Innate Immunity Flashcards

Overview of Innate Immune Cells

• Previous lecture: Introduction to innate immune cells and Toll-like receptors (TLRs) & NOD-like receptors (NLRs).

• Focus for today: Detailed signaling mechanisms of TLRs & NLRs; basic defense mechanisms such as antimicrobial peptides (defensins).

Epithelial Barriers

• Epithelium: Outward facing barrier (skin, gastrointestinal, pulmonary, urogenital tracts).

  • Functions as a physical barrier against pathogens.

  • Colonized by normal microflora (microbiota) that maintain symbiotic relationships and prevent overgrowth of harmful microbes.

• Types of Epithelium:

  • Simple squamous epithelium: Single layer of cells.

  • Stratified squamous epithelium: Multiple layers for increased protection (like bricks in a wall).

• Cilia: Hair-like structures on the epithelium help move mucus and pathogens out of the body; mucus also has antimicrobial properties.

• Antimicrobial Peptides (Defensins): Secreted from epithelial cells to disrupt microbial membranes and recruit immune cells.

Antimicrobial Properties

• Defensins: Small, cationic peptides with two types:

  • Alpha defensins: Produced by immune cells (e.g., neutrophils, Paneth cells).

  • Beta defensins: Secreted by mucosal epithelial cells.

• Mechanism:

  • Cationic nature allows interaction with negatively charged bacterial membranes, disrupting them, leading to lysis or internal disruption upon uptake.

• Defense mechanism against pathogens and recruitment of immune response if epithelial damage occurs.

Toll-like Receptors (TLRs)

• TLRs: Membrane-bound receptors that recognize pathogen-associated molecular patterns (PAMPs).

  • Typically found in immune and epithelial cells.

  • Types of TLRs: TLR1 & TLR2 (bacterial lipopeptides), TLR4 (LPS from gram-negative bacteria).

• Heterodimers: TLRs usually function as dimers, enhancing specificity and binding affinities.

• Leucine Rich Repeats (LRRs): Recognition domain of TLRs that senses pathogens.

• Signaling Mechanism:

  • TIR Domain: Activates adaptor proteins (e.g., MyD88, TRIF), which lead to NF-kappa B activation resulting in cytokine production, chemokine release, and immune activation.

NOD-like Receptors (NLRs)

• NLRs: Cytosolic sensors that recognize intracellular bacteria and DAMPs.

  • Types: NLRA, NLRB, NLR-C; mainly focused on NLRA, NLRB, NLR-C.

• Signaling Mechanism:

  • Oligomerization required for activation.

  • Activates RIPK2, leading to NF-kappa B activation, producing inflammatory cytokines.

  • Specialized in detecting bacterial components; NLRB recognizes flagellin.

Danger-Associated Molecular Patterns (DAMPs)

• DAMPs signify cellular stress or damage.

• Released upon necrosis (cell injury) whereas apoptotic cells maintain membrane integrity.

• Examples of DAMPs include ATP, uric acid, histones, initial oxidative stress products.

• Recognition via receptors allows immune cells to respond to self-patterns and activate, ensuring effective immune response.

NF-kappa B Activation

• Central transcription factor in innate immunity.

• Activation process:

  • IKB phosphorylated and degraded, freeing P50 and P65 subunits.

  • These translocate to the nucleus to activate immune-related genes (cytokines, adhesion molecules).

  • The NF-kappa B pathway is triggered by both TLRs and NLRs under various pathogen stimuli.

Summary Points

• Importance of epithelial barriers as first line of defense.

• Recognition of pathogens via TLRs and NLRs using LRRs and oligomerization.

• Role of defensins and DAMPs in signaling immune responses.

• Central role of NF-kappa B in activating immune responses.