Innate Immune System - Lecture Notes

Innate Immune System

• The human body is a nutrient-rich source of energy for microbes.
• The innate immune system is what we are born with.

Branches of Innate Defenses

• Three major branches:
  • Security walls.
  • Security cameras.
  • Security teams.

Walls

• Skin.
• Mucous membranes.
• Antimicrobial substances.

Mucous Membranes

• Epithelial layers of:
  • Digestive tract.
  • Respiratory Tract.
  • Urogenital tract.
  • Eyes.
• Barriers of entry for microbes from the external environment.

Antimicrobial Substances

• Salt:
  • Generated by sweat.
  • Creates a hyperosmotic environment, preventing microbial growth.
• Lysozyme:
  • Found in tears and saliva.
  • Breaks down peptidoglycan in bacterial cell walls.
• Peroxidase: Enzyme with antimicrobial properties.

Sensor Systems

Pattern Recognition Receptors (PRRs)

• Membrane-bound proteins, like antennas in cell membranes.
• Recognize pathogen-associated molecular patterns (PAMPs).

Pathogen-Associated Molecular Patterns (PAMPs)

• Examples of patterns exclusively bacterial:

  • Lipopolysaccharide (LPS).
  • Peptidoglycan.
  • Flagellin (protein in bacterial flagella).

• Function as security cameras mounted on cell surfaces to detect foreign invaders.

Types of Receptors

• Toll-like receptors (TLRs):
  • Embedded in membranes.
• Nod-like receptors (NLRs):
  • Reside inside the cell.
  • Detect intracellular pathogens like replicating viruses.
• RIG-like receptors (RLRs):
  • Deals with viruses.

Interferon

• Protein synthesized by virus-infected cells.
• Does not help the initially infected cell (sacrificed).
• Diffuses to neighboring cells.
• Triggers transcription of antiviral proteins (AVPs) in neighboring cells.
• AVPs remain inactive until viral invasion.
• Upon activation, AVPs destroy viral DNA/RNA.
• The cell undergoes apoptosis to prevent further infection.

Complement System

• Complements the adaptive immune system.
• Proteins circulate in the blood and bathing tissues.
• Numbered in order of discovery (C1-C9).
• C3 is a key protein that splits into C3a and C3b.

Activation Pathways

• Three pathways lead to the formation of C3 convertase, which splits C3.

Classical Pathway

• Activated by antibodies bound to antigens.
• Antigens are molecules that provoke an immune response.
• Antibodies (Y-shaped proteins) bind to antigens on pathogens.
• Antibodies binding to microbial invaders triggers a reaction that leads to the formation of C3 convertase.

Role of C3

• C3 convertase splits C3 into C3a and C3b.
• C3a leads to an inflammatory response (blood vessels dilate and become leaky).
• White blood cells leave blood vessels and go to the site of injury or inflammation.
• C3b combines with C3 convertase to form an enzyme that splits C5.
• C5 further increases the inflammatory response and can split into C5a and C5b.

Membrane Attack Complex (MAC)

• C5b becomes part of the MAC.
• MAC attacks the membranes of pathogens.
• C3b results in opsonization, where C3b molecules coat the pathogen surface.
• Opsonization facilitates engulfment (phagocytosis), by phagocytic cells.

Outcomes of Complement System

1. Inflammatory response.
2. Membrane attack complex (MAC).
3. Opsonization.

Classical Pathway Summary

• Triggered by antibodies binding to a foreign pathogen.
• Leads to activation of the inflammatory response, causing blood vessels to dilate.
• White blood cells rush to the insulted area.
• Membrane attack complex forms pores in bacterial cells, making them susceptible to lysis.
• Opsonization covers pathogens in sticky C3b, leading to engulfment by phagocytic white blood cells.

Other Pathways

• Alternative pathway: Triggered by C3b binding directly to microbial invaders.
• Lectin pathway: Mannose-binding lectins (MBLs) bind to mannose on microbial cells, interacting with complement components.

Three Major Outcomes Review

1. Opsonization: C3b binds to bacterial cells and foreign particles, promoting engulfment by phagocytes.
2. Inflammatory Response: C5a attracts phagocytes to the area, C3a and C5a increase blood vessel permeability.
3. Lysis of Foreign Cells: Membrane attack complexes (MAC) create pores, leading to cell lysis.

