This document provides an overview of the pathogenesis of periodontal disease. It begins with definitions of pathogenesis and periodontitis. Key points include: plaque bacteria initiate inflammatory responses leading to tissue damage; the host immune response determines susceptibility; and the transition from gingivitis to periodontitis involves a shift from localized to widespread inflammation and bone/tissue loss. Histopathological changes are described at each disease stage. The roles of bacterial virulence factors and host inflammatory mediators such as cytokines are discussed.

1. BY- DR. OINAM MONICA DEVI

2. TABLE OF CONTENTS
 Introduction
 Gingivitis
 Plaque‐induced gingivitis
 Plaque‐induced Gingivitis on a reduced Periodontium
 Chronic Periodontitis
 Histopathology of Periodontal Disease
 Histopathology of Gingivitis
 Transition from Gingivitis to Periodontitis
 Inflammatory response in the Periodontium
 Host Derived Inflammatory Mediators

3.  Immune Responses in periodontal pathogenesis
 Innate immunity
 Adaptive immunity
 Concept of Host Susceptibility
 Concepts in the Models of Pathogenesis
 Modifiers in Periodontal Disease Pathogenesis
 Linking Pathogenesis to Clinical signs of Disease
 Resolution of Inflammation
 Lipoxins
 Resolvins
 Protectins

4.  Pathogenesis is derived from the Greek work ‘pathos’ meaning suffering
and ‘ genesis’ meaning generation or creation.
 According to Merriam Webster’s Collegiate Dictionary, pathogenesis is
defined as the origination and development of a disease.
 In 1970s and 1980s, bacterial plaque was generally considered to be
preeminent as the cause of periodontitis.
INTRODUCTION

5.  The etiologic role of plaque bacteria is clear in that the bacteria initiate and
perpetuate the inflammatory responses that develop in the gingival tissues.
 However , the major determinants of susceptibility to disease is the nature of the
immune- inflammatory responses themselves.
 These findings were confirmed by the work of Loe and colleagues who studied
Sri Lankan tea laborers who had no access to dental care and who could be
divide into 3 main categories.
 1) 8 % of the population studied= rapid progression of periodontal disease
 2) 81% of the population studied= moderate progression of periodontal disease
 3) 11 % of the population studied = no progression of periodontal disease
beyond gingivitis

6.  Periodontal pocket is a favourable environment for the survival of many
species that are considered important in periodontal pathogenesis.
 Many of the unique features of periodontitis derive from the anatomy of the
periodontium
Hard ,non
shedding surface
(tooth)
Tooth is partly
embedded
within the body
(within
connective
tissue)
Crosses an
epithelial surface
Partly exposed to
the outside world
Bacteria that colonize this surface are effectively outside the
body, yet the inflammatory response that develops is located
within the body

7. Gingivitis
 The rate or speed of development and the degree of the clinical
inflammatory response is variable between individuals, even under similar
plaque accumulation conditions.
 Based on studies using the experimental gingivitis model, one can estimate
that approximately 13% of all individuals represent a ‘‘resistant’’ group.

9. Plaque‐induced gingivitis
 Plaque‐induced gingivitis is inflammation of the Gingiva resulting from
bacteria located at the gingival margin and can spread throughout the
remaining gingival unit.
 It is considered to be the most common form of periodontal disease (Page
1985; AAP 2000).
 In children, the prevalence of plaque‐induced gingivitis continues to increase
until it reaches a zenith at puberty (Parfitt 1957;Hugoson et al. 1981; Stamm
1986; Mombelli et al. 1989).

10.  The initial changes from health to plaque‐induced gingivitis may not be
detectable clinically (Page & Schroeder 1976), but as it progresses to more
advanced forms of this disease, clinical signs and symptoms become more
obvious.
 Clinical signs of gingival inflammation involving changes to gingival contour,
color, and consistency are associated with a stable periodontium which exhibits
no loss of periodontal attachment or alveolar bone.
 The common clinical findings of plaque‐induced gingivitis include erythema,
edema, bleeding, sensitivity, tenderness, and enlargement(Löe et al. 1965;
Suzuki 1988)

11.  In contrast to children and young adults, gingival inflammation in senior
adult populations is more pronounced even when similar amounts of dental
plaque are present (Fransson et al.1996).
 This age related difference in the development and severity of gingivitis
may be associated with the quantity and/or quality of dental plaque,
response of the immune system, and/or morphologic differences in the
periodontium between children and adults (Bimstein & Matsson 1999).

