9.2 Cellular Immunity in the Periodontium

2. Cellular Innate Defence: The Neutrophil Cascade

Polymorphonuclear leukocytes (neutrophils / PMNs) are the primary cellular defence of the periodontium, recruited continuously from the post-capillary venules of the dentogingival plexus.

[Circulating PMN] 
       │ (Selectin-mediated: L-selectin, P-selectin, E-selectin)
       ▼
[Endothelial Rolling] 
       │ (Chemokine Activation: CXCL8, LTB4, C5a)
       ▼
[Firm Arrest & Adhesion] 
       │ (Beta-2 Integrins: LFA-1 [CD11a/CD18], Mac-1 [CD11b/CD18] binding ICAM-1)
       ▼
[Transendothelial Diapedesis] 
       │ (PECAM-1 / CD31)
       ▼
[Haptotactic Migration through Junctional Epithelium]
       │ (Phagocytosis, Degranulation, NETosis)
       ▼
[Microbial Clearance in the Gingival Crevice]

Stepwise Neutrophil Extravasation

1. Tethering and Rolling: Low-affinity transient interactions between endothelial P-selectin (CD62P, translocated from Weibel-Palade bodies) and E-selectin (CD62E, upregulated by IL-1 and TNF-α) and their leukocyte ligands, primarily Sialyl Lewis X (sLe^x / CD15s) and PSGL-1. Leukocyte L-selectin (CD62L) binds endothelial carbohydrates.
2. Chemokine Triggering and Integrin Activation: Chemokines displayed on the luminal endothelial glycocalyx—chiefly CXCL8 (IL-8), leukotriene LTB4, and complement fragment C5a—bind leukocyte G-protein-coupled receptors. This triggers an "inside-out" signalling cascade that converts low-affinity β2-integrins into a high-affinity extended conformation.
3. Firm Adhesion (Arrest): Activated β2-integrins—LFA-1 (Lymphocyte Function-Associated Antigen-1; CD11a/CD18) and Mac-1 (Macrophage-1 antigen; CD11b/CD18)—bind firmly to endothelial ICAM-1 (CD54) and ICAM-2.
4. Diapedesis (Transmigration): Neutrophils crawl through endothelial intercellular junctions via homophilic binding of PECAM-1 (CD31) and junctional adhesion molecules (JAMs), penetrate the perivascular basement membrane via release of matrix-degrading collagenases, and follow the CXCL8 gradient through the junctional epithelium.

Phagocytosis and Oxidative Killing

Upon entering the gingival sulcus, neutrophils recognize bacteria directly via pathogen recognition receptors (PRRs) or through opsonisation:

• Opsonins: Host IgG antibodies (recognized by FcγRIIa / CD32 and FcγRIIIb / CD16) and complement split products C3b and iC3b (recognized by Complement Receptor 1 [CR1 / CD35] and CR3 [Mac-1 / CD11b/CD18]).
• Respiratory Burst: Engulfment into a phagosome triggers assembly of the multi-component NADPH oxidase enzyme complex (gp91phox, p22phox, p47phox, p67phox, and Rac2) at the phagosomal membrane. NADPH oxidase transfers electrons to molecular oxygen, generating the superoxide anion (O₂•⁻):

NADPH + 2 O₂ ➔ (NADPH Oxidase) ➔ NADP⁺ + H⁺ + 2 O₂•⁻

Superoxide is rapidly converted to hydrogen peroxide (H₂O₂) by superoxide dismutase (SOD). Subsequently, myeloperoxidase (MPO), released from azurophilic granules, combines H₂O₂ with chloride ions (Cl⁻) to yield hypochlorous acid (HOCl), a potent microbicidal oxidant identical to household bleach:

H₂O₂ + Cl⁻ + H⁺ ➔ (Myeloperoxidase) ➔ HOCl + H₂O

Neutrophil Extracellular Traps (NETs / NETosis)

In addition to intracellular phagocytosis, neutrophils undergo NETosis—a regulated form of neutrophil death wherein decondensed chromatin decorated with antimicrobial granular proteins (histones, neutrophil elastase, MPO, and calprotectin) is extruded into the extracellular space. In the periodontal pocket, NETs physically entrap spirochaetes and non-motile anaerobes, preventing tissue invasion. However, excessive or prolonged NET formation combined with impaired enzymatic clearance contributes to host collateral tissue destruction.

