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HOST RESPONSE AND IMMUNITY AS RELATED TO PERIODONTAL HEALTH AND DISEASE

Postgraduate Periodontology — Comprehensive Theory Examination Notes

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SECTION 1: INTRODUCTION AND CONCEPTUAL FRAMEWORK

• The common periodontal diseases found in humans — gingivitis and periodontitis — are inflammatory responses in the periodontal tissues induced by microorganisms in dental plaque, which contribute to tissue destruction, bone loss, and eventually tooth loss. (Carranza's Clinical Periodontology, 10th Ed. [Carranza 10th], Chapter 12)
• The immune system is a network designed for the homeostasis of large molecules (oligomers) and cells based on specific recognition processes. Recognition of the structural features of an oligomer by receptors on immune cells is an important component of the specificity of the immune system. (Carranza 10th, Chapter 12)
• A landmark concept established in periodontal literature: although plaque bacteria initiate and perpetuate the inflammatory response, most of the tissue damage results from the host response, which is influenced by genetic factors as well as environmental and acquired risk factors. (Newman & Carranza's Clinical Periodontology and Implantology, 14th Ed. [Newman 14th], Chapter 8)
• The immune–inflammatory response is fundamental for determining which individuals may progress to developing periodontitis; it is likely that inflammatory responses vary between individuals who develop periodontitis as compared with those who never progress beyond gingivitis. (Newman 14th, Chapter 8)

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SECTION 2: CLASSIFICATION OF IMMUNE RESPONSES

2.1 Innate vs. Adaptive Immunity

Key concept (Newman 14th): "Innate immune responses are not 'switched off' once adaptive immunity is elicited, as there are reciprocal cross-activating and modulating influences; innate and adaptive immune responses are in fact a dynamic continuum."

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SECTION 3: HOST DEFENSE MECHANISMS IN PERIODONTAL HEALTH

3.1 Physical/Structural Barriers

1. Maintenance of an intact epithelial barrier (the junctional and sulcular epithelia)
   • Junctional epithelium: nonkeratinized; forms the floor of the sulcus; wraps around the tooth like a collar; wider at floor (15–30 cells thick), tapers apically to 3–4 cells thick; surface cells attach to the tooth through hemidesmosomes.
2. Outflow of GCF from the sulcus — dilution effect and flushing action
3. Sloughing of surface epithelial cells of the junctional and sulcular epithelia
4. Presence of neutrophils and macrophages in the sulcus to phagocytose bacteria
5. Presence of antibodies in the GCF (Newman 14th, Chapter 8)

3.2 Salivary Host Defense Mechanisms

• Secretory IgA (sIgA) — present in saliva; targets specific antigens; inhibits bacterial adherence to periodontal pathogens.
• Shear forces associated with saliva flow are important for preventing the attachment of bacteria. (Newman 14th, Chapter 8)

3.3 Epithelial Barrier — Active Role in Innate Immunity

• The epithelium is "more than simply a passive barrier: it also has an active role in innate immunity." (Newman 14th, Chapter 8)
• Antimicrobial peptides (AMPs) — also called defensins — are expressed by epithelial cells:
  • hBD-1 (human β-defensin-1) and hBD-2 (human β-defensin-2) are expressed by gingival epithelial cells
  • LL-37 (cathelicidin class AMP) — found in lysosomes of neutrophils; also expressed in gingiva
  • AMPs are important for determining outcomes of host–pathogen interactions at the epithelial barrier (Newman 14th, Chapter 8)
• Epithelial cells in the junctional and sulcular epithelia respond to bacterial products by secreting chemokines (e.g., IL-8, CXCL8) to attract neutrophils up the chemotactic gradient toward the pocket.

