13 Host Immunoinflammatory Response to Dental Biofilm

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CHAPTER 13 Host Immunoinflammatory Response to Dental Biofilm

Inflammatory Response

  • Activation: Initiated by the immune system in response to an offending agent or injury.
  • Functions:
    • Traps offending agents.
    • Begins healing process of injured tissue.
  • Duration: Not intended for long-term activation.
  • Consequence of Prolonged Activation: Failure to resolve results in chronic inflammation.

Periodontal Disease

  • Nature: Biofilm-induced infection leading to a complex immunoinflammatory response.
  • Pathogens: Presence of periodontal pathogens alone is insufficient for causing the tissue destruction observed in periodontitis.
  • Host Response: The host's immunoinflammatory response, triggered by microbial biofilm, directly causes nearly all destruction seen in periodontal disease.

Inflammatory Response and Resolution

  • Phases of Inflammation:
    1. Microbial invasion
    2. Acute inflammation
    3. Unresolved inflammation
    4. Sustained chronic inflammation
  • Protective Mechanisms:
    • Host-produced pro-resolving lipid mediators facilitate:
    • Resolution of inflammation.
    • Protection from further inflammatory damage.
    • Stimulation of tissue regeneration and repair.
  • Conditions Associated with Periodontal Disease:
    • Diabetes
    • Cardiovascular disease
    • Rheumatoid arthritis
    • Chronic obstructive pulmonary disease
    • Neurological disorders
    • Organ fibrosis
  • Outcome: Return to homeostasis.

Factors Enhancing the Microbial Challenge

  • Virulence Factors: Mechanisms that enable biofilm bacteria to colonize and damage periodontium tissues.
    • Primary Virulence Factors Include:
    • Presence of lipopolysaccharide (LPS).
    • Ability to invade tissues.
    • Ability to produce enzymes.

Factors Modulating the Host Immunoinflammatory Response

  • Genetic Factors:
    • Example: Papillon-Lefèvre syndrome (genetic origin).
  • Environmental Factors:
    • Example: Tobacco smoking.
  • Acquired Factors:
    • Example: Diabetes mellitus.

Acute Inflammation

  • Host Response Components:
    • Various cells involved include inflammatory cells such as:
    • PMNs (Polymorphonuclear leukocytes).
    • Antigen-presenting cells.
    • T- and B- lymphocytes.
    • Fibroblasts.
    • Epithelial cells.
  • Role: Acute inflammation serves a host-protective effect and functions as a first line of defense against microbial invasion.
  • Benefits:
    • Eliminates harmful stimuli.
    • Replaces injurious host cells.
    • Creates an environment favorable for tissue repair.
  • Requirement for Termination: Must be dampened after microbial challenge is eliminated.

Resolution of Acute Inflammation

  • Interaction: Acute inflammation and resolution must work cooperatively.
  • Effectiveness: The effectiveness of the acute inflammation determines whether the outcome is favorable or detrimental.
  • Regulation: Recent findings show that resolution of inflammation and return to a non-inflammatory state is an actively regulated biological process.

Catabasis

  • The return to homeostasis after the inflammatory process.
  • Nature: Considered a biologic process as complex as the onset of inflammation.
  • Pro-Inflammatory Mediators in Periodontitis: Include prostaglandins, thromboxanes, prostacyclins, and leukotrienes.
    • Mentioned the influence of pharmaceuticals that impact these pathways.

Catabasis: Mediators and Effects

  • Lipid Mediators in Periodontitis: Associated with recruitment of PMNs, destruction of connective tissue matrix, and resorption of alveolar bone.
  • Overrecruitment of PMNs: Can amplify the inflammatory process and lead to further tissue damage.
  • Pro-resolving Lipid Mediators: Function systematically in a programmed manner to:
    • Terminate PMN recruitment to the site.
    • Stimulate macrophages to clear dead cells.
    • Promote antibacterial activities.
    • Encourage tissue repair and regeneration.

Chronic Inflammation

  • Occurs when the host is unable to subdue inflammation shortly after the removal of microbial challenges.
  • Consequences: Leads to uncontrolled, unresolved chronic inflammation with pathological effects on the host tissue.

Inflammatory Biochemical Mediators of the Host Response

  • Definition: “Middlemen” sent by host cells to induce an inflammatory response.
  • Important Biochemical Mediators Include:
    • Cytokines
    • Prostaglandins
    • Matrix metalloproteinases (MMPs)

Cytokines

  • Definition: Powerful regulatory proteins secreted by host immune cells influencing other cells' behaviors.
  • Functions:
    • Transmit information and activate the immune system for assistance.
    • Produced by PMNs, macrophages, B-cells, epithelial cells, gingival fibroblasts, and osteoblasts.

Functions of Cytokines

  • Cytokines bind to specific receptors on target cells leading to:
    • Increased vascular permeability.
    • Initiation and perpetuation of irreversible tissue destruction in chronic inflammatory diseases.
  • Key Cytokines in Periodontitis: IL-1, IL-6, IL-8, TNF-α.

Prostaglandins

  • Definition: Biochemical mediators derived from fatty acids found on the surface of most cells.
  • Significant Prostaglandins: Include Prostaglandins D, E, F, G, H, and I.
    • Prostaglandins of the E series (PGEs) are particularly crucial in bone destruction associated with periodontitis.

