Kuby Immunology Eighth Edition - Chapter 4: Innate Immunity

Kuby Immunology, Eighth Edition - Chapter 4: Innate Immunity

Chapter Overview

• Copyright: 2019 by W. H. Freeman and Company

• Authors: Punt, Stranford, Jones, Owen

• Presentation format: Lecture PowerPoint

Anatomical Barriers to Infection

• Types: Physical and chemical barriers exist to prevent pathogens from accessing deep tissues.

  • Physical barriers: Epithelial layers of skin and mucosal/glandular tissues.

  • Chemical barriers: Acidic pH, antimicrobial proteins, and peptides.

• Innate Immune System Activation: If barriers are breached, pathogen-associated molecular patterns (PAMPs) on microbes are recognized.

  • DAMPs: Damaged self-structures can also be recognized.

  • PRRs: Pattern recognition receptors recognize both PAMPs and DAMPs for clearance.

Key Components and Responses of Innate Immunity

1. Physical and Chemical Barriers

   • Skin and mucosal membranes form the first line of defense.

   • Antimicrobial substances: Produce antimicrobial proteins and peptides.

2. Cellular Responses

   • Phagocytic cells: Macrophages and dendritic cells are involved in pathogen elimination by phagocytosis.

   • Natural Killer (NK) cells: Kill infected cells and secrete cytokines to modulate immune responses.

3. Activation of Adaptive Immune Responses

   • T-cell responses, antibody production, and cytokine/chemokine signaling.

   • Cell activation leads to increased inflammation and pathogen elimination.

Comparison of Innate and Adaptive Immunity

• Table 4-1: Key Attributes

  Attribute	Innate Immunity	Adaptive Immunity
  Response Time	Minutes to hours	Days
  Specificity	Specific for PAMPs and DAMPs	Highly specific to minor differences
  Diversity	Limited, germ line-encoded receptors	Highly diverse due to gene recombination
  Memory Responses	Some memory observed	Persistent memory observed
  Self/Non-self Discrimination	Good discrimination	Occasional failure leads to autoimmune disease
  Soluble Components	Antimicrobial peptides, proteins, cytokines	Antibodies, cytokines
  Major Cell Types	Phagocytes, NK cells, leukocytes, epithelial cells	T cells, B cells, antigen-presenting cells

Innate Mechanisms Protecting Various Organs

• Organ or Tissue: Examples of innate mechanisms in different body locations:

  • Skin: Antimicrobial peptides, fatty acids in sebum.

  • Mouth & Upper Alimentary Canal: Enzymes and directional fluid flow.

  • Stomach: Low pH and digestive enzymes.

  • Small & Large Intestine: Normal flora and fluid flow for microbial competition.

  • Airway & Lungs: Cilia that expel mucus and macrophages in alveoli.

  • Urogenital Tract: Flushing by urine and mucus, low pH.

  • Salivary, Lacrimal, & Mammary Glands: Antimicrobial peptides and proteins.

Epithelial Barriers

• Epithelial layers prevent pathogen entry into the body:

  • Produce protective substances: acidic pH, enzymes, and binding proteins.

  • Example: Lysozyme in mucosal/glandular secretions disrupts bacterial cell walls.

Cellular Responses and PRRs

• PRRs recognize PAMP ligands such as:

  • TLRs (Toll-like receptors)

  • CLRs (C-type lectin receptors)

  • RLRs (RIG-I-like receptors)

  • NLRs (NOD-like receptors)

Toll-like Receptors (TLRs)

• Structural Features: Dimers with extracellular LRR domains.

• Function: Recognize various pathogen molecules.

• Microbial Ligands and TLRs Mapping:

  TLR	Ligand(s)	Microbes
  TLR1	Triacyl lipopeptides	Mycobacteria, Gram-negative bacteria
  TLR2	Peptidoglycans, GPI-linked proteins	Gram-positive bacteria, fungi
  TLR3	dsRNA	Viruses
  TLR4	LPS, Mannans	Gram-negative bacteria, RSV, VSV
  TLR5	Flagellin	Bacteria
  TLR7	ssRNA	Viruses
  TLR8	ssRNA	Viruses

Signaling Pathways of TLR Activation

• TLR binding activates specific signaling pathways which include:

  • NF-κB Activation: Transcription of pro-inflammatory cytokines.

  • IRF Pathways: Stimulating type I interferon production.

  • MAP Kinase Pathways: Induces various cellular responses.

Induced Cellular Innate Responses

• Activation pathways lead to synthesis of antimicrobial peptides, type I interferons, cytokines (IL-1, IL-6, TNF-α), chemokines, and enzymes (iNOS, COX2).

Phagocytosis

• Defined as the engulfment and internalization of materials, especially microbes.

  • Process Overview:

  1. Microbe binds to PRR on phagocyte.

  2. Formation of a phagosome.

  3. Fusion of the phagosome with Lysosomes.

  4. Death of the microbe through degradation.

Inflammatory Responses

• Triggered by tissue damage and presence of pathogens. Includes:

  • Increased vascular permeability and fluid influx to the site of infection.

  • Recruitment of neutrophils and phagocytes for destruction of pathogens.

Natural Killer (NK) Cells

• Function: Innate lymphocytes that recognize and kill altered self-cells via perforin and granzymes, and produce cytokines to enhance adaptive immunity.

Regulation and Evasion of Responses

• Importance: Regulation is central to avoid inflammatory conditions or defects in response.

• Pathogen Evasion Strategies: Include mutations preventing PAMP detection and blocking PRR signaling.

Summary of Innate Immunity

• Understanding immunity requires knowledge of anatomical barriers, pathogen recognition, cellular responses, and signaling pathways leading to effective immune responses.