[Recent Terminology Note]: The term "MAMP" (Microbe-Associated Molecular Pattern) is now preferred alongside PAMP (Pathogen-Associated Molecular Pattern), as recognized by Pattern Recognition Receptors (PRRs). MAMPs are "molecules associated with microorganisms that activate innate immunity through specific signaling pathways." (Newman 14th, Chapter 8)

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SECTION 4: HISTOPATHOLOGICAL STAGES OF GINGIVAL LESION — PAGE AND SCHROEDER (1976)

A landmark study — Page and Schroeder (1976) described the histologic changes that occur in the gingival tissues as the initial, early, established, and advanced gingival lesions. (Newman 14th, Chapter 8; Carranza 10th, Chapter 20)

4.1 Flowchart: Progression of Periodontal Lesion

PLAQUE BIOFILM ACCUMULATION
          |
          v
  [INITIAL LESION]
  • Clinically healthy gingival tissues
  • Slightly elevated vascular permeability and vasodilation
  • GCF flows out of the sulcus
  • Migration of leukocytes (primarily NEUTROPHILS) in relatively small numbers
    through gingival connective tissue → across junctional epithelium → into sulcus
  • No clinical sign of inflammation (only detectable histologically)
          |
          v
  [EARLY LESION]
  • Corresponds with early gingivitis (evident clinically)
  • Increased vascular permeability, vasodilation, and GCF flow
  • Large numbers of infiltrating leukocytes (mainly NEUTROPHILS and LYMPHOCYTES)
  • Early lymphocytic infiltrate dominated by T CELLS (eventually B cells become dominant)
  • Degeneration of fibroblasts
  • Collagen destruction → collagen-depleted areas in connective tissue
  • Proliferation of junctional and sulcular epithelia into collagen-depleted areas
  • Junctional epithelium proliferates forming rete pegs
  • Early clinical signs: redness, bleeding; increased GCF flow
          |
          v
  [ESTABLISHED LESION]
  • Corresponds with established gingivitis
  • Dense inflammatory cell infiltrate (PLASMA CELLS, LYMPHOCYTES, NEUTROPHILS)
  • Predominance of PLASMA CELLS (B cell-dominated stage)
  • Accumulation of inflammatory cells in connective tissues
  • Elevated release of MATRIX METALLOPROTEINASES (MMPs) and lysosomal contents from neutrophils
  • Significant collagen depletion; proliferation of epithelium
  • Formation of pocket epithelium containing large numbers of neutrophils
  • Stage of TRANSITION from innate response to ACQUIRED IMMUNE RESPONSE
  • Clinically: moderate-to-severe gingivitis
          |
          v
  [ADVANCED LESION]
  • Marks TRANSITION FROM GINGIVITIS TO PERIODONTITIS
  • Predominance of neutrophils in pocket epithelium and pocket
  • Dense inflammatory cell infiltrate in connective tissues (primarily PLASMA CELLS)
  • Apical migration of junctional epithelium (to preserve intact epithelial barrier)
  • Continued collagen breakdown → large areas of collagen-depleted connective tissue
  • OSTEOCLASTIC RESORPTION of alveolar bone
  • IRREVERSIBLE tissue destruction: attachment loss, bone resorption, connective tissue degradation

Note from Carranza 10th: "Page and Schroeder report a predominance of plasma cells in the established lesion. Although several studies of human experimental gingivitis have failed to demonstrate plasma cell dominance, increases in the proportions of plasma cells are evident with long-standing gingivitis."

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SECTION 5: INNATE IMMUNITY IN PERIODONTAL DISEASE

5.1 Pattern Recognition Receptors (PRRs) — Key Concept

• PRRs are essential receptors of innate immunity. The term MAMP (Microbe-Associated Molecular Pattern) / PAMP refers to molecular patterns recognized by PRRs. (Newman 14th, Chapter 11)

5.2 Toll-Like Receptors (TLRs)

• TLRs represent a class of PRRs that recognize MAMPs (e.g., LPS) and signal cytokine secretion in innate cells. (Newman 14th)
• TLRs are found on dendritic cells, PMNs, and macrophages, among others, and have the ability to recognize structures known as pathogen-associated molecular patterns (PAMPs) that are highly conserved across a wide variety of pathogens.
• PAMPs include: lipopolysaccharide (LPS), peptidoglycan, bacterial DNA, double-stranded RNA, and lipoprotein. (Lindhe 6th, Chapter 13)

TLR-2 vs. TLR-4 — Differential Immune Responses:

Examiner Keyword: P. gingivalis LPS activates TLR-2 (not TLR-4 as with E. coli LPS) — this differential signaling may represent a mechanism of susceptibility to periodontitis.

