Lecture 4 - Innate immunity (the molecules pt1)

• Innate immune cells

  Sense pathogens through the recognition of broad and conserved Pathogen Associated Molecular Patterns (PAMPs) by a small number of Pattern Recognition Receptors (PRRs)
• PAMPs

  Essential for microbial survival and found on (nearly) all members of a pathogen class, such as lipopolysaccharide (LPS) on the surface of gram-negative bacteria or double-stranded RNA in dsRNA viruses
• Families of PRRs involved in pathogen recognition

  • Toll-like receptors (TLR)
  • Nucleotide-binding oligomerisation domain (NOD)-like receptors (NLR)
  • C-type lectin receptors (CLR)
  • RIG-1 like receptors (RLR)
• Toll-like receptors (TLR)

  • Localised at the plasma membrane or in the membranes of endosomes and have a broad range of specificities
• NOD-like receptors (NLR)

  • Cytoplasmic proteins that form multiprotein complexes known as inflammasomes
• C-type lectin receptors (CLR)

  • Localised at the plasma membrane and recognise glycans from the wall of fungi or some bacteria
• RIG-1 like receptors (RLR)

  • Cytoplasmic proteins that sense viral RNA and signal through mitochondrial adaptor proteins
• Inflammasomes

  Cytosolic multiprotein oligomers responsible for the activation of inflammatory responses and are initiated by different kinds of cytosolic PRRs, such as NLRs
• Major inflammasome pathways

  • NLRP1b
  • NLRP3
  • NLRC4
  • AIM2
• Activation of PRRs

  Leads to the production of cytokines, chemokines, and type I interferons, which play a crucial role in the immune response to pathogens
• Type 1 interferon cascade

  1. Activation of the IRF family transcription factors

  2. Production of IFN beta and other interferon-stimulated genes (ISGs)
• Following PRR activation

  1. IRF3 and IRF7 induce the transcription of IFN beta and IFN alpha (Type I interferons)

  2. Type I interferons are secreted and bind to the IFNAR (interferon A receptor)

  3. Positive feedback loop, resulting in the second wave of interferon-Stimulated genes (ISGs) through the action of other transcription factors of the IRF and STAT families
• Function of IFN beta

  • Inhibition of pathogen (virus, parasite) replication through the inhibition of protein translation in the infected cell
  • Induction of cell-death (apoptosis) of infected and neighbouring cells
  • Activation of other innate immune cells (e.g. NK cells)
  • Activation of the antigen presentation machinery, particularly in dendritic cells and macrophages, leading to the initiation of adaptive immunity
• Type I interferons, including IFN beta, are also used as immunotherapeutic agents in cancer therapy and have been approved for the treatment of leukemia, melanoma and renal cell carcinoma
• Interferonopathies

  A class of hereditary inflammatory diseases characterised by upregulated type I interferon and downstream ISGs, associated with a wide clinical spectrum of symptoms and largely unknown in etiology, but linked to genetic mutations associated with nucleic acid regulation and the failure of antiviral systems to differentiate between host and viral DNA and RNA
• NF-KB

  A transcription factor that plays a crucial role in regulating the expression of genes involved in immune and inflammatory responses
• Activation of NF-KB

  Essential for the production of cytokines such as interleukin 1B (IL-1B), tumour necrosis factor alpha (TNF alpha), and interleukin 6 (IL-6), which are key mediators of inflammation
• Regulation of NF-KB

  • By various post-translational mechanisms, including deubiquitinases such as A20 and CYLD, which act to inhibit NF-KB signalling by removing ubiquitin chains from NF- KB signalling molecules
  • By negative regulators such as microRNAs and RNA binding proteins (RBPs), which play a role in controlling NF-KB activity, e.g. miR-146 silences IRAK-1 and TRAF6, leading to inhibition of NF-KB signalling
  • By the degradation of mRNA and AU-rich elements, including TNF and IL-6, via the action of the RNA binding protein Tristetraprolin (TTP), contributing to a negative feedback loop in NF-KB signalling
• Tight regulation of the NF-KB cascade is crucial for maintaining immune homeostasis and preventing excessive inflammation, which can lead to tissue damage and disease
• Antigen presenting cells (APCs)

  Process human or microbial proteins to generate small linear peptides that can be checked by T cells
• MHC-I proteins

  Have proteins that can be a self peptide or a microbial (antigenic) peptide
• T cells receptors

  Can only recognise small linear peptides, so the antigen presentation machinery is essential for T cell recognition and activation
• Cytosolic processing

  Processing of endogenous proteins, such as viral proteins or proteins from invading bacteria, through the proteasome and rough endoplasmic reticulum, leading to the presentation of peptides on MHC-I proteins
• Endocytotic processing

  Processing of exogenous proteins, such as foreign antigens, by APCs through phagocytosis or endocytosis, leading to the presentation of peptides on MHC-II proteins
• Both cytosolic and endocytotic processing pathways involve specific molecular processes and interactions to ensure the presentation of antigens to T cells
• The antigen presentation machinery is regulated by type I interferons, which up-regulate components of both cytosolic and endocytotic processing systems
• Negative regulators of innate immunity

  • Play a crucial role in preventing excessive or prolonged immune responses that can lead to tissue damage and disease caused by the immune system rather than the pathogen
  • Induce their own negative regulators, such as anti-inflammatory cytokines like IL-10, which help to dampen the immune response and prevent excessive inflammation
  • Include phosphatases, such as Dual Specificity Phosphatases (DUSPs), that stop the signalling cascade by dephosphorylating key proteins involved in the immune response
  • Include intracellular factors, like IKB, that inhibit inflammatory transcription factors, preventing them from entering the nucleus and activating pro-inflammatory genes
  • Include microRNAs that suppress translation of inflammatory mRNAs, such as miR-146a which suppresses TRAF6 and IRAK1
• These negative regulators are usually induced at the later stages of the innate immune response, providing tight regulation and preventing prolonged inflammation