Innate Immunity: Components, Mechanisms, and Pathogen Recognition

The Hierarchy of the Immune System: Barriers and Lines of Defense

  • The First Line of Defense: Physical and Chemical Barriers

    • Physical Barriers:

      • Skin: Acts as the primary external barrier.

      • Mucus and Saliva: Traps and washes away potential invaders.

      • Vomiting: Acts as a mechanical expulsion mechanism to remove pathogens from the gastrointestinal tract.

    • Chemical Barriers:

      • Sebum: Secreted by the skin to inhibit microbial growth.

      • Lysozyme: An enzyme found in saliva and other secretions that breaks down bacterial cell walls.

      • Gastric Juice: Highly acidic environment in the stomach that destroys most swallowed pathogens.

    • Normal Flora:

      • Acts as a biological barrier by colonizing surfaces (occupying physical space).

      • Utilizes available nutrients to prevent pathogens from obtaining the resources they need to survive.

      • Produces antimicrobial substances capable of killing pathogens.

  • The Second Line of Defense: Innate Immunity

    • Activated when the first-line barriers are defeated or damaged.

    • Properties: Non-specific (responds identically to all pathogens) and acts very quickly.

    • Detection and destruction speed: Bacteria entering through a small wound can be detected and destroyed within a few hours.

  • The Third Line of Defense: Adaptive Immunity

    • A specialized response that differentiates based on the specific pathogen.

Properties and Activation of the Innate Immune System

  • System Activation Overview:

    • Specialized cells circulate in the blood and arrive at the site of infection.

    • Ingestion and Destruction (Phagocytosis): Cells engulf the pathogen and destroy it internally.

    • Extracellular Killing: Cells release toxic chemicals to kill pathogens without ingesting them.

White Blood Cells (Leukocytes) and Blood Composition

  • Blood Film Composition per Cubic Millimeter (mm3mm^3):

    • Red Blood Cells (RBCs): Approximately 5,000,0005,000,000 (5×1065 \times 10^6) cells.

    • White Blood Cells (WBCs): Approximately 4,0004,000 to 11,00011,000 cells.

    • Platelets: Approximately 150,000150,000 to 400,000400,000 units.

  • Leukocyte Types and Prevalence (as percentage of total WBCs):

    • Neutrophils: Approximately 60%60 \%.

    • Lymphocytes: Approximately 30%30 \% (includes NK cells, B-cells, and T-cells).

    • Monocytes: Approximately 8%8 \%.

    • Eosinophils: Approximately 2%2 \%.

    • Basophils: Less than 1%1 \%.

  • Size Comparisons:

    • Red Blood Cells: ∼7 μm\sim 7\,\mu m.

    • Neutrophils: 12−14 μm12-14\,\mu m.

    • Eosinophils: 12−17 μm12-17\,\mu m.

    • Basophils: 14−16 μm14-16\,\mu m.

    • Lymphocytes: Small lymphocytes are 6−9 μm6-9\,\mu m; activated lymphocytes (approx. 10%10 \%) are 10−14 μm10-14\,\mu m.

    • Monocytes: 16−20 μm16-20\,\mu m.

Granulocytes: Morphology and Specialized Functions

  • Neutrophils (Polymorphonuclear Leukocytes / PMN):

    • Morphology: Multi-lobed nucleus containing 33 to 55 lobes connected by fine threads. Cytoplasm lacks staining (granules do not pick up much stain).

    • Function: Primary defense against bacterial and fungal infections.

    • Killing Mechanism: Phagocytosis (engulfing the microbe and killing it internally).

  • Eosinophils:

    • Morphology: Bi-lobed nucleus (often obscured by granules). Cytoplasmic granules stain a bright orange-pink color.

    • Function: Defend against parasites.

    • Killing Mechanism: Extracellular release of granule contents to kill microbes outside the cell.

  • Basophils:

    • Morphology: Dense granules often obscure the nucleus; if visible, the nucleus is typically S-shaped. Granules stain a deep purple color.

    • Function: Releases histamine in response to infection.

    • Biological Impact: Histamine contributes directly to inflammation.

  • Mast Cells:

    • Origin: Derived from bone marrow; released into the blood but undergo terminal differentiation only after recruitment into tissues.

    • Localization: Found in skin and mucosal tissues, situated near small blood vessels and nerves.

    • Morphology: Variable shape with a round nucleus and cytoplasm filled with histamine granules.

    • Function: Expulsion of parasites, allergic reactions, and key players in the inflammatory response.

Non-Granular White Blood Cells

  • Monocytes:

    • Morphology: The largest WBCs in circulation. The nucleus is classically horseshoe-shaped, though it can be kidney-shaped or bean-shaped.

    • Life Cycle: Circulate in blood vessels, migrate to tissues, and differentiate into macrophages.

