Innate Immunity

Innate Immunity: Overview & Barriers - First Line Fortifications

• Core Features: Rapid (minutes-hours), non-specific, no prior exposure, no memory. Germline encoded PRRs.

• First Line Defenses: Prevent pathogen entry & colonization. Barriers are sequential.

  • Physical/Mechanical:
    • Intact Skin (keratin, desquamation).
    • Mucous Membranes (mucus, cilia, peristalsis).
    • Flushing actions (tears, saliva, urine).
  • Chemical:
    • pH: Gastric acid (pH 1-3), skin (pH ~5.5), vaginal lactic acid.
    • Antimicrobial peptides (AMPs): Defensins, Cathelicidins.
    • Enzymes: Lysozyme (tears, saliva) - targets peptidoglycan by hydrolyzing $\beta-(1,4)$ NAM-NAG bonds.
  • Microbiological:
    • Normal Flora: Competitive exclusion, bacteriocins.

⭐ Defensins and Cathelicidins are key antimicrobial peptides (AMPs) that disrupt microbial membranes.

Innate Immunity: Cellular Sentinels - The Immune Foot Soldiers

Key cells for immediate defense:

• Phagocytes: Engulf and destroy pathogens.
  • Neutrophils (PMNs): Abundant first responders. Multi-lobed nucleus. Phagocytosis, NETosis. 📌 Neutrophils: Numerous, Nimble.
  • Macrophages: From monocytes. Phagocytosis, Ag presentation, cytokines. Tissue-specific (Kupffer cells - liver).
• Dendritic Cells (DCs): Potent APCs; bridge innate to adaptive immunity.
• Natural Killer (NK) Cells: Lymphoid origin, innate function. Target virus-infected & tumor cells with ↓MHC-I.

  ⭐ NK cells employ "missing-self recognition," targeting cells with reduced or absent MHC class I molecules.

• Mast Cells & Basophils: Release histamine, mediators in allergy/inflammation.
• Eosinophils: Combat parasites; modulate allergic inflammation.

Phagocytosis Overview:

Innate Immunity: Molecular Mediators - Chemical Warfare Crew

Key soluble factors orchestrating innate defense:

• Cytokines:
  • Pro-inflammatory: TNF-α, IL-1, IL-6 (fever, inflammation). 📌 "Hot T-Bone stEAk": IL-1 (fever), TNF-α, IL-6 (APPs).
  • Type I IFNs (IFN-α, IFN-β): Induce antiviral state in cells.
  • IFN-γ (Type II IFN): Activates macrophages; from NK cells/T-cells.
• Chemokines:
  • IL-8 (CXCL8): Neutrophil chemoattractant.
• Complement System:
  • Key roles: Opsonization ($C_3b$), Inflammation ($C_3a, C_5a$), Lysis (MAC $C_5b-C_9$).
• Acute Phase Proteins (APPs):
  • CRP: Opsonin, classical complement activation. (Produced by liver)
  • MBL: Lectin pathway activation. (Produced by liver)
• Antimicrobial Peptides (AMPs):
  • Defensins, Cathelicidins: Direct microbicidal, membrane disruption.
• Enzymes:
  • Lysozyme: Hydrolyzes peptidoglycan in bacterial cell walls.

⭐ Type I interferons (IFN-α, IFN-β) are crucial for inducing an antiviral state in uninfected cells, limiting viral spread.

Innate Immunity: Recognition & Response - Sensing Danger, Sounding Alarm

• Sensing Danger (Recognition):

  • Microbial PAMPs (LPS, peptidoglycan, viral RNA) & host DAMPs (ATP, HMGB1) detected.
  • Key PRRs (Pattern Recognition Receptors):
    • TLRs (Toll-like Receptors): Surface (TLR2-peptidoglycan, TLR4-LPS, TLR5-flagellin); Endosomal (TLR3-dsRNA, TLR9-CpG DNA).
    • NLRs (NOD-like Receptors): Cytosolic. NOD1/2 (peptidoglycan); NLRP3 (inflammasome → IL-1β/IL-18 via Caspase-1).
    • RLRs (RIG-I-like Receptors): Cytosolic. RIG-I/MDA5 (viral RNA → Type I IFN via IRFs).
    • CLRs (C-type Lectin Receptors): Dectin-1 (fungal β-glucans).

  ⭐ TLR4 (with CD14/MD-2) recognizes Gram-negative LPS, activating NF-κB for pro-inflammatory cytokine release (TNF-α, IL-1, IL-6).

• Sounding Alarm (Response):

  • Signaling Pathways: NF-κB (pro-inflammatory cytokines, chemokines like CXCL8); IRFs (Type I IFNs: IFN-α/β for antiviral state).
  • Key Effector Mechanisms:
    • Inflammation: Vasodilation, ↑vascular permeability, neutrophil recruitment.
    • Phagocytosis: By macrophages/neutrophils; opsonins (C3b, IgG) enhance.
    • Antimicrobial peptides (AMPs): Defensins, cathelicidins.
    • NK cell activation.

High‑Yield Points - ⚡ Biggest Takeaways

• Innate immunity is the rapid, non-specific first defense; lacks immunological memory.
• Key players: phagocytes (neutrophils, macrophages), NK cells, complement, cytokines.
• PRRs (e.g., TLRs) on innate cells detect PAMPs (e.g., LPS, viral RNA).
• Inflammation (redness, heat, swelling, pain) is a core innate response.
• Type I interferons (IFN-α/β) are critical for antiviral defense.
• Complement system enhances phagocytosis, causes cell lysis (MAC), and promotes inflammation.
• NK cells provide early defense against viral infections and tumors without prior sensitization.