12.  Gingivitis and Periodontitis are inflammatory conditions of infectious
nature.
 Gingivitis precedes the onset of Periodontitis; however, not all gingivitis
cases develop into Periodontitis .The reason for this is that accumulation of
plaque bacteria is necessary but not sufficient by itself for the development
of Periodontitis: a susceptible host is necessary.
 A biofilm environment confers certain properties to bacteria that are
not seen in the planktonic state.

13.  It is considered to start as plaque‐induced gingivitis, a reversible condition that if
left untreated may develop into chronic periodontitis.
 Lesions are distinguished by loss of attachment and bone, and are regarded as
irreversible.
CLINICAL FEATURES
(1) Color, texture, and volume alterations of the marginal gingiva
(2) Bleeding on probing (BoP) from the gingival pocket area
(3) Reduced resistance of the soft marginal tissues to probing (increased pocket depth)
(4) Loss of probing attachment level
(5) Recession of the gingival margin
(6) Loss of alveolar bone
(7) Root furcation exposure
(8) Increased tooth mobility
(9) Drifting and eventually exfoliation of teeth
CHRONIC PERIODONTITIS

14. Plaque‐induced Gingivitis on a reduced Periodontium
 Plaque‐induced gingivitis on a reduced periodontium is characterized by the
return of bacteria‐induced inflammation of the gingival margin on a reduced
periodontium with no evidence of progressive attachment loss.
 The clinical findings for Plaque-induced gingivitis on a reduced periodontium are
similar to those for plaque‐induced gingivitis, except for the presence of
pre‐existing attachment and bone loss.

15. HISTOPATHOLGY OF GINGIVITIS
The landmark studies of Page and Schroeder (1976) described the histologic
changes that occur in the gingival tissues as the INITIAL, EARLY,
ESTABLISHED, and ADVANCED gingival lesions.
Initial Lesion
 Corresponds to 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 the gingival connective tissue, across the junctional epithelium, and into
the sulcus.

16. Early Lesion
 Corresponds to early gingivitis that is evident clinically
 Increased vascular permeability, vasodilation, and GCF flow
 Large numbers of infiltrating leukocytes ( mainly neutrophils and lymphocytes)
 Degeneration of fibroblasts
 Collagen destruction, resulting in collagen depleted areas of the connective
tissue.
 Proliferation of the junctional and sulcular epithelium into collagen- depleted
areas.

17. Established Lesion
 Corresponds to established, chronic gingivitis.
 Dense inflammatory cell infiltrate ( plasma cells, lymphocytes, neutrophils)
 Accumulation of inflammatory cells in the connective tissues.
 Elevated release of MMPs and lysosomal contents from neutrophils.
 Significant collagen depletion and proliferation of epithelium
 Formation of pocket epithelium containing large numbers of neutrophils.

18. Advanced Lesion
 Marks the transition from gingivitis to periodontitis
 Predominance of neutrophils in the pocket epithelium and in the pocket
 Dense inflammatory cell infiltrate in the connective tissues ( primarily
plasma cell)
 Apical migration of junctional epithelium to preserve intact epithelial
barrier
 Continued collagen breakdown resulting in large areas of collagen depleted
connective tissue
 Osteoclastic resorption of alveolar bone

19. HISTOPATHOLOGY OF PERIODONTAL DISEASE
 Susceptibility of periodontitis suggests that individuals who are more
susceptible to the disease mount an excessive, or dysregulated, immune-
inflammatory response for a given bacterial challenge, leading to increased
tissue breakdown compared to those individuals who have a more normal
inflammatory response.
 Junctional epithelium has great relevance in periodontal pathogenesis as a
result of lower density of desmosome, therefore intrinsically leaky.
 The intercellular spaces in the junctional epithelium permit migration of
neutrophils and macrophages from the gingival connective tissues to enter the
sulcus to phagocytose bacteria, as well as the ingress to bacterial products and
antigens.

20. PATHOGENESIS OF PERIODONTAL POCKET
 The initial lesion in the development of periodontitis is the inflammation of the
gingiva in response to a bacterial challenge.