  • Macrophages (Mononuclear Phagocytes):

    • Transformation Process: Upon migrating from blood to tissue:

      1. The nucleus becomes more rounded.

      2. The cell increases in total size.

      3. The number of cytoplasmic granules and cellular enzymes increases.

      4. Phagocytic abilities increase significantly.

    • Residency: Some are permanent residents in normal tissues, while others transform from monocytes upon reaching an infection site.

  • Lymphocytes:

    • Morphology: Densely stained, round nucleus that fills nearly the entire cell, leaving only a thin rim of visible cytoplasm.

    • NK (Natural Killer) Cells: Part of the innate immunity. Contain granules with enzymes to kill tumor cells or virus-infected cells.

    • B and T Cells: Part of the adaptive immunity.

  • Dendritic Cells:

    • Origin: Formed as monocytes migrate from blood to tissue.

    • Morphology: Possesses projections that look like a neuron (though it is not a nerve cell).

    • Function: Ingests fragments of microorganisms via endocytosis and acts as the bridge/link to activate the adaptive immune response.

Mechanisms for the Elimination of Pathogens

  • Direct Pathogen Killing:

    • Phagocytosis: The process of ingesting microbes.

      1. Attachment: The phagocytic cell attaches to the pathogen.

      2. Ingestion: The pathogen is engulfed.

      3. Phagosome Formation: A vesicle containing the ingested microbe buds from the outer membrane.

      4. Phagolysosome Formation: Fusion of the phagosome with a lysosome containing digestive enzymes.

      5. Destruction: The pathogen is digested, forming a residual body.

      6. Elimination: Indigestible waste materials are expelled from the cell.

    • Granule Release: Releasing toxic chemicals extracellularly, specifically targeting parasites through eosinophils.

  • Elimination of Infected Host Cells (Natural Killer Cells):

    • Signaling Balance: NK cells utilize a balance between activating and inhibitory receptors.

    • Self-Recognition (MHC I): Normal healthy cells express Major Histocompatibility Complex Class I (MHC I). NK cell inhibitory receptors recognize MHC I and "switch off" the killing mechanism.

    • Targeting Logic: Cancer cells and infected cells often lose MHC I expression. Activating receptors recognize molecules on these cells and "switch on" the NK cell.

    • Cytotoxic Action: NK cells release granules containing Perforin and Granzymes.

      • Perforin: Forms pores in the target cell's membrane.

      • Granzymes: Enter through the perforin pores to induce lysis of the target cell.

The Physiological Process of Inflammation

  • Definition: A physiological reaction in host tissue caused by microbial invasion.

  • Symptoms: Redness, swelling, heat, and pain.

  • Triggers: Activation of macrophages, neutrophils, and mast cells, and the release of pro-inflammatory mediators.

  • Key Biological Steps:

    1. Injury and Infection: Bacteria penetrate the skin.

    2. Chemical Signaling:

      • Mast cells secrete histamine.

      • Endothelial cells and macrophages produce Nitric Oxide (NO).

      • Macrophages produce Cytokines, which are responsible for inflammatory reactions.

    3. Three Key Processes:

      • Vasodilation: Brings more blood to the damaged area.

      • Vascular Permeability: Blood vessels become "leaky," resulting in plasma leaking into the area.

      • Extravasation (Emigration): The process by which WBCs like neutrophils migrate out of the blood vessels (capillaries) and into the tissue site of infection.

    4. Resolution: Neutrophils and macrophages engulf bacteria; capillaries return to normal; tissue repair begins as the infection is controlled.

Pathogen Recognition: PAMPs and PRRs

  • Pathogen-associated Molecular Patterns (PAMPs):

    • Definition: Conserved molecular structures produced by microorganisms recognized as foreign by the innate immune system.

    • Key Characteristics: Specific to microorganisms, essential for pathogen survival, and never found in mammalian cells.

    • Specific Examples:

      • Lipopolysaccharides (LPS): Found on gram-negative bacterial cell walls.

      • Flagellin: A protein making up the filament of bacterial flagella.

      • Double-stranded RNA (dsRNA): Derived from viruses.

      • Unmethylated CpG motifs: Specific DNA sequences from bacteria (Cytosine followed by Guanine dinucleotide, lacking a methyl group).

  • Pattern Recognition Receptors (PRRs):

    • Localization: Strategically localized on the cell surface (for bacteria/fungi), in endosomes (for viral nucleic acids), or in the cytoplasm (for viral RNA replication intermediates).

    • Families of PRRs:

      1. Toll-like receptors (TLR)

      2. Nucleotide-binding oligomerization domain-like receptors (NLR)

      3. C-type lectin receptors (CLR)

      4. RIG-1 like receptors (RLR)

    • Ligand-Receptor Pairings:

      • LPS: Recognized by TLR4 (found on macrophages, dendritic cells, and neutrophils).

      • Flagellin: Recognized by TLR5 (found on macrophages and dendritic cells).

      • dsRNA: Recognized by TLR3 and RIG-I (found on macrophages and dendritic cells).

      • Unmethylated CpG motifs: Recognized by TLR9 (found on dendritic cells and B cells).