Innate (Non-Specific) Immunity - Study Notes

Introduction to the Immune System

The immune system is a complex, coordinated network designed to recognize and respond to non-self antigens. Its primary functions include the recognition and elimination of cells that are diseased, damaged, distressed, or dying. The system is split into two complementary branches:

1. Innate Immune System: The first line of defense against invading organisms.
2. Adaptive Immune System: The second line of defense, which also provides protection against re-exposure to the same pathogen.

Both subdivisions utilize cellular and humoral components to execute their protective functions.

Fundamental Differences: Innate vs. Adaptive Immunity

Anatomical and Physiological Barriers to Infection

Anatomical barriers represent the first physical and chemical hurdles a pathogen must overcome to establish an infection.

Mechanical Factors

• Skin and Epithelial Surfaces: These form a physical barrier that is largely impermeable to most infectious agents.
• Cilia and Peristalsis: Movement generated by cilia in the air passages or peristalsis in the gastrointestinal tract helps keep these areas free of microorganisms.
• Flushing Action: The movement of tears and saliva prevents infections in the eyes and mouth, respectively.
• Mucus Trapping: Mucus lining the respiratory and gastrointestinal tracts traps pathogens to protect the lungs and digestive systems.

Chemical Factors

• Fatty Acids: Located in sweat, these inhibit bacterial growth.
• Lysozyme and Phospholipase: Found in tears, saliva, and nasal secretions; these enzymes can break down bacterial cell walls and destabilize bacterial membranes.
• Low pH: The acidic environment of sweat and gastric secretions prevents bacterial growth.
• Defensins: Low molecular weight proteins with antimicrobial activity found in the lungs and gastrointestinal tract.
• Surfactants: Functional proteins in the lung that act as opsonins.

Biological Factors

• Normal Flora: Commensal microorganisms on the skin and in the gastrointestinal tract prevent the colonization of pathogenic bacteria by competing for resources and space.

Humoral Barriers to Infection

If physical barriers are breached, humoral (soluble) factors in the serum or at the site of infection initiate the innate defense mechanism known as acute inflammation.

• Complement System: The primary humoral non-specific defense mechanism. Activation leads to increased vascular permeability, recruitment of phagocytic cells, and the lysis and opsonization of bacteria.
• Coagulation System: Activated based on the severity of tissue damage. Products of this system increase vascular permeability and act as chemotactic agents.     * Beta-lysin: A protein produced by platelets during coagulation that acts as a cationic detergent to lyse many Gram-positive bacteria.
• Lactoferrin and Transferrin: These proteins sequester iron, an essential nutrient for bacteria, thereby limiting bacterial growth.
• Interferons (IFNs): Proteins that limit viral replication within host cells.
• Lysozyme: Functions by breaking down the bacterial cell wall.
• Interleukin-1 (IL-1): Induces fever and the production of acute-phase proteins, some of which are antimicrobial opsonins.

Cellular Components of Innate Immunity

Neutrophils (Polymorphonuclear cells / PMNs)

• Identification: Identified by a characteristic lobed nucleus or the cell surface antigen CD66.
• Function: Motile cells recruited to infection sites to phagocytose and kill organisms intracellularly.
• Granule Contents:     * Cationic proteins and defensins (bactericidal).     * Proteolytic enzymes (e.g., elastase, cathepsin G) to break down proteins.     * Lysozyme (cell wall degradation).     * Myeloperoxidase: Involved in generating bacteriocidal compounds.
• Side Effects: Can contribute to collateral tissue damage during the inflammatory process.

Macrophages and Monocytes

• Identification: Monocytes have a kidney-shaped nucleus and the surface marker CD14. They differentiate into tissue macrophages.
• Components: They lack traditional granules but possess numerous lysosomes containing materials similar to PMN granules.
• Functions:     * Phagocytosis and intracellular killing.     * Extracellular killing of infected or altered self target cells.     * Tissue repair.     * Acting as Antigen-Presenting Cells (APCs).