22. Pocket formation starts as an inflammatory
change in connective tissue wall of gingival
sulcus
Inflammatory exudate causes degeneration of
surrounding connecting tissue including the
gingival fibers
Just apical to Junctional epithelium, collagen fibers
are destroyed and area becomes occupied by
inflammatory cells and edema
Two mechanisms associated with collagen loss:
• Collagenases and other enzymes (MMPs)
• Fibroblasts phagocytize collagen fibers

23. Apical cells of Junctional epithelium proliferate along the root
Coronal portion of the Junctional epithelium detaches from the root
As a result of inflammation, PMNs invade the coronal end of Junctional
epithelium in increasing number
When the relative volume of PMNs reaches approximately 60% of the Junctional
epithelium
Tissue losses cohesiveness and detaches from the tooth surface
Thus, the sulcus bottom shifts apically
And the Oral Sulcular Epithelium occupies a gradually increasing portion of the
sulcular lining
Initial deeening of pocket has been described as occuring between the J.E and the
tooth or the intraepithelial cleavage within the J.E.

24. NORMAL GINGIVA

25. Extension of supragingival plaque
into the gingival sulcus:
Accumulation of supragingival
plaque:

26. Detachment and apical migration of
junctional epithelium:
Phagocytic action of neutrophils:

27. Ulceration of pocket epithelium: Periodontal pocket is established

28. HISTOPATHOLOGY OF LATERAL WALL OF
POCKET
 Most severe degenerative changes.
 Epithelium presents striking proliferative and degenerative changes.
 Epithelial buds or interlacing cords of epithelial cells project from the lateral
wall into the adjacent inflamed connective tissue and may extend farther
apically than the junctional epithelium.
 These epithelial projections, as well as the remainder of the lateral
epithelium, are densely infiltrated by leukocytes and edema from the
inflamed connective tissue.
 The cells undergo vacuolar degeneration and rupture to form vesicles.
 Progressive degeneration and necrosis of the epithelium lead to ulceration of
the lateral wall, exposure of the underlying inflamed connective tissue, and
suppuration.
 In some cases, acute inflammation is superimposed on the underlying
chronic changes.

30. TRANSITION FROM GINGIVITIS TO PERIODONTITIS
 The numbers of B cells increase from health to gingivitis to periodontitis as does
the ratio of B cells to T cells.
 Higher B-cell levels in active periodontitis lesions suggests that B-cell activation
contributes to disease progression.
 There is apical proliferation of the junctional epithelium following
attachment loss and further destructive events in the connective tissues in
response to plaque irritation.

31.  The lesion is no longer localized.
 The inflammatory cell infiltrate extends apically and laterally into the
underlying connective tissues, including the periodontal ligament and
the alveolar bone.
 Alveolar bone loss is evident and there is breakdown of fibres of the
periodontal ligament.

32. INFLAMMATORY RESPONSES IN THE PERIODONTIUM
MICROBIAL VIRULENCE FACTORS
1. Lipopolysaccharide
• Found in the outer membrane of gram- negative bacteria and act as endotoxins.
• Immune systems in animals have evolved to recognize LPS via toll- like
receptors (TLRs).
• TLR- 4 recognizes LPS from gram- negative bacteria and functions as part of a
complex of cell surface molecules, including CD14 and MD-2.

33.  Porphyromonas gingivalis has an atypical form of LPS and is recognized by
both TLR-2 and TLR-4.
 Lipoteichoic acid also stimulates immune responses, although less potently than
LPS and signals through TLR-2.
 LPS in particular is of key importance in initiating and sustaining inflammatory
responses in the gingival and periodontal tissues.

34. 2.Bacterial Enzymes and Noxious Products
• Ammonia, hydrogen sulfide, short- chain carboxylic acids, butyric acid ,
propionic acid are the noxious products that directly cause tissue damage.
• The short –chain fatty acids may aid in
 P. gingivalis infection through tissue destruction
 Create a nutrient supply for the organism by increasing bleeding into the
periodontal pocket.
 Influence cytokine secretion by immune cells
 Potentiate inflammatory responses after exposure to proinflammatory stimuli
such as LPS, interlukin-1 beta, and tumor necrosis factor alpha.

35.  Plaque bacteria produce proteases, which are capable of breaking down structural
proteins of the periodontium such as collagen, elastin, and fibronectin.
 Bacterial proteases disrupt host responses, compromise tissue integrity, and
facilitate microbial invasion of the tissues.
 P. gingivalis produces gingipains
1. lysine specific gingipain Kgp
2.arginine specific gingipains RgpA and RgpB
 Gingipains can disrupt immune- inflammatory responses leading to increased
tissue breakdown
 Reduce the concentrations of cytokines in cell culture systems, can digest and
inactivate TNF- α
 Can stimulate cytokine secretion via activation of protease- activater receptors(
PARS).

