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University of Ottawa

Periodontitis
Inflammatory Mechanisms and Treatment

Michael Caverly, 6107205

Periodontitis: Inflammatory Mechanisms and Treatment

Michael Caverly, 6107205

Dental plaque accumulation on teeth can lead to periodontitis, a destructive disease


resulting in the loss of overall dentition, surrounding hard and soft periodontal tissues, and
ultimately the loosening and loss of teeth [1, 2]. Biofilm composition of dental plaque associated
with periodontitis shows mixed colonies of S. mutans and Gram-negative anaerobes (A.
actinomycetemcomitans and P. gingivalis). Presence of these colonies showed an increased local
antibody production within gingival crevicular fluid, with degradation of supporting connective
tissues (i.e. periodontal ligament) occurring via aminopeptidase, alkaline phosphatase, trypsin,
and hydrolytic activities within the periodontium of inflamed gingiva [3, 4]. Resulting tissue
injury and inflammation have been classified as allergic inflammation and has been defined by
four hypersensitivity reaction types (Table 1). Type I and II reactions may not contribute
extensively to pathogenesis, but Type I and III reactions play a major role in the inflammatory
response [4]. Mast cell IgE-mediated cytokine production (via NF-B activation) plays a role in
allergic inflammation (type I) and IFN- production (type III) plays a role in prostaglandin E 2
(PGE2) release; as well as leukocyte stimulation, increased natural killer (NK) cell activity, and B
cell regulation [5, 6, 7]. Leukocyte stimulation (via Type I or III reaction products) may induce
expression of major histocompatibility complex (MHC) Class II surface antigens within
epidermal Langerhans cells (within the gingival epithelium), resulting in T lymphocyte
stimulation [8]. T-lymphocyte dominated lesions within inflamed gingiva in both children [9]
and adults [10] did not develop periodontitis, suggesting conversion of T-cell to B-cell dominated
lesions may be a driving force in autoimmune periodontitis progression [11]. Progression may
be facilitated through B-cell generated IgG antibodies directed towards Type I hypersensitivity
reactions.

Periodontitis: Inflammatory Mechanisms and Treatment

Michael Caverly, 6107205

Aveolar bone loss (Figure 1) occurs as PGE2 release from osteoblasts facilitates osteoclast
differentiation through interactions between the receptor activator of NF-B (RANK) to the
RANK ligand (RANKL). RANKL surface expression is stimulated by PGE 2, IL-1 (type I
product), and IL-6 (type I product) [12, 13]. Binding of RANKL to RANK on osteoblast surfaces
can also activate the nuclear transcription factor-B (NF-B), recruit TNF receptor associated
factors (TRAFs), or activate the mitogen-activated protein kinases (MAPKs) pathways [14, 15].
Toll-like receptor (TLR) signals also produces PGE2, IL-1, and IL-6 thus promoting RANKLRANK interactions and osteoclast differentiation. TLR4 is a known receptor for LPS, whose
presence within mouse gingiva was shown to lead to significant increases in osteoblast PGE 2
synthesis, leading to alveolar bone resorption/degradation through increased RANK-RANKL
interactions [16]. TLR heterodimers TLR1/2 and TLR2/6 have also been shown to recognize
Gram-negative components and induce PGE2 synthesis and subsequent bone loss [17, 18].
Current periodontitis treatment has focused on antiproteinases (not discussed), antiinflammatory drugs, and the inhibition of osteoclast differentiation [19]. Osteoclast
differentiation inhibition serves two purposes, stopping osteoclast differentiation itself and
stopping the synthesis of pro-inflammatory cytokines and/or PGE 2 to further reduce RANKL
surface expression. Sanguinarine, a natural plant extract, reduces expression of osteoclast marker
genes and impairs NF-B signalling through IB phosphorylation and degradation [20].
Telmisartin (TELM) inhibits induction of NF-B signalling within gingival cells by reducing
serum TNF- and IL-1 levels, also reducing COX-2 expression (i.e. reducing PGE 2 production)
[21]. Non-steroidal anti-inflammatory drugs (NSAIDs) supress PGE 2 levels through inhibition of
cyclooxygenase activity of COX-1/2, also lowering IL-1 through PGE2 regulation. Treatment
with the NSAID Aulin resulted in a 42% and 37% reduction of IL-1 and PGE 2 within gingival
2