5.3 NF-κB Pathway

• Ligand binding to TLRs triggers a signal transduction cascade involving recruitment of various adaptor proteins and kinases.
• MyD88 is an adaptor protein required for signaling by all TLRs, except TLR3 (which signals via TRIF).
• Downstream of MyD88: IRAK/TRAF6 and TAK1 activate NF-κB and MAP kinases, inducing expression of pro-inflammatory mediators and inflammasome proteins. (Newman 14th, Chapter 11)

5.4 NLRP3 Inflammasome

• NLRP3 inflammasome activation can be induced by various ligands (DAMPs, ROS, ATP).
• Results in assembly of a multi-protein complex including oligomerization of NLRP3, ASC, and pro-Caspase-1 proteins.
• Autoproteolytic cleavage of oligomerized pro-caspase-1 → activated (cleaved) caspase-1 → cleaves IL-1β and IL-18 into their biologically active forms.
• Also cleaves gasdermin-D, forming pores on the cellular membrane causing death by pyroptosis and allowing secretion of active IL-1β.
• A positive correlation exists between NLRP3 levels with IL-1β and IL-18 expression levels in periodontally diseased versus healthy tissues. (Newman 14th, Chapter 11)

5.5 NOD Receptors

• NOD1/NOD2 are cytosolic PRRs that recognize peptidoglycan fragments of the bacterial cell wall and can activate NF-κB and MAPK, signaling via Rip2. (Newman 14th, Chapter 11)

5.6 Complement System

Three Pathways of Complement Activation:

CLASSICAL PATHWAY                    LECTIN PATHWAY                ALTERNATIVE PATHWAY
(Antigen-antibody complex           (MBL + MASP complexes         (Spontaneous C3 hydrolysis
activates C1 complex)               recognize microbial surfaces)  "tick-over" mechanism)
           \                                  |                            /
            \                                 |                           /
             \________________________________|__________________________/
                                              |
                                   CONVERGENCE AT C3
                                              |
                            C3 → C3a + C3b (via C3 convertase)
                                /                       \
                     [C3a + C5a]                      [C3b]
                     Anaphylatoxins                    Opsonin
                     (promote inflammation             (opsonization
                     via G-protein-coupled             for phagocytosis)
                     receptors C3aR, C5aR1)
                           |                              |
                    Cross-talk with TLRs            Promotes phagocytosis
                    (Synergistic activation        
                    of inflammatory leukocytes)
                                              |
                                   [C5b-C9 MAC]
                             Membrane Attack Complex
                             (lyses susceptible bacteria;
                              also implicated in destructive
                              inflammation)

Complement Table (Selected Components):

Examiner Keyword: C5a is a chemotaxin (chemoattractant) for neutrophils; iC3b is an opsonin that enables phagocytes to ingest microorganisms.

• GCF in periodontal disease contains complement components C3, C3 proactivator (Factor B), and C4 — evidence of complement cleavage in gingival fluid. (Periodontics Medicine Surgery Implants [PMSI], Chapter 6 references)

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SECTION 6: NEUTROPHILS — THE FIRST LINE OF CELLULAR DEFENSE

6.1 Classical Protective Role

• Neutrophils are key components of the innate immune system and play a fundamental role in maintaining periodontal health, despite the constant challenge presented by the plaque biofilm. (Newman 14th, Chapter 8)
• Neutrophils are protective leukocytes that phagocytose and kill bacteria.
• Deficiencies in neutrophil functioning result in increased susceptibility to infections in general and to periodontal disease.
• Neutrophils are the first to arrive to an area of infection; they engulf and kill infecting agents. (PMSI, Chapter 6)