36. 3. Microbial Invasion
• P. gingivalis and Aggregatibacter actinomycetemecomitans have been reported to
invade the gingival tissues including the connective tissues.
• Fusobacterium nucleatum can invade oral epithelial cells, bacteria that rotinely
invade host cells may facilitate the entry of nnoninvasive bacteria by
coaggregating with them.
• A.actinomycetemecomitans can invade epithelial cells and persist intracellularly.
• Some investigators suggest tissue invasion by subgingival bactria as an active
process whereas others consider it to be a passive translocation process.
• Bacteria in the tissues represent a “ reservoir for reinfection” after nonsurgical
management.

37. 4. Fimbriae
 Helps the bacteria to attach to the pellicle
5. Bacterial Deoxyribonucleic Acid and Extracellular
Deoxyribonucleic Acid

38. HOST- DERIVED INFLAMMATORY MEDIATORS
 The accumulated dental bacterial plaque has the potential to cause
periodontal tissue damage directly, through mechanisms such as matrix
degrading enzymes and molecules that impair the functions of host cells.
 The inflammatory infiltrate of periodontitis is characterized by PMNs,
macrophages, lymphocytes, plasma cells, and substantial loss of collagen.

39. 1. Cytokines
• Soluble proteins
• Act as messengers to transmit signals from one cell to another.
• Effective in very low concentrations
• Produced transiently in the tissues and primarily act locally in the tissues in
which they are produced
• Induce their own expression either in an autocrine or paracrine fashion.
• The most important cytokines in periodontal pathogenesis are the
proinflammatory cytokines IL‐1β and TNF‐α

40. A) Interleukin- 1 Family Cytokines
IL- 1β
• Induces the synthesis and secretion of other mediators that contribute to
inflammatory changes and tissue damage.
 Produced by monocytes, macrophages, and neutrophils also by other cell types
such as fibroblasts, keratinocyes, epithelial cells, B- cells, and osteocytes.
 Increases the expression of ICAM-1 o endothelial cells and stimulates secretion
of the chemokine CXCL8 facilitatng the infiltration of neutrophils into the
affected tissues.
 Synergizes with other proinflammatory cytokines and PGE2 to induce bone
resorption.
 Plays a role in adaptive immunity
 Regulates the development of antien- presenting cells, such as dendritic cells,
stimulates IL-6 secretion by macrophages
 Enhance antigen- mediated stimulation of T- cells

41. IL-1 α
 Intracellular protein
 Biologically active IL-1 α mediates inflammation only
when released from necrotic cells
 Act as ‘ alarmin’ to signal the immune system during
immune system during cell and tissue damage.
 Acts as a signalling cytokine and contribute to bone
resorptive activity.

42. IL-1 Ra
 Antagonizes the action of IL- 1β
 Antiinflammatory cytokine
 Levels are found to be elevated in the GCF and tissue of patients with
periodontal disease, suggesting a role in immunoregulation in periodontitis.

43. IL-18
 Results in proinflammatory responses, including activation of neutrophils.
 It is a chemoattractant for T- cells, thereby activating cell- mediated
immunity.
 Ability to induce either Th1 or Th2 differentiation , it is likely to play an
important role in periodontal disease pathogenesis.

44. Tumor Necrosis Factor Alpha
 Increases neutrophil activity, mediates cell and tissue turnover by inducing
MMP secretion.
 Stimulates the development of osteoclasts and limits tissue repair by induction
of apoptosis in fibroblasts.
 Secreted by activated macrophages, as well as other cell types, particularly in
response to bacterial LPS.
 GCF levels of TNF-α increase as gingival inflammation develops, and higher
levels are found in periodontitis
 Proinflammatory effects of TNF-α include stimulation of endothelial cells to
express selectins that facilitate leukocyte recruitment, activation of
macrophage, IL- 1β production, induction of PGE2 by macrophages and
gingival fibroblasts

45. Interleukin-6 and Related Cytokines
 Include IL-6, IL-11, Leukemia- inhibitory factor, Oncostatin M
 IL- 6 secretion is stimulate by cytokines such as IL- 1 β and TNF- α
 Produce by T-cells, B-cells, macrophages, dendritic cells, keratinocytes,
endothelial cells, and fibroblasts
 IL- 6 is also secreted by osteoblasts and stimulates bone resorption and
development of osteoclasts.
 IL- 6 is elevated in the cells, tissues, GCF of patients with periodontal
disease.