Periodontitis: Inflammatory Mechanisms and Treatment

Michael Caverly, 6107205

crevicular fluid [22]. Although effective, current treatments for periodontitis are very specific in
their mechanisms (i.e. acting directly on osteoclast differentiation or COX-2 cyclooxygenase
activity). Primarily in osteoclast differentiation, COX-2 selective inhibitors such as celecoxib or
rofecoxib may further increase the specificity of PGE2 inhibition. Various agents used in
osteoporosis treatment may also be beneficial since they aim to reduce osteoclast differentiation
as well.
Improvements toward periodontitis treatment may involve stopping the upstream
production of cytokines to limit immune responses. Limitation of plaque biofilm size is a trivial
solution to preventing pathogenesis. Removal of Gram-negative bacteria in the first place
prevents tissue damage via lytic enzymes and downstream TLR signalling that results in
cytokine-promoted osteoclast differentiation. Even in inflamed gingiva, removal of plaque in
conjunction with various other treatments (anti-inflammatory, anti-proteinase, etc) may
drastically improve recovery rates. Considering the hypersensitivity reactions (Table 1), it may
be beneficial to stop cytokine production (and further inflammatory responses) by restricting
mast cell-immunoglobulin G interactions; thereby hindering cytokine-induced hypersensitivity
reactions. Possible treatment could be similar to treatment of common allergies. Administration
of various antihistamines and/or steroid hormones (i.e. corticosteroids/glucocorticoids) may have
local effects on periodontal inflammation. Additionally, it was previously suggested that T celldependent activation of B-cells may be a driving force in autoimmune periodontal disease
proliferation. B-cell proliferation inhibition may prevent IgG synthesis, thus reducing
hypersensitivity reactions, but this mechanism requires experimental data to be valid.

Periodontitis: Inflammatory Mechanisms and Treatment

Michael Caverly, 6107205

Tables and Figures


Table 1: Mechanisms and important cytokines involved in the hypersensitivity reactions within gingiva. Cytokines
listed may not be complete, but major types are listed for illustrative purposes.

Hypersensitivity Reaction [23]


Type I
Anaphylactic hypersensitivity
Type II
Cytotoxic reactions
Type III
Immune complex-mediated
disease
Type IV
Delayed hypersensitivity

Mechanism
IgE antibody binds to mast cell
surface, releasing histamine and
inflammatory mediators [24]
IgG or IgM antibody lyses
antibody-coated cells through
complement fixing [26]
Phagocytic cells lyse complement,
releasing hydrolytic enzymes [4]
and triggering pro-inflammatory
effects [28]
Non-antibody mediated activation,
releasing interleukins [4]

Induced Cytokines
TNF-, IL-1, IL-2, IL8, GM-CSF, RANTES*
[5, 25]
IL-10 [27]

TNF, IFN- [4]

Variable (IL-1 through


IL-7) [4]

*Many cytokines are produced through macrophages as a result of the extravasation effect type I reactions
induce via histamine and chemokine release

Periodontitis: Inflammatory Mechanisms and Treatment

Michael Caverly, 6107205

Figure 1: Overview of periodontitis. Type I hypersensitivity reaction is observed between a mast cell and IgG
antibody, releasing histamine/chemokines for macrophage extravasation. Macrophage surface TLR interacts with
various Gram-negative components to produce IL1, IL6, TNF (not shown), and PGE 2. PGE2 increases RANKL
expression, leading to osteoclast differentiation and subsequent alveolar bone resorption. Various lytic enzymes
(aminopeptidase shown) also degrade periodontal tissues (i.e. periodontal ligand).

Periodontitis: Inflammatory Mechanisms and Treatment

Michael Caverly, 6107205

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Periodontitis: Inflammatory Mechanisms and Treatment

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