1.5 General Pathology, Inflammation & Immunity Concepts

General Pathology, Inflammation & Immunity Concepts

NBDHE Core Concept: Understanding the vascular and cellular sequences of inflammation, chemical mediator cascades, complement activation, hypersensitivity mechanisms, and autoimmune pathology is essential for recognizing oral mucosal diseases and understanding periodontal destruction.

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1. Vascular Response & Hemodynamic Events in Acute Inflammation

Acute inflammation is the immediate, non-specific vascular and cellular response to tissue injury or pathogen invasion. The vascular sequence occurs in predictable hemodynamic steps:

Injury ──► Transient Vasoconstriction ──► Vasodilation (Hyperemia) ──► Permeability Increase ──► Exudation & Stasis

Hemodynamic Sequence

1. Transient Vasoconstriction: Lasts only seconds; neurogenic reflex protecting against blood loss.
2. Arteriolar Vasodilation: Induced by vasoactive mediators (histamine, bradykinin, prostaglandins). Causes increased blood flow to the injured area (active hyperemia), responsible for two cardinal signs: Rubor (redness) and Calor (heat).
3. Increased Vascular Permeability: Endothelial cells contract, creating intercellular gaps in post-capillary venules. Protein-rich fluid (exudate) escapes into extravascular tissue, causing Tumor (swelling/edema).
4. Stasis & Hemoconcentration: Loss of fluid concentrates red blood cells in vessels, slowing blood flow and allowing leukocytes to marginate along vessel walls.
5. Pain & Loss of Function: Dolor (pain) is triggered by pressure from edema and direct nerve stimulation by bradykinin and prostaglandin E2 ($PGE_2$). Combined symptoms result in Functio Laesa (loss of function).

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2. Cellular Events, Extravasation & Phagocytosis

The cellular phase is dominated by Polymorphonuclear Neutrophils (PMNs) during the first 24–48 hours, followed by Macrophages.

Leukocyte Extravasation Cascade

1. Margination: PMNs move from central axial stream to peripheral vessel walls.
2. Rolling & Pavementing: PMNs roll along endothelium via weak, transient binding of Selectins (E-selectin, P-selectin on endothelium; L-selectin on PMN).
3. Firm Adhesion: PMNs firmly bind to endothelial cell surface via Integrins (LFA-1, MAC-1 on PMN binding to ICAM-1 and VCAM-1 on endothelium).
4. Transmigration (Diapedesis): PMNs squeeze through endothelial junctional gaps into tissue spaces, mediated by PECAM-1 (CD31).
5. Chemotaxis: Unidirectional migration of PMNs along a chemical gradient toward the injury site. Key chemoattractants include C5a, Leukotriene B4 ($LTB_4$), Interleukin-8 (IL-8), and bacterial N-formyl peptides.

Phagocytosis & Intracellular Killing

• Opsonization: Pathogens are coated with Opsonins (IgG antibodies and C3b complement fragments) to facilitate recognition by PMN surface receptors.
• Engulfment & Killing: PMN extends pseudopods to form a phagosome, which fuses with lysosome forming a phagolysosome.
  • Oxygen-Dependent Killing: Most potent mechanism; mediated by Myeloperoxidase (MPO) producing hypochlorous acid ($HOCl$) from hydrogen peroxide ($H_2O_2$) and chloride.
  • Oxygen-Independent Killing: Mediated by lysozyme, defensins, and lactoferrin.

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3. Acute vs Chronic Inflammation & Granulomatous Patterns

Granulomatous Inflammation

A specialized pattern of chronic inflammation characterized by microscopic aggregates of epithelioid histiocytes (modified macrophages) surrounded by a collar of lymphocytes and multinucleated Langhans giant cells (fused macrophages with horseshoe ring nuclei). Classic examples include tuberculosis, sarcoidosis, foreign body reactions, and deep fungal infections.

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4. Chemical Mediators & Complement System

Key Inflammatory Mediators

• Vasoactive Amines: Histamine (released by mast cells and basophils; causes immediate vasodilation and vascular permeability).
• Arachidonic Acid Metabolites:
  • Cyclooxygenase (COX) Pathway: Produces Prostaglandins ($PGE_2$ causes pain and fever; $TXA_2$ causes vasoconstriction/platelet aggregation). NSAIDs and aspirin inhibit COX-1/COX-2.
  • Lipoxygenase (LOX) Pathway: Produces Leukotrienes ($LTB_4$ causes PMN chemotaxis; $LTC_4$, $LTD_4$, $LTE_4$ cause bronchospasm and increased permeability).
• Cytokines: TNF-alpha and IL-1 drive systemic acute phase response (fever, leukocytosis).
• Kinins: Bradykinin causes potent vasodilation, non-vascular smooth muscle contraction, and pain.

The Complement Cascade

A system of plasma proteins circulating in inactive forms, activated via three pathways:

1. Classical Pathway: Triggered by antigen-antibody complexes (IgG or IgM bound to antigen).
2. Alternative Pathway: Triggered directly by bacterial endotoxins (LPS) and cell wall polysaccharides.
3. Lectin Pathway: Triggered by mannose-binding lectin binding microbial carbohydrates.

Essential Complement Cleavage Products

• C3a & C5a (Anaphylatoxins): Trigger mast cell degranulation, releasing histamine.
• C5a: Potent chemotactic factor attracting PMNs to injury site.
• C3b: Major opsonin coating microbes for phagocytosis.
• C5b–C9 (Membrane Attack Complex / MAC): Forms transmembrane pores in bacterial cell walls, causing osmotic lysis.

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5. Hypersensitivity Reactions (Types I–IV) & Autoimmune Oral Disease

Coombs and Gell classified hypersensitivity reactions into four immunological types:

Autoimmune Oral Mucosal Manifestations

1. Pemphigus Vulgaris: Autoantibodies target Desmoglein-3 (intraepithelial desmosomes). Causes intraepithelial acantholysis (suprabasal split). Clinical presentation: fragile bullae that rupture into painful erosions; positive Nikolsky sign (sloughing of tissue upon gentle pressure); Tzanck cells on cytology.
2. Mucous Membrane Pemphigoid (Cicatricial): Autoantibodies target hemidesmosomes (BP180 in basement membrane). Causes subepithelial split (entire epithelium detaches from lamina propria). Clinical presentation: thick-walled bullae, desquamative gingivitis, negative Nikolsky sign, scarring of ocular and oral mucosa.
3. Sjögren's Syndrome: Autoimmune destruction of exocrine glands. Triad of xerostomia, keratoconjunctivitis sicca (dry eyes), and rheumatoid arthritis. Diagnostic markers: anti-SSA (Ro) and anti-SSB (La) autoantibodies.