Harvey's Garden

Pattern recognition receptors

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Pattern Recognition Receptors (PRRs)

Innate immune receptors that recognize conserved Pathogen-Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs), triggering inflammatory responses via transcription factors NF-κB and IRFs.

  • Toll-Like Receptors (TLRs)
    • Function: Recognize extracellular or endosomal pathogens. Signal mainly via MyD88 to activate NF-κB.
    • Key Examples:
      • TLR4: On cell surface; recognizes LPS from Gram-negative bacteria.
      • TLR2: On cell surface; recognizes peptidoglycan/lipoteichoic acid from Gram-positive bacteria.
      • TLR3, 7, 8: In endosomes; recognize viral nucleic acids (dsRNA, ssRNA).
  • NOD-Like Receptors (NLRs)
    • Function: Cytosolic sensors of intracellular pathogens and cell damage.
    • Key Examples:
      • NOD2: Recognizes bacterial peptidoglycan. Mutations are strongly associated with Crohn’s disease.
      • NLRP3 Inflammasome: A cytosolic complex activated by diverse DAMPs (e.g., uric acid crystals). Its activation leads to caspase-1 activation, which cleaves pro-IL-1β into active IL-1β. This pathway is central to the inflammation seen in gout.
  • RIG-I-Like Receptors (RLRs)
    • Function: Cytosolic sensors specializing in viral RNA. Their activation is crucial for producing Type I Interferons (IFN-α/β).
    • Key Example:
      • RIG-I: Recognizes specific RNA structures common in viral genomes (e.g., 5’-triphosphate RNA).
  • High-Yield Associations
    • TLR4 Deficiency: Increased susceptibility to Gram-negative sepsis.
    • NOD2 Mutation: Increased risk for Crohn’s disease, particularly ileal disease.
    • NLRP3/Inflammasome: Gout (activated by uric acid crystals), autoinflammatory syndromes.

NF-κB pathway

  • Function
    • Master pro-inflammatory transcription factor.
    • Drives expression of genes for inflammation (cytokines), immunity, and cell survival (anti-apoptosis).
  • Canonical Pathway (Most Common)
    • Resting Cell: NF-κB is held inactive in the cytoplasm by its inhibitor, IκB.
    • Activation State:
      1. Triggers (TNF-α, IL-1, LPS) activate IKK (IκB Kinase).
      2. IKK phosphorylates IκB.
      3. Phosphorylated IκB is ubiquitinated and degraded by the proteasome.
      4. Freed NF-κB translocates to the nucleus to initiate gene transcription.
  • Key Gene Products
    • Pro-inflammatory cytokines: TNF-α, IL-1, IL-6
    • Chemokines & Adhesion Molecules
    • Anti-apoptotic proteins (e.g., B-cell lymphoma 2 [Bcl-2] family)
  • Inhibition & Clinical Relevance
    • Negative Feedback: NF-κB induces transcription of its own inhibitor, IκBα, to terminate the signal.
    • Glucocorticoids: Inhibit NF-κB by increasing IκBα production.
    • Proteasome Inhibitors (e.g., Bortezomib): Block IκB degradation, trapping NF-κB in the cytoplasm.
    • Pathology: Dysregulation leads to chronic inflammation (RA, IBD), cancer, and septic shock (due to massive cytokine release from LPS stimulation).

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