Innate Immune Responses - Part II

Chapter 3: Innate Immune Responses - Part II

I. Introduction

• Innate Immunity

  • Acts immediately to eliminate pathogens without disease development in the host.

  • If overwhelmed, bypassed, or evaded by pathogens, it necessitates adaptive immune responses.

II. The Inflammatory Response

• Inflammation

  • Caused by physical or chemical insults or infections with microorganisms.

  • Acute Inflammation

  • Short duration, initial response to infectious agents.

  • Causes minimal tissue damage to the host.

  • Chronic Inflammation

  • Longer duration (months to years) in the presence of persistent infectious agents.

  • Characterized by activated macrophages and T cells.

  • Often leads to significant tissue destruction due to continuous release of:

    • Oxygen metabolites

    • Nitric oxide (NO)

    • Proteases by inflammatory cells.

  • Further details covered in Chapter 12: Immune Responses to Pathogens - Part II.

Example of Inflammatory Response

• Illustrated through a scenario of a cut finger infected with bacteria.

Figure 3.1: The Inflammatory Response

• Bacterial infection triggers a series of responses by:

  • Activation of the alternative complement pathway.

  • Stimulation of tissue-resident macrophages that detect bacterial-derived Pathogen-Associated Molecular Patterns (PAMPs).

  • Recruitment of additional innate cells and proteins to eliminate the infection.

Steps in the Inflammatory Response

Step 1: Recognition of Bacteria

• Tissue resident macrophages immediately recognize bacteria in the wound.

• Phagocytic Pattern Recognition Receptors (PRRs):

  • Bind to bacterial structures triggering phagocytosis.

  • Toll-like Receptors (TLRs) bind to PAMPs.

  • Initiates a signaling cascade activating transcription factor NF-κB.

  • NF-κB activation transcribes genes encoding several pro-inflammatory cytokines:

    • Tumor Necrosis Factor Alpha (TNF-α)

    • Interleukin-1 (IL-1)

    • Interleukin-6 (IL-6).

    • TNF-α, IL-1, and IL-6 promote inflammatory responses.

  • Chemokine CXCL8 (IL-8) serves as a chemoattractant guiding phagocytic cells to the infection site.

Step 2: Initiation of the Inflammatory Response

• Initiation by tissue-resident macrophages and mast cells upon tissue injury:

  • Mast Cells Release Histamine and Inflammatory Molecules:

  • Histamine causes blood vessel dilation, increasing blood flow.

  • Results in redness and heat at the site.

  • Cytokines from Macrophages:

  • Act on blood vessel walls, increasing permeability and inducing adhesion molecule expression on endothelial cells.

  • Increased vascular permeability allows:

    • Leakage of fluid, complement proteins, coagulation proteins, antibodies, and cells (neutrophils and monocytes) into tissues.

    • Accumulation of fluid causes swelling and pain.

  • Adhesion Molecules:

  • Allow leukocytes (neutrophils and monocytes) to adhere to endothelial cells of blood vessels and extravasate into tissues.

Step 3: Recruitment of Phagocytes

• Large numbers of neutrophils and monocytes are recruited within hours post-infection detection.

• Phagocytosis Process:

  • Neutrophils immediately begin to phagocytose bacteria.

  • Monocytes must mature into macrophages to effectively phagocytose.

  • When bacteria are phagocytosed, they are enclosed in a membrane-bound vesicle known as a phagosome.

  • The phagosome is acidified and fuses with membrane-bound granules (lysosomes) forming a phagolysosome.

  • Within the phagolysosome, several agents kill and degrade bacteria:

  • Nitric oxide (NO)

  • Superoxide anion (O2–)

  • Hydrogen peroxide (H2O2)

  • Cationic peptides (defensins)

  • Proteases.

Figure 3.2: Phagocytosis and Killing of Pathogens

• Macrophages and neutrophils express several surface receptors that bind microbes for subsequent phagocytosis.

• Microbes ingested into phagosomes that fuse with lysosomes to form phagolysosomes, where they are killed by enzymes and toxic substances produced therein.

Step 4: Activation of Repair Mechanisms

• Clotting Mechanisms and Skin Repair activated to:

  • Wall off the infection site

  • Immobilize the bacteria.

Step 5: Formation of Pus

• Pus consists of:

  • Aggregation of macrophages, neutrophils, and skin cells (both live and dead)

  • Dead and dying bacteria

  • Plasma (fluid component of blood).

III. Summary

• Key Characteristics of Innate Immune Response:

  • Fast, non-specific, triggered by components of pathogens.

  • Pathogens recognized as foreign or non-self through PAMPs, which bind to PRRs on immune cells, causing phagocytosis and cytokine production.

  • Inflammation begins after tissue damage.

  • Histamine from mast cells increases blood vessel permeability.

  • Cells, proteins, and fluid leak into tissues, causing swelling.

  • Macrophages activated by pathogens release alarm cytokines and recruit more blood-derived cells.

  • Macrophages and neutrophils phagocytose and destroy pathogens.

  • Coagulation proteins seal off inflamed areas, complement activation increases recruitment, phagocytosis, and destruction of pathogens.