6.2 Neutrophil Killing Mechanisms:

OXIDATIVE MECHANISMS:
Phagocytosis → Phagosome formation → Phagosome-lysosome fusion (phagolysosome)
→ O2 reduction → formation of reactive oxygen species (ROS):
  - Superoxide (O2•−)
  - Hydrogen peroxide (H2O2)
  - Hydroxyl radical (•OH)
  - Myeloperoxidase (MPO) converts H2O2 → Hypochlorous acid (HOCl)

NON-OXIDATIVE MECHANISMS:
Phagosome-lysosome fusion → Secretion of lysosomal components:
  SPECIFIC GRANULES: Lysozyme, Lactoferrin (designed for extracellular AND intraphagolysosomal secretion)
  AZUROPHIL GRANULES: Defensins, neutral serine proteases (designed mainly for intraphagolysosomal secretion)

6.3 Neutrophil Chemotaxis

• Neutrophils detect a 1% gradient over the length of its cell body at nanomolar concentrations.
• Chemotaxins for neutrophils: C5a, IL-8, LTB4, N-formyl-methionyl peptides, platelet-activating factor, mast cell-derived neutrophil chemotactic factor. (Carranza 10th, Chapter 12)
• The interaction of adhesion molecules (ICAM-1) on endothelial and epithelial cells with β2 integrins on neutrophils facilitates neutrophil migration.
• Immunohistochemistry studies indicate existence of gradients of IL-8 (CXCL8) and gradients of ICAM-1, which direct neutrophils from the vasculature into the tissues and toward the junctional epithelium. (Newman 14th, Chapter 8)

6.4 NETs (Neutrophil Extracellular Traps)

• An aspect of neutrophil-mediated immunity is the formation of neutrophil extracellular traps (NETs). (Newman 14th, Chapter 8)

6.5 Dual/Paradoxical Role of Neutrophils

• Neutrophils also release large quantities of destructive enzymes (e.g., MMP-8 and MMP-9) as they migrate through the tissues — breakdown of structural components of the periodontium → collagen-depleted areas.
• Also release potent lysosomal enzymes, cytokines, and reactive oxygen species (ROS) extracellularly → further collagen depletion and tissue damage.
• Patients with periodontitis have neutrophils that demonstrate enhanced enzymatic activity and that produce increased levels of ROS. (Newman 14th, Chapter 8)

Paradigm Shift — Dual Role of Neutrophils:

6.6 Systemic Diseases with Neutrophil Disorders and Periodontal Risk:

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SECTION 7: MACROPHAGES

• Macrophages are attracted to an area of infection and differentiate from monocytes; they appear after neutrophils and digest dying neutrophils and phagocytize remaining infecting agents. (PMSI, Chapter 6)
• Monocytes that enter the tissues and mature are called macrophages — the "professional phagocytes" of the body. (Robbins, Chapter 6)
• All tissues contain resident macrophages; they not only sense the presence of microbes but also ingest (phagocytose) these invaders and destroy them.

7.1 Macrophage Polarization (M1/M2 Phenotypes):

• These cells "express functional PRRs and produce inflammatory mediators that stimulate other immune cells." (Newman 14th)

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SECTION 8: ADAPTIVE IMMUNITY IN PERIODONTAL DISEASE

8.1 Key Features of Adaptive Immunity

• Adaptive immunity is slower and reliant on complex interactions between APCs and T and B lymphocytes.
• Key element: antigen specificity — enables specific targeting of a diverse range of effector elements.
• Key facet: ability to improve over time (memory). (Newman 14th, Chapter 8)

8.2 T Lymphocytes (T Cells)

• Several different subsets of thymic lymphocytes (T cells) develop in the bone marrow and thymus and migrate to peripheral tissues.
• Expression of cell surface molecules (CD4 or CD8) or particular T-cell antigen receptors (αβ or γδ) broadly defines functional T-cell subsets. (Newman 14th, Chapter 8)

CD4+ T-Cell Subsets — Summary Table:

The Th1/Th2 Paradigm in Periodontitis:

GINGIVITIS (Stable lesion)                    PERIODONTITIS (Progressive/destructive lesion)
      |                                                   |
  Th1 predominance                                Th2 predominance
  (cell-mediated immunity)                        (humoral immunity)
      |                                                   |
  IFN-γ → activates macrophages,              IL-4, IL-5 → B-cell activation
  NK cells, CD8+ cytotoxic T cells            → Plasma cell formation
      |                                                   |
  Phagocytosis and killing of                 Production of specific antibodies
  microbial pathogens                         RANKL expression → bone resorption

Examiner Keyword: A dynamic interaction between Th1 and Th2 cells may provide, in part, an explanation for fluctuations in disease activity and the progression of periodontal disease.