Natural Killer (NK) and Lymphokine Activated Killer (LAK) Cells

• Function: Kill virus-infected cells and tumor cells non-specifically via apoptosis.
• Role: Important for tumor surveillance and non-specific viral immunity, though not typically part of the standard inflammatory response.
• Receptors: NK cells employ two types: Killer Activating Receptor (KAR) and Killer Inhibiting Receptor (KIR).
• Regulation: Activity is increased by interferons and IL-12.

Eosinophils

• Contain specialized proteins in granules effective at killing certain parasites.

Phagocytosis and the Inflammatory Response

The Inflammatory Process

1. Vascular Activation: Starts with the activation of the vascular endothelium at the site of the breach.
2. Mediator Release: Tissue damage releases cytokines and inflammatory mediators.
3. Adhesion: Selectin-type adhesion molecules are expressed on epithelial cells, allowing neutrophils to bind and extravasate into the tissue. This is followed by monocytes and macrophages.

Response of Phagocytes (SOS Signals)

Phagocytes respond to danger signals including:

• N-formyl-methionine containing peptides released by bacteria.
• Clotting system peptides.
• Complement products.
• Cytokines from tissue macrophages.

These signals stimulate endothelial cells to express adhesion molecules like ICAM-1 and selectins. Vasodilators facilitate the passage of phagocytes across the endothelial barrier.

Stages of Phagocytosis

1. Chemotaxis: Movement of phagocytic cells toward the antigen.
2. Engulfment: Extension of pseudopodia around the material.
3. Phagosome Formation: Fusion of pseudopodia to trap the material.
4. Phagolysosome Formation: Fusion of the phagosome with a lysosome.
5. Digestion: Break down of the material.
6. Exocytosis: Release of digested contents.

Opsonization and Killing

• Opsonization: The process where antigens are coated by antibodies or complement components. Since macrophages and neutrophils have membrane receptors for these, phagocytosis is enhanced by $4000 \times$ (4K fold).
• Intracellular Killing:     * Respiratory Burst: A metabolic process activating membrane-bound oxidase to generate oxygen metabolites (oxygen-dependent mechanism).     * Oxygen-independent mechanism: Uses lysosomal degradative materials.

Systemic Inflammation and Cytokine Action

Systemic inflammation is driven primarily by IL-1, TNF-\alpha, and IL-6. These cytokines have several systemic targets:

• Hypothalamus: Targeted by IL-1 and TNF-\alpha; induces Prostaglandins leading to Fever.
• Liver: Targeted by IL-1, TNF-\alpha, and IL-6; induces production of Acute-phase proteins such as C-reactive protein (CRP), mannose-binding protein, and complement components.
• Bone Marrow: Targeted by IL-1, TNF-\alpha, and IL-6; induces Leukocytosis.

Innate Response to Viruses

There are two primary mechanisms for handling viral infections:

1. Interferons (IFN-\alpha and IFN-\beta): Produced by infected cells. They act on target cells to inhibit viral replication and protein synthesis (they do not act on the virus directly).
2. NK Cells: Kill virally infected cells by inducing apoptosis.

Bridging Innate and Adaptive Immunity

Migration to Secondary Lymphoid Tissue

Following the acute response, professional APCs (like Dendritic Cells) leave the tissue via lymphatic vessels. Pro-inflammatory cytokines change the phagocyte phenotype and migration pattern.

• Activated Dendritic Cells (DCs): Begin expressing the chemokine receptor CCR7.
• Chemokines: Produced by the endothelium, these bind to CCR7, allowing DCs to exit the tissue and head to draining lymph nodes.
• Functional Shift: DCs switch from antigen-capture to antigen-presentation and become trapped in the paracortex of the lymph node.
• T Cell Interaction: Naïve T cells expressing CCR7 bind chemokines on High Endothelial Venules (HEVs) to migrate to the paracortex.

Antigen-Presenting Cells (APCs)

Antigen Processing Pathways

• Endogenous Pathway: Handles intracellular threats (viruses, tumors). Peptides are transported through the TAP complex (transporter of antigen processing). Tapasin bridges the TAP transporter to the MHC class I molecule. Complexes are presented to CD8+ T cells.
• Cross-Presentation: A process where dendritic cells can ingest infected cells and present viral antigens via Class I MHC to CD8+ T cells even if the DC itself is not infected.