and adaptive immunity recognise pathogens in different ways
• Proteins/receptors of the innate immune system

  Recognise danger signals that signify infection (tissue damage and pathogens)
• Macrophages


  Detect infection, initiate immune responses, and recruit other innate immune cells
• The Complement System


  Collection of proteins working together as an early warning system and to destroy pathogens, Labels microbes for phagocytosis by other cells, Recruitment of immune cells, The oldest example of pathogen recognition, Evolved 700 million years ago
• How does complement detect microbes?

  Activated in 3 ways: Alternative Pathway, Lectin Pathway, Classical Pathway, Direct Pathogen Recognition via adaptive immunity and antibodies
• Complement as an Innate Sensor: Alternative Pathway


  Complement proteins C3b spontaneously produced, C3b binds to amino and hydroxyl groups on microbes, But amino and hydroxyl groups also on host cells, Host cells have to block C3b activity or it will attack the host, Better to detect molecules specific for microbes
• Complement as an Innate Sensor: Lectin Pathway


  Mannose Binding Lectin (MBL) recognises mannose, a carbohydrate found on the surface of many common pathogens, MBL does not bind to carbohydrates found on healthy mammalian cells, Complement effector mechanisms activated
• PAMPs


  Pathogen Associated Molecular Patterns, Evolutionary conserved molecules shared by various classes of microbes and not present on normal host cells
• PRRs


  Pattern Recognition Receptors, Proteins/receptors of innate immunity that recognise PAMPs, e.g. Mannose Binding Lectin, TLR, RIG, NLR
• Innate Immune cells


  Have PRRs on their surface allowing them to detect DANGER
• Phagocytes


  E.g. Macrophages and Neutrophils, Use phagocytosis as a killing mechanism
• Sentinel cells and Phagocytosis

  Use phagocytosis to sample the environment for microbes, Talk to T cells and show them any microbial molecules they've detected (Antigen Presenting Cells, APC), Activate T cells
• Macrophages as sentinels


  Found in all barrier tissue, In their resting state: Mop up apoptotic cells, Remove debris, Sample the environment, Scan for danger via PRRs
• DAMPs


  Damage-Associated Molecular Patterns, Molecules released from damaged or necrotic cells, Potential break in barrier, Pathogen that is causing damage whilst invading, Damage is a warning (yellow alert), but does not necessarily mean infection, First danger signal = tissue damage
• Activated Macrophage


  Yellow alert - ready for action, Better at phagocytosis - killing/sampling environment, Express surface receptors for communicating with adaptive immune cells (MHC), Activated by DAMPs, Activation of complement pathway, Cytokines e.g. IFN-γ, TNF-α
• All microbes have essential core conserved molecules that differ from host, Different classes of microbes express different PAMPs, PAMP molecules should be evolutionarily conserved, Can recognise a wide range of microbes using a limited number of PRRs
• Receptors can be germline encoded and are immediately ready to go
• Necrotic cells


  Damage-Associated Molecular Patterns (DAMPs)
• Potential break in barrier

  Pathogen that is causing damage whilst invading
• Damage is a warning (yellow alert), but does not necessarily mean infection
• First danger signal = tissue damage
• Activated Macrophage


  Yellow alert – ready for action
• Activated Macrophage


  • Better at phagocytosis – killing/sampling environment
  • Express surface receptors for communicating with adaptive immune cells (MHC)
• Macrophages as sentinels


  DAMPs (Damage Associated Molecular Patterns)
• Activation of complement pathway

  1. Cytokines

  2. E.g. IFN-γ, TNF-α
• All microbes have essential core conserved molecules that differ from host
• Different classes of microbes express different PAMPs
• PAMP molecules should be evolutionarily conserved
• Can recognise a wide range of microbes using a limited number of PRRs
• One innate cell can express multiple PRR and so can recognise and respond to a wide range of microbes
• Innate cells can directly tell whether you have been exposed to a microbe