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Innate Immunity & Inflammation – Lecture Review

Innate Immunity – General Framework

  • Innate vs. Adaptive
    • Innate (nonspecific) = inborn, always present, no prior exposure needed.
    • Adaptive = acquired after exposure; based on learning & memory.
  • Pathogen = any harmful agent
    • Living: bacteria, archaea, parasites (e.g., helminths).
    • Non-living: viruses (non-cellular), prions (misfolded proteins).
    • Even non-infectious particles (e.g., pollen) may trigger innate responses (allergy).

Physical (Mechanical) Barriers – “1st Line of Defense”

  • Skin
    • Epidermis built of keratinocytes; superficial layers = dead, keratin-filled, tightly packed → formidable wall.
    • Keratin-rich secretions add waterproofing / antimicrobial effects.
  • Mucous membranes
    • Line all entry tubes (respiratory, gastrointestinal, urogenital).
    • GI lumen is still “outside” until absorption occurs; epithelial tissue & mucus coat keep contents from internal milieu.
    • Mucociliary escalator (trachea): ciliated epithelium sweeps mucus + trapped debris upward for swallowing/expulsion; failure in cystic fibrosis due to faulty Cl⁻ channels.
  • Flushing & Filtration mechanisms
    • Tears and saliva: wash surfaces; contain antimicrobial chemicals.
    • Guard hairs of nose/ear block entry.
    • Urinary “trickle” mechanically flushes urogenital tract to discourage colonization.
  • Cilia – mechanical sweeping in airways.

Chemical Barriers

  • Low pH Environments
    • Stomach gastric juice: \text{pH} \approx 1–3 (would burn skin).
    • Vaginal canal: acidic secretions (protective microflora, lactic acid).
  • Lysozyme
    • Enzyme in tears, saliva, mucus, neutrophil granules.
    • Hydrolyzes bacterial peptidoglycan cell wall → lysis.
  • Defensins
    • Small cationic peptides that insert in microbial membranes → pore formation & death.
  • General characteristic: nonspecific; act against broad spectrum, not tailored to a single pathogen.

Genetic Deterrents & Evolutionary Adaptations

  • Sickle-cell trait vs. malaria
    • Sickle Cell Anemia: homozygous recessive; lethal complications.
    • Sickle Cell Trait: heterozygous carriers (one recessive allele) → distorted RBCs appear under low O₂, hinder Plasmodium life-cycle → resistance to malaria.
    • Illustrates regional selection (equatorial zones with high mosquito burden).

The Human Microbiome (Commensal/Symbiotic Flora)

  • > Not an official immune organ but critical adjunct.
    • Diverse bacteria, archaea, viruses, yeasts, molds living on skin, GI, urogenital, etc.
    • We supply nutrients & habitat; microbes secrete toxins/competitors that limit pathogenic invasion.
    • Microbial outnumbering of host cells; mutualism contributes to baseline defense.

Innate Immune Cells (Leukocytes)

  • Overview
    • Leukocytes = WBCs.
    • Two leukocyte sub-groups (T & B lymphocytes) belong primarily to adaptive immunity; others listed below are key for innate.

  • Neutrophils
    • ≈ 70\% of circulating WBCs in healthy adults; ≈ 25\text{ billion} in circulation at any given moment.
    • Lifespan ≈ 2 days; rapidly replenished.
    • Functions: phagocytosis, degranulation releasing lysozyme & defensins, early inflammation.

  • Monocytes / Macrophages
    • Monocytes circulate; when they leave blood ⇒ tissue-resident macrophages.
    • Potent phagocytes; also Antigen-Presenting Cells (APCs) – bridge to adaptive immunity by displaying pathogen peptides to T cells.

  • Basophils / Mast Cells
    • Basophils in blood; mast cells permanent in tissues.
    • Release histamine (vasodilation), chemokines → recruit WBCs.
    • Important in parasitic infections & allergies.

  • Eosinophils
    • Combat parasites (helminths); contribute to allergic responses.