46. 2. Prostaglandins E2
 Produced by macrophages and fibroblasts.
 Levels are increased in the tissues and GCF at sites undergoing periodontal
attachment loss.
 Induces secretion of MMPs and osteoclastic bone resorption and contributes
significantly to the alveolar bone loss seen in periodontitis.

47. 3. Matrix Metalloproteinases
 MMPs play a key role in periodontal tissue destruction.
 In healthy tissues, MMP are mainly produced by fibroblasts, which produce
MMP1, which have a role in the maintenance of the periodontal connective
tissue.
 The great majority of MMP activity in the periodontal tissue derives from
infiltrating inflammatory cells rather than from bacteria.
 MMP-8, MMP-9, are secreted by neutrophils and are very effective at
degrading type 1 collagen, the most abundant collagen type in the periodontal
ligament.
 MMP-8 and MMP-9 levels increase with increasing severity of periodontal
disease and decrease after treatment.
 MMPs are expressed by osteoclasts and are important in alveolar bone
destruction.

49. IMMUNE RESPONSES IN PERIODONTAL
PATHOGENESIS
INNATE IMMUNITY
 Innate immunity refers to the elements of the immune response that are
determined by inherited factors, have limited specificity, and are “ fixed”, in as
much as they do not change or improve during an immune response or as the
result of previous exposure to a pathogen.
 If innate immune responses fail to eliminate infection, then the effector cells of
adaptive immune responses are activated.

50. 1. Saliva

51. 2. Epithelial Tissues
 The keratinized epithelium of the sulcular and gingival epithelial tissues not only
provides a protection for the underlying periodontal tissue but also acts as a
barrier against bacteria and their products.
 The spaces between the cells of Junctional epithelium widen with inflammation,
resulting in increased GCF flow.
 In periodontitis, epithelial cells become more rounded and tend to detach from
the underlying connective tissue.

52.  Infection through the basement membrane and into the underlying
connective tissues is facilitated by bacterial- derived proteases and host
proteases derived from infiltrating neutrophils.
 Epithelial cells express antimicrobial peptides and the synthesis and
secretion of these molecules is upregulated in response to periodontal
bacteria.
 Epithelial cells also secrete cytokines like IL-1β, TNF- α, IL-6, IL-8, MCP-
1 serve to signal neutrophil and monocyte migration from the vasculature
into periodontal tissue.

53. 3. Gingival Crevicular Fluid
 It has a flushing action in the gingival crevice but also likely functions to
brig the blood components of the host defenses into the sulcus.
 The flow of GCF increases in inflammation, and neutrophils are an
especially important element of GCF in health and disease.

54. 4.Pathogen Recognition and Activation of Cellular
Innate Responses

55. 5. Neutrophil Function
 ‘Professional phagocytes’ critical to clearance of bacteria that may invade host
tissues.
 Neutrophil migration through the intercellular spaces of the junctional
epithelium is a part of “ low grade defense” against plaque bacteria and is
necessary to prevent inflammation and periodontal tissue damage.
 The presence of a layer of neutrophils in the junctional epithelium forms a
host defense barrier between subgingival plaque and gingival tissue.

56.  Inactivated PMNs have been shown to cause damage to gingival epithelial
cells and periodontal ligament fibroblasts.
 Increased tissue levels of PMNs have been associated with active
(destructive) periodontal lesions , whereas salivary or gingival crevicular
fluid levels of neutrophil proteolytic enzymes such as collagenase and
elastase correlate with disease activity or clinical indices of disease

57. ADAPTIVE IMMUNITY
 Adaptive immunity is slower and reliant on complex interactions between
antigen- presenting cells and T- and B- Lymphocytes.
 The importance of adaptive immune responses in periodontal pathogenesis
is endorsed by histologic studies of established lesions in periodontal
disease.
 In active periodontitis, B-cells and plasma cells predominate and are
associated with pocket formation and progression of disease.