Leukocyte Adhesion Deficiencies (LAD)

Inherited defects in neutrophil recruitment highlight the absolute necessity of functional PMNs in periodontal homeostasis:

• LAD Type 1 (LAD-1): Autosomal recessive disorder caused by mutations in the ITGB2 gene on chromosome 21, encoding the CD18 subunit common to all β2-integrins (LFA-1, Mac-1, p150,95). Because neutrophils cannot synthesize functional heterodimers, they fail to achieve firm adhesion to endothelial ICAM-1 and cannot extravasate into tissues.
  • Clinical hallmarks: Classic history of delayed separation of the umbilical cord (>3 weeks), persistent and marked peripheral blood neutrophilia (since PMNs remain trapped in the circulation), recurrent necrotic skin infections that characteristically fail to form pus, and rampant, aggressive, generalised periodontitis beginning immediately upon deciduous tooth eruption, culminating in early complete edentulism.
• LAD Type 2 (LAD-2): Caused by mutations in the SLC35C1 gene, encoding a GDP-fucose transporter. The resulting lack of fucosylated carbohydrate ligands (Sialyl Lewis X / CD15s) leads to failure of selectin-mediated rolling. Manifestations include severe periodontitis, growth retardation, intellectual disability, and the Bombay blood phenotype.

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3. Adaptive Immunity in the Periodontium

When innate defences fail to clear subgingival biofilm challenge, adaptive immunity is engaged. Antigen-presenting cells (APCs)—including intraepithelial Langerhans cells (CD1a+, containing racquet-shaped Birbeck granules), interstitial dendritic cells, and macrophages—internalise periodontal antigens, process them into peptides, and present them via MHC Class II molecules to naive CD4+ T helper (Th0) cells in regional cervical lymph nodes.

T-Helper Subsets in Periodontal Pathology

The B-Cell / Plasma Cell Transition (Page & Schroeder Model)

Roy Page and Hubert Schroeder (1976) defined four progressive stages in the histopathogenesis of periodontal disease:

1. Initial Lesion (2–4 days of plaque accumulation): Subclinical vasculitis in the dentogingival plexus beneath the junctional epithelium. Increased GCF flow; extensive transmigration of neutrophils across the JE into the sulcus; loss of perivascular collagen (~5–10% loss).
2. Early Lesion (4–7 days): Classic acute gingivitis. Marked lymphoid infiltrate occupying up to 15% of the connective tissue, dominated by T lymphocytes (~75%, primarily CD4+ Th1 cells) with minimal B cells. Cytotoxic alteration of junctional epithelial cells and lateral proliferation of rete pegs; approximately 60–70% of collagen destroyed in the infiltrated zone.
3. Established Lesion (2–3 weeks): Chronic gingivitis. A pivotal cellular transition occurs: the lesion becomes dominated by B lymphocytes and plasma cells (accounting for 10–30% of the infiltrate). Pocket epithelium forms with micro-ulcerations, but there is no loss of connective tissue attachment and no alveolar bone resorption. This lesion can remain stable for months or years without progression.
4. Advanced Lesion (True Periodontitis): Conversion to irreversible, destructive disease. Plasma cells dominate (>50% of the inflammatory infiltrate). The junctional epithelium detaches from the enamel-cementum surface and migrates apically along the root surface, creating a true periodontal pocket. Extensive, irreversible destruction of the periodontal ligament (principal Sharpey's fibres) and resorption of alveolar bone.

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