• Strong innate immune response → high levels of IL-12 → associated with Th1 response (gingivitis)
• Poor innate immune response and relatively low levels of IL-12 → favor Th2 response (periodontitis) (Lindhe 6th, Chapter 13)

8.3 B Lymphocytes and Plasma Cells

• B cells are a consistent feature of the established and advanced periodontal lesion.
• B cells can be activated by specific antigens or by polyclonal activators.
• Putative periodontal pathogens including P. gingivalis, A. actinomycetemcomitans, and Fusobacterium nucleatum have been shown to have profound polyclonal B-cell activation properties. (Lindhe 6th, Chapter 13)
• Approximately 30% of B cells may be stimulated by a single polyclonal activator; different activators act on different B-cell subpopulations.
• Antibodies produced by polyclonal activation are likely to be of low affinity, and the memory component may not be induced. (Lindhe 6th, Chapter 13)
• The principal immunoglobulin class produced in the periodontal tissues is IgG, followed by IgM and some IgA. (Lindhe 6th; Newman 14th)
• Relevance of B cells is also associated with:
  • Capacity to secrete immunoglobulins, pro-inflammatory cytokines, and MMPs
  • Antigen presentation
  • Role as osteoclast precursors (Newman 14th, Chapter 11)

8.4 Antibodies

• Specific antibodies are produced in response to the bacterial challenge and are the endpoint of B-cell activation; commensurate with the appearance of antibodies is the appearance of differentiated plasma cells.
• High levels of antibodies appear in GCF — produced locally by plasma cells in periodontal tissues.
• Antibodies to periodontal pathogens are primarily IgG, with few IgM or IgA types produced. (Newman 14th, Chapter 8)

Antibody Function — Protective vs. Pathogenic:

Antibody Response in Localized Aggressive Periodontitis (LAP):

• LAP: predominant involvement of A. actinomycetemcomitans with high titers of IgG2
• Fcγ receptor (FcγRIIIb) on neutrophils does not efficiently bind IgG2, which is a basis for disease susceptibility
• Patients with elevated antibody response have significantly less loss of attachment
• In generalized early-onset periodontitis: patients do not develop a strong antibody response — supports hypothesis that antibodies function to limit the disease process (Carranza 10th)

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SECTION 9: HOST-DERIVED INFLAMMATORY MEDIATORS

9.1 Cytokines

• Cytokines are soluble proteins that act as messengers to transmit signals from one cell to another; bind to specific receptors on target cells and initiate intracellular signaling cascades.
• Effective in very low concentrations; produced transiently in tissues; primarily act locally. (Newman 14th, Chapter 8)

9.2 Key Cytokines Table:

9.3 IL-1 Family Classification (Recent/Current Nomenclature):

9.4 Prostaglandins

• Prostaglandin E2 (PGE2) is a key inflammatory mediator — lipid compound derived from arachidonic acid.
• PGE2 stimulates production of other inflammatory mediators and cytokine production.
• PGE2 also stimulates bone resorption and plays a key role in periodontitis progression.
• Synthesized by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) from arachidonic acid. (Newman 14th, Chapter 8)

Resolution of Inflammation:

• Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4) — arachidonic acid derivatives involved in the resolution of inflammation. (Newman 14th)

9.5 Matrix Metalloproteinases (MMPs)

• MMPs are a family of zinc-dependent enzymes capable of degrading extracellular matrix molecules, including collagens.
• Secreted by majority of cell types in the periodontium: fibroblasts, keratinocytes, endothelial cells, osteoclasts, neutrophils, and macrophages.

