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.