Pathogen Recognition – PAMPs vs. Self

  • Self-Markers (surface proteins) identify host cells—normally prevent attack.
  • PAMPs (Pathogen-Associated Molecular Patterns)
    • Conserved molecular motifs on microbes (e.g., LPS, flagellin, dsRNA).
    • Innate cells have pattern-recognition receptors (PRRs) to detect PAMPs → activation cascade.
  • Failure of distinction ⇒ autoimmune disease (self-attack).

Inflammation – Central Innate Response

  • Primary Goals
    1. Eradicate/eliminate intruding pathogen.
    2. Block spread (wall-off).
    3. Mobilize/attract immune cells (chemotaxis) & initiate tissue repair.
  • Classic Signs: redness, heat, swelling (edema), pain, loss of function.

Molecular & Vascular Events (Illustrated with Infected Big Toe)

  • Baseline Circulation
    • Arteriole → Capillary (exchange, small pores) → Venule → Vein → Heart.

  • Stage 1 – C-Reactive Protein (CRP) Release
    • Macrophages + endothelial cells secrete cytokines → liver synthesizes & releases CRPs.
    • CRP levels clinically measured; chronic elevation ↔ cardiovascular risk (systemic inflammation).

  • Stage 2 – Hemodynamic Changes
    • Venule vasoconstriction ⇒ ↑ upstream pressure, slows outflow ("damming").
    • Arteriole histamine-induced vasodilation (from basophils/mast cells) ⇒ ↓ resistance, ↑ inflow.
    • Result: capillary bed engorgement – more blood & WBCs delivered.

  • Stage 3 – Increased Capillary Permeability
    • Histamine + other mediators widen endothelial gaps (like enlarging “soaker-hose” holes).
    • Allows otherwise excluded plasma proteins (> size cutoff) to exit.
    – Antibodies (immunoglobulins) – part of adaptive defense, now reach tissue.
    – Fibrinogen (inactive clotting factor) – precursor to fibrin barrier.

  • Stage 4 – Exudation & Edema
    • Plasma that leaves vessels = exudate; once accumulated in tissue, swelling = edema (edematous exudate).
    • Contains WBCs (neutrophils, monocytes → macrophages), antibodies, complement, clotting factors.

  • Stage 5 – Wall-Off Effect (Containment)
    • Fibrinogen → fibrin mesh around infection focus.
    • Creates physical barrier restricting pathogen spread.
    • Strength of wall correlates with pathogen toxin potency; stronger toxins → stronger containment attempts.

  • Stage 6 – Cellular Recruitment & Positive Feedback
    • Chemokines/cytokines secreted by resident & arriving cells (mast cells, macrophages, neutrophils).
    • Chemotaxis “breadcrumb trail” brings more leukocytes.
    • Phagocytosis, degranulation, respiratory burst destroy invaders; debris removed by macrophages.

  • Stage 7 – Resolution & Repair
    • After clearance, anti-inflammatory mediators dampen response.
    • Fibroblasts, growth factors restore damaged tissue architecture.

Practical / Clinical Connections

  • CRP Blood Test – marker for systemic inflammation & cardiovascular disease risk.
  • Histamine Blockers (antihistamines) for allergy symptom relief (reduce vasodilation/permeability).
  • Autoimmune disorders – dysregulation of self vs. PAMP recognition.
  • Cystic Fibrosis – defective mucociliary escalator → impaired mechanical barrier.

Key Numerical & Terminology Recap

  • 25\text{ billion} circulating neutrophils; \approx 70\% of WBC count.
  • Innate chemical pH barrier: \text{pH} < 7 (acidic) lethal to many microbes.
  • Heterozygous sickle-cell carriers = malaria resistance.
  • Exudate = plasma + proteins + WBCs in tissue; edema = swelling produced.
  • PAMPs = “Pathogen-Associated Molecular Patterns”; PRRs = Pattern-Recognition Receptors.

Integrative Perspective

  • Innate immunity sets the stage: slows pathogen, buys time, signals adaptive arm.
  • Many components (e.g., macrophages) straddle both innate & adaptive (antigen presentation).
  • Non-specific but highly effective through redundancy: physical, chemical, cellular, genetic, microbial allies.