MMP Classification:

• MMPs are secreted in a latent (inactive) form and are activated by proteolytic cleavage — e.g., by cathepsin G produced by neutrophils.
• MMP activity regulated by tissue inhibitors of metalloproteinases (TIMPs) — most important in periodontal disease: TIMP-1.
• Serum inhibitors: α1-antitrypsin and α2-macroglobulin (a large plasma protein produced by the liver).
• Tetracycline class of antibiotics inhibit MMPs — led to development of subantimicrobial doxycycline as adjunctive treatment for periodontitis. (Newman 14th, Chapter 8)
• Greater collagenase activity (mainly from PMNs) found in GCF of periodontitis patients compared to controls.
• MMP-9 (produced by PMNs) prominent in GCF and gingival tissue samples in periodontitis.
• Increases in MMP-1, -2, -3, -9 and active form of MMP-9 correlated with number of CD22-positive B cells — suggests mechanism by which B cells contribute to tissue destruction. (Lindhe 6th, Chapter 13)

9.6 Reactive Oxygen Species (ROS)

• ROS — highly reactive oxygen-based molecules, including hydroxyl radical, superoxide, and peroxide.
• Produced extracellularly by neutrophils → further collagen depletion and tissue damage. (Newman 14th)

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SECTION 10: BONE RESORPTION MECHANISM — RANKL/OPG SYSTEM

10.1 Pathway:

Inflammatory Cytokines (IL-1β, TNF-α, IL-6, PGE2)
          |
          v
Stimulation of OSTEOBLASTS
          |
          v
Production of RANKL (Receptor Activator of NF-κB Ligand)
[also known as: OPG-L (Osteoprotegerin ligand), TRANCE/RANKL]
          |
          v
RANKL binds to RANK on osteoclast precursors
          |
          v
OSTEOCLAST DIFFERENTIATION and ACTIVATION
          |
          v
Osteoclasts produce acids and acid hydrolases
→ Decalcification of mineral content of bone
→ Break down of organic matrix
→ Phagocytosis of broken-down organic matrix
= BONE RESORPTION
          |
(Regulation)
          |
OSTEOPROTEGERIN (OPG) — decoy receptor produced by variety of cells
→ Binds RANKL → prevents activation of RANK → inhibits osteoclastogenesis

• Osteoclasts share a common origin with cells of the macrophage/monocyte lineage.
• RANKL/RANK/OPG system has regulatory effects on immune cell function — critical for T-cell maturation and the production of cytokines such as IFN-γ, IL-2, and IL-4. (Lindhe 6th)
• Osteocytes — most abundant cell type in bone — are a major source of RANKL in the periodontal microenvironment; also respond to MAMPs. (Newman 14th, Chapter 11)

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SECTION 11: CELLS AND THEIR ROLES IN PERIODONTAL MICROENVIRONMENT

11.1 Comprehensive Cell Table (Newman 14th, Chapter 11):

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SECTION 12: DENDRITIC CELLS AND ANTIGEN PRESENTATION

• Dendritic cells (DCs) are antigen-presenting cells central to the interface between innate and adaptive immunity.
• DC-SIGN (Dendritic cell-specific intercellular adhesion molecule (ICAM)-3–grabbing nonintegrins) — cell surface molecule on DCs with a role in cell-to-cell interactions and antigen presentation. (Newman 14th)
• DCs may assume different phenotypes:
  • "Activated" state — in dysbiotic/diseased states
  • "Tolerogenic" state — in homeostatic/healthy states
• DC phenotypes determine the phenotype of the adaptive T helper-type response and consequently have a profound influence on the "yin-yang" cytokine balance in the periodontal microenvironment. (Newman 14th, Chapter 11)

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SECTION 13: MICROBIAL IMMUNE EVASION STRATEGIES

13.1 Virulence Factors of P. gingivalis Interacting With the Immune System:

13.2 A. actinomycetemcomitans Immune Evasion:

• Produces leukotoxin (Ltx) — specifically targets leukocytes by binding to LFA-1 (specifically expressed on white blood cells)
  • Triggers rapid degranulation of lysosomal enzymes of neutrophils
  • Causes apoptosis of T-cells
  • Stimulates activation and secretion of pro-inflammatory cytokines IL-1β and IL-18 from monocytes/macrophages
• Produces cytolethal-distending toxin (Cdt) — causes DNA damage, triggering cell cycle arrest and apoptosis (Newman 14th, Chapter 8)