Functions of Prostaglandins

  • Sources: Majorly derived from macrophages, but also produced by PMNs and gingival fibroblasts.
  • Functions:
    • Increase the permeability and dilation of blood vessels.
    • Stimulate osteoclasts to facilitate alveolar bone destruction.
    • Can enhance overproduction of destructive MMP enzymes.

Matrix Metalloproteinases (MMPs)

  • Definition: A family of at least 12 proteolytic enzymes involved in the breakdown of connective tissue matrix.
  • Sources: Produced by PMNs, macrophages, gingival fibroblasts, and junctional epithelial cells.
    • PMNs and gingival fibroblasts are the primary sources of MMPs in periodontitis.

MMP Effects in Health

  • Normal MMP activity maintains the turnover of periodontal connective tissue matrix.
  • Overactivity is tightly controlled by host-derived tissue inhibitors of matrix metalloproteinases (TIMP).
  • The balance of MMPs and TIMPs is crucial for connective tissue health.

MMP Effects in Chronic Infection and Inflammation

  • Triggers: Cytokines and prostaglandins stimulate the release of MMPs by leukocytes and fibroblasts.
  • Consequences of Excess MMP Release:
    • Levels may overwhelm TIMPs' regulatory capacity.
    • Leads to extensive collagen destruction in periodontal tissues.
    • Periostat (20-mg doxycycline) is known to inhibit MMP activity.

Current Theory of Pathogenesis

  • Data Reference: Meyle J, Chapple I., "Molecular aspects of the pathogenesis of periodontitis," Periodontol 2000, 2015.
  • Gingival Health: Linked with a symbiotic biofilm and a balanced immunoinflammatory response.
  • Pathogenic Bacteria: Accumulate when the dental biofilm is not adequately managed, disrupting normal tissue function and host responses.
  • Dysbiosis: In susceptible individuals, dysbiotic biofilm activates host responses, producing excessive cytokines, reactive oxygen species, and MMPs, leading to:
    • Collagen breakdown.
    • Bone resorption.
    • Periodontal tissue damage.

Histologic Stages in the Development of Periodontal Disease

  • Staged by Page and Schroeder in 1976, stages include:
    1. Initial lesion
    2. Early lesion
    3. Established lesion
    4. Advanced lesion

Bacterial Accumulation (Initial Lesion)

  • Process: Bacteria colonize the tooth surface near the gingival margin.
  • Initial Response: Gram-negative bacteria initiate the immune response through the release of cytokines, BGE2, MMPs, TNF-α.
  • Cell Activity: Activation of PMNs, vascular dilation within the dentogingival complex leading to increased gingival crevicular fluid volume.
  • Clinical Impression: Gingiva appears healthy.
  • Timeline: Initial lesion develops 2 to 4 days after plaque biofilm accumulation.

Early Gingivitis (Early Lesion)

  • Progression: Continuous bacterial accumulation and biofilm maturation.
  • Pathophysiology: Toxins and byproducts penetrate and disrupt the junctional epithelium.
  • Cellular Defense: Recruitment of additional PMNs leading to significant collagen loss (60% to 70%).

Established Gingivitis (Established Lesion)

  • Features: The plaque biofilm extends into the gingival sulcus, which disrupts epithelial attachment.
  • Immune Response: Increased activity of plasma cells, macrophages, and T-cells.
  • Clinical Presentation: Signs of inflammation become more pronounced, with high cellular infiltrations.

Periodontitis (Advanced Lesion)

  • Characterization: Biofilm grows apically, creating an environment conducive for subgingival bacterial growth.
  • Tissue Effects: Chronic infection leading to significant tissue destruction beyond the repair capabilities of the host, with migration of junctional epithelium and periodontal pocket formation.
  • Clinical Findings: Includes bleeding on probing, periodontal pocket formation, and tooth mobility.

Bone Remodeling

  • Process Overview: Involves osteoclasts (bone-resorbing cells) and osteoblasts (bone-forming cells).
  • Activation Mechanisms: Mediated by the receptor activator of nuclear factor kappa-β (RANK) system.
  • Osteoclasts break down bone minerals and gain stimulation through RANKL binding.

Bone Remodeling Cycle

  1. Resorption: Osteoclasts create erosion cavities in bone.
  2. Reversal: Mononuclear cells prepare the bone for new osteoblasts.
  3. Resting: A resting period occurs before a new remodeling cycle can begin.
  4. Formation: Osteoblasts form new bone matrix to replace what was resorbed.

Regulation of the Bone Remodeling Cycle

  • RANKL: Protein expressed on osteoblast membranes that drives osteoclast differentiation through binding to its receptor.
  • Osteoprotegerin (OPG): A protective signaling molecule produced by osteoblasts that inhibits excessive bone resorption by blocking RANKL from binding to RANK.
  • Balance Maintenance: Homeostasis is achieved when RANKL and OPG are in balance within the periodontal tissues.

Biochemical Mediators in Bone Metabolism

  • Stimulators of Resorption: Include RANKL, and stimulatory cytokines (e.g., IL-1β, TNF-α).
  • Inhibitors of Resorption: Include OPG and inhibitory cytokines like IL-4 and IL-10.

The Link Between Periodontitis and RANKL-Mediated Bone Resorption

  • Infection leads to the release of pro-inflammatory cytokines that play a pivotal role in modifying the bone remodeling process.