ADAPTIVE IMMUNITY IN PERIODONTAL DISEASE

Long Note for Post-Graduate Examination

INTRODUCTION

BRIDGE BETWEEN INNATE AND ADAPTIVE IMMUNITY

• DCs residing in gingival tissue recognize microbial antigens via Toll-like receptors (TLRs) and Pattern Recognition Receptors (PRRs)
• Upon recognizing PAMPs (pathogen-associated molecular patterns) such as LPS, peptidoglycans, bacterial DNA, and lipoproteins, DCs mature and travel to regional lymph nodes
• During migration, DCs upregulate MHC class II molecules and present processed antigen to CD4+ T helper cells
• The type of antigen and co-stimulatory signals received during TLR activation determine which T cell subset is polarized, thereby shaping the quality of the adaptive response

T LYMPHOCYTES IN PERIODONTAL DISEASE

1. CD4+ T Helper Cells (Th cells)

Th1 Cells

• Produce IL-2 and IFN-γ (interferon-gamma)
• Non-susceptible subjects to periodontal disease show increased Th1 activation (Bártová et al., 2000)
• IFN-γ exerts a protective role by preventing RANKL signaling and consequently suppressing osteoclastogenesis (Takayanagi et al., 2000)
• IFN-γR2 expression is significantly elevated in endothelial cells of gingival tissue in chronic periodontitis patients, correlating with disease severity (Franco-Topete et al., 2018)
• However, recent evidence suggests Th1 cells, along with Th17, are more abundant in chronic periodontal disease — implying a dual role (Chen et al., 2016)

Th2 Cells

• Produce IL-4, IL-5, IL-6, IL-10, IL-13, and TNF-α
• Predominate in subjects with established periodontitis compared to non-susceptible individuals (Bártová et al., 2000)
• IL-10 has a counter-regulatory role; however, the overall Th2 skewing promotes antibody production and B cell activation

Th17 Cells — Key Pathogenic Subset

• Produce the pro-inflammatory cytokine IL-17
• IL-17 is critical in periodontitis pathogenesis:
  • Aggravates gingival tissue inflammation
  • Promotes alveolar bone loss
  • Induces expression of RANKL, IL-1β, and TNF-α
  • Facilitates osteoclast differentiation and bone resorption in vitro and in vivo (Song et al., 2019)
• Studies in rhesus monkeys showed overexpression of Th17 versus Treg (Th17/Treg axis imbalance) at the onset of periodontal disease, with progressive Th17 dominance as periodontitis advances (Ebersole et al., 2014)
• In Wistar rat models, the evolution from gingivitis to periodontitis correlates with increased Th1 lymphocytes and increased IL-17 (Sommer et al., 2019)
• The primary cytokines from both Th1 and Th17 promote TNF-α and IL-1β production, which activate NF-κB pathway → RANKL upregulation → osteoclast activation → bone resorption (Monasterio et al., 2018)

Regulatory T Cells (Treg)

• Suppress: cytokine release, T cell proliferation, and innate responses
• Play a protective role — suppress excess inflammation and limit tissue damage in periodontal disease (Wang et al., 2014)
• Th17/Treg axis is critical: when Th17 dominates over Treg, disease progresses
• Therapeutic strategies targeting Treg expansion (e.g., all-trans retinoic acid) suppress experimental periodontitis by modulating the Th17/Treg imbalance

2. CD8+ T Cells (Cytotoxic T Cells)

• CD8+ T cells are believed to play a suppressive/regulatory role in periodontal disease
• CD8+ regulatory T cells (CD8+Foxp3+) affect alveolar bone homeostasis by:
  • Reducing osteoclastogenesis
  • Modulating the local immune response
  • Affecting Treg/Th17 balance
• Adoptive transfer experiments in Sprague-Dawley rats demonstrated that CD8+ Treg cells protect alveolar bone in healthy and periodontitis-induced animals (Han et al., 2018a)

B LYMPHOCYTES AND HUMORAL IMMUNITY IN PERIODONTAL DISEASE

Functions of B Cells

1. Antibody secretion — B cells differentiate into plasma cells, producing antibodies against periodontal pathogens. This helps eliminate bacteria and limits disease progression in the early chronic phase.
2. Cytokine production — Plasma cells secrete TNF-α, IL-6, IL-10, and matrix metalloproteinases (MMPs). While IL-10 is anti-inflammatory, the MMPs and pro-inflammatory cytokines contribute to periodontal tissue degradation.
3. Memory B cell function — Memory B cells may participate in long-term antigen-specific responses.

Dual Role of B Cells: Protective and Destructive

• In the chronic phase, B cells help control the infection by stopping disease progression — a protective role (Zouali, 2017)
• However, gingival tissue memory B cells promote osteoclastogenesis by producing RANKL, thereby driving alveolar bone erosion independently of antibody production during periodontitis (Han et al., 2018b)
• TNF-α produced by plasma cells can further induce RANKL expression on T and B cells, amplifying bone destruction
• B cells thus have a complex, context-dependent role — both limiting and perpetuating periodontal destruction

THE RANKL/OPG AXIS: KEY EFFECTOR MECHANISM OF ADAPTIVE IMMUNITY-MEDIATED BONE LOSS

• Th1 and Th17 cytokines (TNF-α, IL-1β, IL-17) → upregulate RANKL expression
• TNF-α can directly induce T and B cells to produce RANKL
• LPS/TLR4 interaction on macrophages/DCs → upregulates TNF-α and IL-6 → stimulates RANKL
• RANKL binds RANK on osteoclast precursors → activates mature osteoclasts
• Osteoclasts degrade alveolar bone via resorption lacunae through pH gradient mechanism
• IFN-γ (Th1-derived) inhibits RANKL signaling — a counter-regulatory mechanism
• OPG/RANKL ratio determines net bone loss or preservation

CYTOKINE NETWORK IN ADAPTIVE IMMUNITY OF PERIODONTAL DISEASE

Bacterial antigens → DCs → T cell activation
                               ↓
           ┌──────────────────┼──────────────────┐
          Th1               Th17               Treg
       IFN-γ, IL-2        IL-17, TNF-α       IL-10, TGF-β
           ↓                  ↓                   ↓
   Inhibits RANKL      ↑RANKL, IL-1β       Suppresses 
   (protective)         (destructive)      inflammation
                              ↓                (protective)
                        B cells → Plasma cells
                              ↓
                    Antibodies + RANKL + MMPs
                              ↓
                    RANKL → RANK → Osteoclasts
                              ↓
                     ALVEOLAR BONE RESORPTION

ADAPTIVE IMMUNITY IN GINGIVITIS vs. PERIODONTITIS

SUMMARY TABLE: KEY CELLS AND THEIR CONTRIBUTIONS

CLINICAL IMPLICATIONS

1. Th17/Treg imbalance as a therapeutic target — agents promoting Treg (e.g., all-trans retinoic acid) reduce experimental periodontitis
2. Anti-TNF-α therapy reduces RANKL expression and osteoclastogenesis — relevant to patients with periodontitis and RA/diabetes
3. OPG supplementation or anti-RANKL biologics (e.g., denosumab) represent potential adjuncts to periodontal therapy
4. IFN-γ holds promise as an immunomodulatory agent given its RANKL-inhibiting properties
5. B cell-targeted therapies (rituximab, B cell depletion) are being explored for severe periodontitis with autoimmune overlap

CONCLUSION