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SECTION 14: ACUTE PHASE RESPONSE

• The acute phase response involves the production of acute phase proteins such as C-reactive protein (CRP) by the liver.
• CRP: opsonizes bacteria and makes them more easily phagocytized.
• Increased CRP level is associated with periodontal disease activity or untreated periodontal disease.
• Increased CRP has been indicated as a risk factor for atherosclerosis — basis for speculations of a possible relation between the immunopathogenesis of periodontal disease and atherosclerotic diseases. (PMSI, Chapter 6)

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SECTION 15: GINGIVAL CREVICULAR FLUID (GCF) AS HOST RESPONSE INDICATOR

• GCF is a serum exudate that flows from the gingival sulcus (particularly in individuals with periodontitis) and contains molecular and cellular elements of the immune response. (Newman 14th)
• Contains: neutrophils, lymphocytes, antibodies, complement components, cytokines, MMPs, PGE2
• GCF concentrations of IL-1β are increased at sites affected by gingivitis and periodontitis
• GCF contains complement components C3, C3 proactivator (Factor B), and C4 (evidence of complement cleavage)
• At least 45 different antimicrobial peptides belonging to different biochemical classes are found in the saliva and GCF. (Newman 14th, Chapter 11)

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SECTION 16: RESOLUTION OF INFLAMMATION — HOST MODULATION

• A homeostatic equilibrium or disease is ultimately determined by the "net balance" of pro- and anti-inflammatory mediators. (Newman 14th, Chapter 11)
• After adequate host response, non-progressive/stable lesions are associated with the predominance of a pro-reparative microenvironment characterized by the increased prevalence of immune cells with repair functions. (Newman 14th)
• The concept of "metastatic inflammation" — endocrine dissemination of locally produced inflammatory mediators — is considered one possible biological mechanism for systemic influences of periodontal inflammation. (Newman 14th, Chapter 11)

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SECTION 17: COMPARISON TABLE — DIFFERENT REFERENCE VIEWPOINTS

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SECTION 18: RECENT TERMINOLOGY CHANGES

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SECTION 19: SUMMARY FLOWCHART — HOST RESPONSE IN PERIODONTAL DISEASE

DENTAL BIOFILM
(Subgingival plaque)
      |
      | MAMPs (LPS, peptidoglycan, bacterial DNA, LTA)
      v
EPITHELIAL BARRIER
(Junctional/Sulcular epithelium)
      |
      | Secretion of chemokines (IL-8, CXCL8)
      | Production of AMPs (hBD-1, hBD-2, LL-37)
      | Activation of PRRs (TLRs, NODs)
      v
INNATE IMMUNE RESPONSE
      |
      +---> NEUTROPHILS (primary defenders)
      |         - Phagocytosis, oxidative burst
      |         - Degranulation (MMPs, defensins)
      |         - NETs formation
      |         - Also: tissue destruction via MMPs, ROS
      |
      +---> MACROPHAGES
      |         - M1: Pro-inflammatory (IL-1β, TNF-α, IL-6, IL-12)
      |         - M2: Pro-repair (IL-10, TGF-β)
      |         - Antigen processing and presentation
      |
      +---> DENDRITIC CELLS
      |         - Antigen presentation to naive T cells
      |         - Determine Th1 vs. Th2 response
      |
      +---> COMPLEMENT SYSTEM
      |         - Classical, Lectin, Alternative pathways → C3b (opsonin), C5a (chemotaxin)
      |         - C5aR cross-talk with TLRs → amplified inflammation
      |
      +---> INFLAMMATORY MEDIATORS
                - Cytokines: IL-1β, TNF-α, IL-6, IL-17, IL-18
                - Chemokines: CXCL8 (IL-8), CCL2, CCL5
                - Prostaglandins: PGE2
                - MMPs: MMP-1, -2, -3, -8, -9
                - RANKL ↑ / OPG ↓ → Bone resorption
      |
      v
      [If innate immunity fails to eliminate infection]
      |
ADAPTIVE IMMUNE RESPONSE
      |
      +---> T CELLS (CD4+)
      |         - Th1 → IFN-γ → Cell-mediated immunity (stable lesion)
      |         - Th2 → IL-4, IL-5 → B-cell activation (progressive lesion)
      |         - Th17 → IL-17 → Neutrophil activation
      |         - Treg → TGF-β, IL-10 → Immunosuppression
      |
      +---> B CELLS / PLASMA CELLS
                - IgG, IgM, IgA antibodies (predominantly IgG)
                - Opsonization of bacteria
                - Complement activation
                - Production of MMPs, proinflammatory cytokines
                - Role as osteoclast precursors
      |
      v
BALANCE OF PRO- vs. ANTI-INFLAMMATORY MEDIATORS
      |
      +---> [NET PRO-INFLAMMATORY] → TISSUE DESTRUCTION
      |           Connective tissue degradation
      |           Alveolar bone resorption (via RANKL/OPG)
      |           Pocket formation
      |           PERIODONTITIS
      |
      +---> [RESOLUTION/REPAIR] → HOMEOSTASIS
                  Resolution mediators (LXA4, LXB4)
                  M2 macrophages predominate
                  Treg cells active
                  = Stable/non-progressive lesion