58. 1.Antigen- Presenting Cells
 Sentinel cells in mucosal tissues such as the periodontium.
 Detect and take up microorganisms and their antigens, after which they may
migrate to lymph nodes and interact with T-cells to present antigen.
 B-cells, macrophages, dermal dendritic cells, Langerhans cells, fibroblasts,
epithelial cells express major histocompatibility complex Class II molecules
necessary for antigen presentation to cognate T- cell receptors.

59. 2. T- Cells
 T-cells are the predominant phenotype in the stable periodontal lesion.
 Alterations in the balance of effector T-cell subsets within the CD4 population
may lead to progression toward a destructive, B- cell dominated lesion.
 The best defined functional subsets of CD4 T-cells are the Th1 and Th2 cells, and
a dynamic interaction between Th1 and Th2 cells may provide an explanation for
fluctuations in disease activity and progression of periodontal disease.

61.  Cytokines produced by differentiated T- cell subsets feedback to stimulate
differentiation and sustain the activity of the cells from which they are derived.
 The plethora of functional subsets of T- cells, their anatomic location, and their
ability to switch phenotype is a reflection of the requirement for effective
responses against diverse pathogens.
 Periodontal pathogenesis involves complex interactions between a number of
interacting T-cell subsets that not only modulate adaptive immune function (
Th1, Th2 and Treg cells ) but also feedback to modify and enhance innate
function ( Th17 cells ).

62. 3. Antibodies
• Circulating antibodies may be more important than locally produced
antibodies.
• High levels of antibodies appear in GCF, and these are produced locally by
plasma cells in periodontal tissues.
• Antibodies to periodontal pathogens are primarily IgG with few IgM or IgA
types produced.
• Many species of oral bacteria elicit a polyclonal B-cell response which
augment responses against nonoral bacteria and lead to production of
autoantibodies.

63.  The incidence and levels of specific serum and GCF IgG antibodies are
raised in chronic periodontitis, which suggests that local and peripheral
generation of antibodies may be important in the immune response to
periodontal pathogens.
 Specific antibodies are generated by serotype specific carbohydrate
antigens.
 The subclass distribution of antibodies is influenced by cytokines derived
from monocytes.
 The significance of antibodies whether they have a protective function or
they participate in disease pathogenesis is unclear.

64. CONCEPT OF HOST SUSCEPTIBILITY
 A number of risk factors increase susceptibility to
periodontal disease, including smoking, systemic diseases
such as diabetes, nutritional factors, stress etc
 Individuals possessing a hyperinflammatory phenotype
accounts for the increased susceptibility to chronic
inflammatory conditions such as periodontitis.
 It is likely that there are many reasons contributing to
disease variation between individuals, such as variation in
immune responses, pathogenesis, and the plaque biofilm,
resulting in an uneven disease experience in the
population.

65. Molecular aspects of the pathogenesis of periodontitis
Host response and local inflammation
 The colonizing microbes on mucosal surfaces, together with extracellular ATP
or extracellular DNA, activate the inflammasome.
 The release and secretion of proinflammatory cytokines activates PMNs
 Reactive oxygen species are also required
 Together with neutrophil diapedesis and chemotactic migration toward
the site of bacterial infection ,local capillaries also release an enhanced
amount of serum as a result of the effects of histamine and complement
C3a and C5a upon vascular permeability.

66. Barrier function of the oral epithelium and the role of dendritic
cells
 Keratinocytes are physical barrier cells as, upon stimulation by pathogens
contribute to the local host response by releasing proinflammatory cytokines.
 Gingival keratinocytes produce defensins, which act on microbes to effect their
killing.
 Dendritic cells capture and process antigens and express the costimulatory
molecules and cytokines required for antigen presentation to B- and T-
lymphocytes.
 When dendritic-cell-mediated immune homeostasis is disrupted, dendritic cells can
contribute to the pathogenesis of different destructive inflammatory conditions.

67. Natural killer cells
 They are a distinct subgroup of cytotoxic lymphocytes.
 Kill target cells without prior sensitization, by direct contact and indirectly by
producing proinflammatory cytokines, especially interferon γ.
 Ability to distinguish between self and foreign antigens and, in contrast to T-
cells.
 Interferon γ inhibits most of the activities induced by T-helper 2 cytokines
indicating potential importance of natural killer cell activities in the
pathogenesis of inflammatory periodontal diseases.

