Leukocytes are the body's defenders, rushing to infected areas through a complex process. They roll along blood vessel walls, stick tightly, then squeeze through to reach tissues. Chemical signals guide them to the infection site.

Once there, leukocytes use special receptors to spot invaders. They recognize common patterns on pathogens or tag them for easier detection. This triggers a rapid response, followed by a more targeted attack as the immune system adapts.

Leukocyte Migration and Pathogen Recognition

Leukocyte migration to infected tissues

• Leukocyte adhesion and migration involves several steps
  • Margination moves leukocytes to the periphery of blood vessels
  • Rolling adhesion loosely adheres leukocytes to endothelial cells via selectins (L-selectin, P-selectin)
  • Tight adhesion occurs when integrins on leukocytes bind to adhesion molecules on endothelial cells (ICAM-1, VCAM-1)
  • Diapedesis or transmigration squeezes leukocytes between endothelial cells to enter tissues (extravasation)
• Chemotaxis directs leukocytes along a concentration gradient of chemotactic factors towards the site of infection
  • Chemotactic factors include bacterial products (fMLP), complement proteins (C5a), and cytokines (IL-8, MCP-1)
  • Cytokines play a crucial role in orchestrating the inflammatory response and leukocyte recruitment

Mechanisms of pathogen recognition

• Pattern recognition receptors (PRRs) on leukocytes detect pathogen-associated molecular patterns (PAMPs)
  • Toll-like receptors (TLRs) recognize various PAMPs such as lipopolysaccharide (LPS), peptidoglycan, and viral RNA (TLR4, TLR2, TLR7)
  • C-type lectin receptors (CLRs) recognize fungal cell wall components such as β-glucan (dectin-1)
  • NOD-like receptors (NLRs) detect bacterial peptidoglycan components in the cytoplasm (NOD1, NOD2)
• Opsonization coats pathogens with opsonins making them more easily recognized by leukocytes
  • Antibodies (IgG) bind to pathogens and are recognized by Fc receptors on leukocytes (FcγRI, FcγRII)
  • Complement proteins (C3b) coat pathogens and are recognized by complement receptors on leukocytes (CR1, CR3)

Innate and Adaptive Immunity

• Innate immunity provides rapid, non-specific defense against pathogens
• Adaptive immunity develops more slowly but offers specific, long-lasting protection
• Inflammation is a key process in innate immunity, involving increased blood flow, vascular permeability, and leukocyte recruitment
• Antigen presentation by innate immune cells bridges innate and adaptive immunity, activating T cells

Phagocytosis and Pathogen Elimination

Steps of phagocytosis

1. Recognition and attachment: phagocytes recognize PAMPs or opsonized pathogens and bind to them via receptors (FcγR, CR, TLR)
2. Engulfment: phagocyte membrane extends around the pathogen, forming a phagosome (actin polymerization)
3. Phagosome-lysosome fusion: phagosome fuses with lysosomes to form a phagolysosome (acidification, hydrolytic enzymes)

• Pathogen elimination within phagolysosomes occurs through oxygen-dependent and oxygen-independent mechanisms
  • Oxygen-dependent mechanisms
    • Respiratory burst generates reactive oxygen species (ROS) such as superoxide anion ($O_2^-$), hydrogen peroxide (H2O2), and hypochlorous acid (HOCl) via NADPH oxidase
    • Nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) generates reactive nitrogen species (RNS)
  • Oxygen-independent mechanisms
    • Acidification of the phagolysosome (pH 4.5-5.0) creates an inhospitable environment for pathogens
    • Antimicrobial proteins and peptides such as lysozyme, defensins, and cathelicidins degrade bacterial components (peptidoglycan, membrane)
    • Proteolytic enzymes such as elastase and cathepsins degrade bacterial proteins