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SECTION 20: KEY EXAMINER KEYWORDS SUMMARY

1. Steady-state equilibrium — balance between low-grade inflammation and bacterial biofilm in health
2. MAMP / PAMP — microbe-associated/pathogen-associated molecular patterns
3. PRRs (Pattern Recognition Receptors) — TLRs, NOD1/2, NLRP3
4. MyD88 — adaptor protein for TLR signaling (all TLRs except TLR3)
5. NLRP3 inflammasome — produces active IL-1β; cell death by pyroptosis
6. Gingipains (Kgp, RgpA, RgpB) — P. gingivalis cysteine proteases
7. Leukotoxin (Ltx) — A. actinomycetemcomitans exotoxin targeting leukocytes via LFA-1
8. RANKL/RANK/OPG — central regulatory axis for bone resorption
9. Th1/Th2 paradigm — Th1 = stable lesion; Th2 = progressive/destructive lesion
10. Polyclonal B-cell activation — non-specific B-cell response to periodontal pathogens
11. Radius of action — "1.5–2.5 mm within which bacterial plaque can induce loss of bone" (Page and Schroeder)
12. Subantimicrobial doxycycline — MMP inhibitor used as adjunctive therapy
13. NETs (Neutrophil Extracellular Traps) — component of neutrophil-mediated immunity
14. Metastatic inflammation — endocrine dissemination of locally produced inflammatory mediators
15. Dynamic continuum — innate and adaptive immunity as a continuum, not separate entities
16. hBD-1, hBD-2, LL-37 — antimicrobial peptides/defensins of epithelial origin
17. TIMP-1 — most important tissue inhibitor of MMPs in periodontal disease
18. Pyroptosis — pro-inflammatory cell death via gasdermin-D pores (NLRP3/caspase-1 pathway)
19. IL-1F nomenclature — expanded IL-1 family naming system
20. Host modulation therapy — therapeutic targeting of host inflammatory pathways (e.g., MMP inhibitors, complement inhibitors, NSAIDs, complement-targeted therapies)

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• Newman and Carranza's Clinical Periodontology and Implantology, 14th Edition — Chapters 8 and 11
• Carranza's Clinical Periodontology, 10th Edition — Chapters 12, 20, 28
• Clinical Periodontology and Implant Dentistry (Lindhe), 6th Edition — Chapter 13
• Periodontics Medicine Surgery Implants — Chapter 6
• Robbins and Cotran Pathologic Basis of Disease — Chapter 6
• Biomarkers in Periodontal Health and Disease — Chapter 2---

EXAMINER'S QUICK REVISION CHECKLIST