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Innate Immunity: Anatomical and Physical Barriers

Learning Objectives

  • Describe and understand the mechanisms of protection of anatomical and physical barriers against pathogens in different organs/systems.
  • References cited: Day’s Veterinary Immunology, Principles and Practice, Chapter 3; Veterinary Immunology book, Chapter 22.

Organization of the Immune System

  • Innate immunity (First line of defense, non-specific)
    • Immediate, non-antigen specific response
    • Non-antigen dependent
  • Adaptive immunity (Second line of defense, specific)
    • Antigen-specific response
    • Delayed in time
    • Generates memory (with exceptions)
  • Overall structure:
    • Innate immunity → First line of defense (non-specific)
    • Adaptive immunity → Second line of defense (specific)
    • Cellular component and Humoral component contribute to both arms

Innate Immunity vs Adaptive Immunity

  • Innate immunity (Non-specific):
    • Immune response is not dependent on the antigen
    • Response is immediate
    • Does not typically leave memory (exceptions exist)
  • Adaptive immunity (Specific):
    • Immune response is antigen-specific
    • Response is delayed
    • Immune response leaves memory

What is Innate Immunity?

  • Natural or native immunity
  • Present from birth
  • Protects the organism from injury or infection without prior contact with the infectious agent
  • Especially active at primary contact sites: skin, respiratory tract, gastrointestinal tract, urogenital tract, mammary gland, ocular mucosa

Innate Immunity: Three Major Lines of Defense

  • 1st line: Mechanical and chemical barriers (Skin, mucous membranes, chemicals)
  • 2nd line: Nonspecific cellular and humoral defenses (Phagocytosis, complement system, interferon, inflammation, fever)
  • Adaptive immunity (3rd line): Specific defenses (Lymphocytes, antibodies)
  • Overall framework: Three major lines of defense

Innate Immunity: Phases of Initial Response to Infection

  • Infection occurs
  • Recognition by preformed, non-specific and broadly specific effectors
  • Inflammation and recruitment/activation of effector cells
  • Transport of antigen to lymphoid organs
  • Recognition by naïve B and T cells (adaptive activation)
  • Clonal expansion and differentiation to effector cells
  • Removal of infectious agent
  • Timeline:
    • Early immediate innate response: 0-4\,\text{hours}
    • Early induced innate response: 4-96\,\text{hours}
    • Adaptive immune response: >96\,\text{hours}

Innate Immunity: Physical Barriers, Humoral Barriers, Cellular Barriers, and Commensals

  • Physical barriers: Skin and mucous membranes
  • Humoral barriers: Complement system, antibacterial enzymes
  • Cellular barriers: Phagocytic system, natural killer (NK) cells
  • Commensal organisms contribute to barrier function

Innate Immunity: Physical Barriers and Anatomical Sites

  • Mechanical barriers
  • Chemical barriers
  • Microbiological barriers (normal flora)
  • Key anatomical sites: Skin, Gut, Lungs, Eyes/Nose, Reproductive and Mammary Tracts, Urinary Tract
  • Specific features per site discussed below

Skin: Mechanical, Chemical, and Microbiological Factors

  • Acts as a continuous physical barrier; keratinized epidermis
  • Mechanical factors: dense epidermis, shedding of cells
  • Chemical factors: secretions (sebum, sweat) with antimicrobial properties
  • Microbiological factors: cutaneous microflora (commensal bacteria)
  • Phagocytic cells present within the dermal microenvironment
  • Role: prevents entry and removes microbes

Mucus and Mucociliary Clearance (Respiratory Tract)

  • Respiratory tract lined with mucociliary epithelium; ciliated columnar cells
  • Ciliary movement drives mucus and particulates toward oropharynx for swallowing/clearance (mucociliary escalator)
  • Antimicrobial secretions from mucosal glands
  • Leukocytes resident in lamina propria contribute to defense
  • Electron microscopy shows cilia structure (illustrative)

Other Innate Respiratory Defenses and Particle Deposition

  • Innate defenses protect the respiratory tract; particle size influences deposition site
  • Only the smallest particles can reach alveoli

Mucus and Mucociliary Clearance in Multiple Tracts

  • Respiratory, Digestive, and Reproductive tracts produce mucus
  • Mucus coats epithelial layers to prevent microorganism attachment
  • Mucociliary clearance aids removal of inhaled or ingested pathogens
  • Ciliary dyskinesia (e.g., in dogs) reduces clearance and increases susceptibility to respiratory infections

Mucus: Protective Coating Across Tracts

  • Secretion of large amounts of mucus creates a viscous barrier
  • Mucus plus mucociliary clearance prevents microbial attachment
  • Additional notes on secretions contributing to barrier function in various tracts

Chemical Factors in Innate Immunity

  • Fatty acids present in sweat inhibit bacterial growth
  • Lysozyme and phospholipase in tears, saliva, nasal secretions inhibit microbes
  • Low pH of sweat and gastric juice provides antibacterial effects
  • Surfactants in lungs can act as opsonins to enhance phagocytosis
  • Additional antimicrobial peptides contribute to chemical defense

Secretions and Barrier Chemicals

  • Gastric mucosa secretes HCl with ext{pH} \le 2
  • Bile and pancreatic secretions contain detergents that disrupt microbes
  • Physical flushing of secretions (milk, saliva, tears, urine) removes microbes from mammary gland, mouth, eyes, and urinary tract

