Innate Immunity

Overview & Components - First Line Defenders

• Nature: Rapid, non-specific, immediate defense. Present from birth; no memory.
• Function: Prevents pathogen entry/colonization. Recognizes PAMPs (Pathogen-Associated Molecular Patterns) via PRRs (Pattern Recognition Receptors).
• First Line Barriers:
  • Physical/Mechanical:
    • Intact skin (keratin, desquamation) & mucous membranes (mucus, cilia).
    • Flushing actions: Tears, saliva, urine, coughing, sneezing.
  • Chemical:
    • Lysozyme: In tears, saliva, nasal secretions; targets peptidoglycan.
    • Gastric acid: Low pH (e.g., pH 1.5-3.5) in stomach.
    • Defensins & Cathelicidins: Antimicrobial peptides on epithelial surfaces.
    • Sebum & Lactic acid: Skin surface.
  • Biological:
    • Normal flora (microbiota): Competitive exclusion, produce bacteriocins.

⭐ Toll-like Receptors (TLRs), a major PRR family, recognize diverse PAMPs: LPS (Gram-negative bacteria) by TLR4, flagellin by TLR5, viral dsRNA by TLR3.

Recognition & Signaling - Stranger Danger Detectors

• Pattern Recognition Receptors (PRRs): Detect conserved microbial molecules (PAMPs) & endogenous danger signals (DAMPs).
  • PAMPs (Pathogen-Associated Molecular Patterns): E.g., LPS (Gram -ve bacteria), peptidoglycan, viral RNA.
  • DAMPs (Damage-Associated Molecular Patterns): E.g., HMGB1, ATP, uric acid from stressed/necrotic cells.
• Major PRR Families & Key Examples:
  • TLRs (Toll-like Receptors): Cell surface & endosomes. E.g., TLR4 recognizes LPS; TLR3, 7, 8, 9 recognize nucleic acids.
  • NLRs (NOD-like Receptors): Cytosolic. Some form inflammasomes (e.g., NLRP3).
  • RLRs (RIG-I-like Receptors): Cytosolic. Detect viral RNA.
  • CLRs (C-type Lectin Receptors): Cell surface. Bind fungal glycans.
• Signaling Outcomes: PRR activation → triggers intracellular signaling (e.g., NF-κB, IRFs) → production of:
  • Pro-inflammatory cytokines (e.g., TNF, IL-1, IL-6)
  • Type I Interferons (IFN-α/β)
  • Chemokines

⭐ NLRP3 inflammasome (an NLR complex) is activated by diverse stimuli including microbial products, crystals (e.g., uric acid in gout), and other DAMPs, leading to caspase-1 activation and secretion of IL-1β and IL-18.

Phagocytosis & Inflammation - The Clean-Up Crew

• Phagocytosis: Cell eating by phagocytes (Neutrophils, Macrophages).
  • Process:
    • Chemotaxis/Adherence: Opsonins (C3b, IgG Fc) enhance.
    • Ingestion: Pseudopods → Phagosome.
    • Fusion: Phagosome + Lysosome → Phagolysosome.
    • Killing/Digestion:
      • Oxygen-dependent: Respiratory burst (NADPH oxidase: $O_2 \rightarrow O_2^-$); Myeloperoxidase (MPO): $H_2O_2 + Cl^- \rightarrow HOCl$.
      • Oxygen-independent: Lysozyme, lactoferrin, defensins.
• Inflammation: Response to eliminate cause & consequence of injury.
  • Cardinal Signs: Rubor (redness), Tumor (swelling), Calor (heat), Dolor (pain), Functio laesa (loss of function). 📌 PRISH.
  • Key Vascular Events: Vasodilation (histamine, NO), ↑ permeability (histamine, leukotrienes).
  • Key Cellular Events: Leukocyte recruitment (margination, rolling, adhesion, transmigration). Chemotaxins: C5a, LTB4, IL-8.

⭐ Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase (impaired oxygen killing). Recurrent infections by catalase-positive organisms (e.g., S. aureus, Aspergillus).

NK Cells, IFN & Complement - Special Ops & Body Alarms

• NK Cells (CD16/CD56+): Innate lymphoid cells; cytotoxic.
  • Target: Virus-infected & tumor cells (↓MHC-I - "missing self" or stress ligand expression).
  • Kill via: Perforin, Granzymes.
  • ADCC: CD16 (FcγRIII) binds IgG.
• Interferons (IFN): Cytokine alarms.
  • Type I (α, β): By most cells. Induce antiviral state; ↑MHC I.
  • Type II (γ): By NK, T cells. Activates macrophages; ↑MHC expression.
• Complement System: Plasma protein cascade.
  • Pathways converge at C3 convertase:

-   Key Functions:
    -   Opsonization: **C3b**.
    -   Lysis: MAC (**C5b-C9**).
    -   Inflammation/Chemotaxis: **C3a, C5a** (anaphylatoxins).
-   📌 **Mnemonic (Functions):** O-L-I-C (Opsonization, Lysis, Inflammation, Clearance).
> ⭐ **C3b** is the central molecule and major opsonin of the complement system.

High‑Yield Points - ⚡ Biggest Takeaways

• Innate immunity: First line of defense, rapid, non-specific, no immunological memory.
• Key cells: Neutrophils, macrophages (phagocytosis); NK cells (cytotoxicity); dendritic cells, mast cells.
• PRRs (e.g., TLRs, NLRs) recognize PAMPs (e.g., LPS from bacteria) & DAMPs.
• Mediators: Cytokines (TNF-α, IL-1, IL-6), chemokines, interferons; complement system.
• NK cells kill virus-infected/tumor cells without prior sensitization using perforins/granzymes.
• Acute Phase Reactants (e.g., CRP, SAA) are systemic markers of acute inflammation.