Innate Immune System: Phagocytosis

Innate Immune System: Phagocytosis

• Phagocytes: Macrophages (tissue resident) and neutrophils (blood-derived) are key phagocytic cells.
• Phagocytosis Steps:
  • Chemotaxis: Attraction to the target.
  • Attachment: Receptors bind to pathogen-associated molecular patterns (PAMPs).
  • Ingestion: Formation of a phagosome around the pathogen.
  • Fusion: Phagosome fuses with lysosomes.
  • Killing & Digestion: Enzymes, reactive oxygen species (ROS) and reactive nitrogen species (RNS), and a reduced pH degrade the pathogen.
  • Release: Waste products are released and some digested material is processed for antigen presentation.
• Recognizing Microbes: PAMPs (on microbes) are recognized by PRRs (on phagocytes), most notably, TLRs.
• Pattern Recognition Receptors (PRRs): Macrophages express TLRs for specific PAMP detection.
• Toll-like Receptors (TLRs): A diverse set of TLRs exist, each recognizing specific PAMPs. Example TLRs:
  • TLR2: Recognizes Peptidoglycan (bacterial cell wall component).
  • TLR4: Recognizes Lipopolysaccharide (LPS) (bacterial cell wall component).
  • TLR5: Recognizes Flagellin (bacterial flagella).
  • TLR7: Recognizes ssRNA (from viruses like influenza and HIV-2).
  • TLR9: Recognizes dsDNA (from bacteria and herpes simplex virus).
  • TLR10: Recognizes Flagellin (bacterial flagella).

PAMPs (Pathogen-Associated Molecular Patterns)

• Characteristics: PAMPs are conserved molecular patterns on microbes. They are not easily mutated, therefore providing consistent markers for immune response.
• Types: Nucleic acids (viral RNA), proteins (flagellin, pilin), lipids (LPS, lipotechoic acid), carbohydrates (mannan, glucans, peptidoglycan).

Opsonization

• Definition: The coating of pathogens with opsonins (e.g., antibodies, complement proteins) to enhance phagocytosis.
• Process:
  • Tagging: Antibodies mark the pathogen for destruction.
  • Recognition: Macrophages recognize the antibody's Fc region.
  • Engulfing: The macrophage binds and engulfs the pathogen.
  • Killing: The pathogen is destroyed inside the macrophage.

Phagosome Maturation

• Phagosome Formation: The phagocyte engulfs the microbe within a phagosome, a large endosome.
• Early Endosome Fusion: The phagosome interacts with early endosomes, which deliver maturation proteins.
• Late Endosome Fusion: Further fusion with late endosomes leads to acidification (pH decrease).
• Lysosome Fusion: The phagosome fuses with lysosomes to create a phagolysosome. Lysosomes contain lytic enzymes and generate ROS for microbial kill.

Microbial Killing and Digestion

• Phagolysosome Contents: The acidic environment, lysosomal enzymes, and ROS destroy and break down microbes.

Debris Clearance

• Disposal: Digested or remaining waste is released or processed for antigen presentation to adaptive immune cells.

Macrophage Killing Mechanisms

• Acidification: Lowering of pH via H+ ATPase pumps.
• Reactive Oxygen Species (ROS): Hypochlorite (bleach), nitric oxide.
• Antimicrobial Peptides (AMPs): Defensins, cationic peptides for membrane disruption.
• Enzymes: Lysozyme degrades peptidoglycan.
• Nutrient Removal: Siderophores and nutrient transporters.

Signaling and Immune Gene Expression

• TLR Signaling: TLR engagement activates downstream signaling, typically involving the transcription factor NF-κB.
• NF-κB Activation: Leads to increased expression of immune response genes, promoting AMP production, enhancing phagocyte killing, inducing cytokine production, and stimulating inflammatory mediators.