Secretions from Epithelial and Endothelial Cells

  • Skin: Sebaceous gland secretion (sebum) provides a hydrophobic, acidic environment
  • Lysozyme: antimicrobial protein found in tears, saliva, milk, and intestinal mucus
  • Defensins and cathelicidins: cationic peptides that disrupt microbial membranes
  • Lactoferrin: sequesters iron, inhibiting bacterial growth
  • Lactoperoxidase: generates reactive oxygen species that damage microbes

Paneth Cells and Intestinal Defensins

  • Paneth cells in the intestine (e.g., horse example) contain large eosinophilic granules rich in defensins
  • Major source of intestinal defensins, contributing to gut barrier defense

Defensins Mechanism of Action

  • Defensins insert into microbial cell membranes (lipid bilayer)
  • Create extracellular pores, causing osmotic imbalance
  • Result: cytoplasmic contents leak, leading to cell lysis
  • Mechanistic overview: Cell membrane disruption leads to microbial death

The Role of Normal Flora in Excluding Pathogens

  • Normal bacterial flora compete with pathogens for nutrients and space
  • In the absence of normal flora, invading organisms face no competition and can colonize surfaces more readily
  • Probiotic supplementation introduces beneficial microbes to support barrier function
  • Commensals influence intestinal development and the adaptive immune response

Commensal Organisms and Examples

  • Commensal bacteria reside in digestive, respiratory, and reproductive tracts
  • In healthy animals, these bacteria do not cause disease
  • Common examples include Lactobacillus species such as Lactobacillus acidophilus
  • Commensals contribute to barrier function and overall host health

The Wide Diversity of Innate Surface Protection Mechanisms

  • Turbulence and mechanical removal (e.g., sneeze, coughing, blinking, desquamation)
  • Sneezing, coughing, vomiting as reflexive clearance mechanisms
  • Lacrimal (tears) and saliva provide antimicrobial factors
  • Desiccation and desquamation remove surface cells that may harbor microbes
  • Fatty acids, normal flora, mucus, cilia contribute to barrier function
  • Acidic environments and enzymatic/antimicrobial components (lysozyme, defensins, proteases)
  • Diarrhea as a flushing defense in the intestinal tract

Innate Immunity: Commensal Organisms (Organ-Specific Summary)

  • Reproductive Tract: low pH as a barrier
  • Upper Respiratory Tract: trapping and removal of particulates in mucus
  • Trachea/Bronchi: mucus production and ciliary clearance; coughing as a clearance mechanism
  • Intestinal Tract: rapid changes in pH, lysozyme, bile acids, peristalsis, defensins, hydrolases, mucus
  • Skin: keratinized barrier; desiccation and desquamation contribute to defense
  • Cornea and Conjunctiva: protection via tear components (lysozyme) and surface barriers
  • Lacrimal Secretions: lysozyme and other antimicrobial components
  • Mammary Gland: keratin plug; flushing; antibacterial environment
  • Flushing mechanisms: mucociliary clearance, urine flow, etc.
  • Complement system, lysozyme, lactoferrin, lactoperoxidase, fatty acids, and low pH contribute across sites
  • Urinary Tract: unidirectional flushing reduces microbial colonization

Additional Notes on Key Components

  • Lysozyme: enzymatic breakdown of bacterial cell walls, especially peptidoglycan
  • Defensins: small cationic peptides forming pores in microbial membranes
  • Cathelicidins: another family of antimicrobial peptides with membrane-disrupting activity
  • Lactoferrin: iron-binding protein limiting bacterial growth due to iron deprivation
  • Lactoperoxidase: converts hydrogen peroxide and halides to reactive halogen species damaging microbes
  • Paneth cell defensins: critical source of antimicrobial peptides in the gut
  • HCl (gastric acid) and bile/pancreatic detergents: create harsh chemical environments hostile to microbes

Conceptual Connections and Practical Implications

  • Innate barriers determine initial infection outcome and influence subsequent adaptive responses
  • Disruption of barriers (e.g., ciliary dysfunction, low sebum production, altered flora) increases infection risk
  • Probiotics can support barrier function and modulate immune development
  • Understanding barrier components informs disease prevention, vaccine strategies, and antiseptic/antibiotic use

Ethical, Philosophical, and Practical Implications

  • Emphasis on the balance between host defenses and resident microbiota raises questions about antibiotic stewardship and microbiome preservation
  • Probiotic use should consider host species, strain specificity, and ecological impact on native flora
  • Animal welfare considerations in managing infections at barrier sites (skin, mucosa, ocular surfaces) require humane and evidence-based approaches

Key Formulas and Numerical References

  • Time course of innate vs adaptive responses:
    • 0-4\,\text{hours}: immediate innate response
    • 4-96\,\text{hours}: early induced innate response
    • >96\,\text{hours}: adaptive immune response
  • Gastric pH barrier:
    • \text{pH} \le 2 (gastric HCl) as an antimicrobial barrier
  • Other numeric notes (illustrative from slides but not needed for calculation):
    • Skin area approximation (human): about 2\,\text{m}^2
    • References to specific organisms (e.g., Lactobacillus acidophilus) as examples of commensals

Summary Takeaways

  • The innate immune system provides rapid, non-specific defense via physical, chemical, and microbiological barriers across all body surfaces
  • These barriers function in an integrated, multi-layered fashion to prevent infection and shape subsequent adaptive responses
  • Normal flora plays a crucial role in excluding pathogens, training the immune system, and supporting barrier integrity
  • Disruption of barrier components can lead to increased susceptibility to infections, illustrating the importance of maintaining healthy barrier function and microbiota balance