Phagocytosis

• Process by which immune cells engulf invading pathogens.

Steps of Phagocytosis

1. Chemotaxis:
   • Phagocytes are recruited by chemoattractants secreted by microorganisms.
   • Movement in the direction of a chemical stimulant.
2. Recognition and Attachment:
   • Direct binding to mannose on the cell surface.
   • Opsonization: Recognition of the sticky C3b coating the cell.
3. Engulfment:
   • Pseudopods surround and form a phagosome.
   • Phagosome: A compartment inside the cell made up of the membrane from the surface of this phagocytic cell.
4. Phagosome Maturation and Phagolysosome Formation:
   • Endosomes fuse.
   • pH lowers (acidification).
   • Lysosomes bring enzymes.
5. Destruction and Digestion:
   • Toxic reactive oxygen species (ROS) and nitric oxide are produced.
   • pH continues to decrease.
   • Enzymes from lysosomes degrade the organic molecules of the bacterial cell.
   • Defensins damage the invader's membrane.
   • Lactoferrin ties up iron.
6. Exocytosis:
   • Phagosome fuses with the plasma membrane, expelling digested material.

Macrophages

• Scavengers and sentinel cells derived from monocytes.
• Can live for weeks or months and regenerate lysosomes.
• Always present in tissues.
• Possess toll-like receptors (TLRs) to detect pathogen-associated molecular patterns (PAMPs).
• Activated upon binding, increasing their power.
• Examples of PAMPs: flagellin, lipopolysaccharide, and mannose.

Neutrophils

• Provide a rapid response.
• Move into an area and eliminate invaders.
• Play a critical role in the early stages of inflammation (first responders).
• Lifespan of 1-2 days.
• Kill microbes via phagocytosis and release of granule content.
• Granules contain hydrolytic enzymes and reactive oxygen species.
• Can release DNA to form neutrophil extracellular traps (NETs).

Neutrophil Extracellular Traps (NETs)

• Neutrophils release their DNA and contents to form entrapment nets.
• Catch and immobilize microbes, allowing digestive enzymes to destroy invading cells.

Tissue Damage and Inflammation

• Purpose of inflammation: to contain the site of damage and localize the response.
• Swelling: Due to increased permeability of vessels.
• Redness: From core blood rushing to the site infection.
• Heat: Core blood is warmer.
• Pain and sometimes loss of function.
• Pattern recognition receptors (PRRs) can trigger inflammation.

Inflammatory Response Steps

1. Bacteria are introduced into the system.
2. Chemotaxis is induced.
3. Pro-inflammatory chemicals cause blood vessels to become leaky.
4. Neutrophils move to the site of infection (diapedesis).
5. Phagocytic cells engulf and destroy the pathogen.
6. Macrophages ingest dead cells and debris.
7. The inflammatory response subsides.

Inflammatory Response Cascade

• Blood vessels dilate, creating greater blood flow and leakage of fluids.
• White blood cells move to the tissues (Diapedesis).
• Endothelial cells grab phagocytes and slow them down.
• Clotting factors wall off the site of infection.
• Dead neutrophils and tissue debris accumulate as pus.

Types of Inflammation

• Acute Inflammation: Short term, mainly by neutrophils and macrophages.
  • Clean up damage by ingesting dead cells and debris.
• Chronic Inflammation: Results if acute inflammation fails.
  • Macrophages can differentiate into giant cells.
  • Granulomas form, walling off digested material, debris, and organisms resistant to destruction.

Granulomas

• Macrophages, giant cells, and T cells form granulomas.
• Prevent escape but can interfere with normal tissue function.

Fever

• Innate defense response.
• The set point of the internal thermostat is raised higher than 98.6°F.
• A strong indicator of infectious disease (typically bacterial).
• Triggered by pyrogens (inflammatory molecules that generate heat).

Pyrogens

• Cytokines (endogenous pyrogens) are produced by macrophages after detection by toll-like receptors.
• Raise the body's temperature set point.

Effects of Fever

• Most bacteria are mesophiles (grow optimally at 37°C).
• Fever creates unfavorable environment for mesophilic bacteria.
• Moderate temperature rise increases rates of enzyme reactions.
• Enhances the inflammatory response and phagocytic killing.
• Increases lactoferrin function, stealing iron away from bacterial cell.