68. T- and B-cell subsets
 The T-helper-cell population is characterized by different cell subsets, such as T-
helper 1, T-helper 2 and T-helper 17 cells, regulatory T-cells and follicular helper
cells.
 Elevated levels of T-helper 17 cells are found in the gingiva from patients with
periodontitis.
 T-helper 2 commitment produce IL-4, IL-5, IL-9, IL-10 and IL-13, and provide
optimal help for humoral immune responses, including IgE and IgG1 isotype
switching, and mucosal immunity.

69. MicroRNAs in the etiopathogenesis of periodontal disease
 Aberrant expression of microRNAs triggers the dysregulation of multiple
cellular processes involved in both innate and adaptive immune responses,
leading either to ineffective countering of microbial challenges or to excessive
catabolic responses.
 The pathways controlling dendritic cell functions are tightly regulated by
micro- RNAs.
 The reduced amount of miR-141 in the diseased state is inversely related to
the increased expression of these proteins in disease.

70. Concepts In The Models Of Pathogenesis
Linear Model
• Mid- 1960s
• Bacteria cause periodontal disease
 Bacterial plaque deposits as the primary, direct factor in the development of
periodontitis
 The abandonment of non-bacterial factors such as trauma from occlusion,
systemic conditions, and diet in the development of periodontitis

72. Basic conceptual model - circa model (1980 model):-
 A dynamic equilibrium between the periodontal microbiota and the host
generally results in a clinical state of periodontal health.
 alterations in the host-parasite equilibrium may result in transient episodes
of tissue destruction
 Specific Gram negative, anaerobic, or microaerophilic bacteria were
implicated in the causation of periodontitis.
 Protective and destructive roles of the immune-inflammatory responses and
the critical role of PMNs in contributing to periodontal damage were
described.

73.  Distinction between the role of the microbial challenge and immune-
inflammatory mechanisms in the pathogenesis of periodontal disease was
apparent.
 Drawbacks: This model could not explain some clinical disease patterns or
phenotypes which had characteristic bacteria and host responses.

74. Critical pathway model
 In 1990 advances has led to the understanding the cellular and molecular
interaction which resulted in periodontal disease progression.
 This led to critical pathway of pathogenesis by Offenbacher in 1996.
 Genetic differences among individuals seemed to be a significant determinant
of risk for periodontal disease.
 Most importantly there were gene variations that altered host responses and
modified the clinical severity of disease.
 Smoking and diabetes were shown to be powerful determinants of
disease severity.

76. Non-linear model
 The basic conceptual model of periodontitis was revised in 1997.
 Host immunoinflammatory mechanisms are activated by bacterial products.
 Host derived enzymes such as matrix metalloproteinase as well as changes in
osteoclast activity driven by cytokines and prostanoids cause most of the tissue
destruction.
 Each combination of genetic variations and environmental factors may define a
specific gene expression pattern.

77. Page and Kornman ; 1997

78. Multilevel hierarchical model
 The top layer includes clinically observable parameters,such as smoking,
whereas the levels below include tissue, cellular, and sub cellular layers, each
divided into biologic networks.
 At the lower levels, the biologic expression of the immune inflammatory
network and bone and connective tissue network are determined by the
microbial factors and the specific combination of environmental factors and
gene variations for that individual.

80. New Biological systems model
 This model involves bacterial components, environmental factors such as
smoking and diabetes.
 The expressed proteins and metabolites provide feedback on the system to
regulate the host response and bone and connective tissue, while helping to
control the bacterial challenge.

82. The Keystone Pathogen Hypothesis
 Holds that certain low-abundance microbial pathogens can orchestrate
inflammatory disease by remodeling a normally benign microbiota into a
dysbiotic one.
 P. gingivalis could be a keystone pathogen of the disease provoking
periodontal microbiota.
 Obligatory participation of the commensal microbiota in disease
pathogenesis was shown by the failure of P. gingivalis alone to cause
periodontitis in germ-free mice, despite its ability to colonize this host.

83. Keystone pathogen-induced dysbiotic disease
 The ability of P. gingivalis to orchestrate inflammatory disease via
community-wide effects, while being a minor constituent of this community,
qualifies it as a keystone pathogen.
 P. gingivalis subverts complement and impairs host defense leading to
overgrowth of oral commensal bacteria, which cause complement-
dependent inflammation.
 Inflammatory bone resorption provides the dysbiotic microbiota with
new niches for colonization.

85. Polymicrobial synergy and dysbiosis model
 The dysbiosis of the periodontal microbiota signifies a change in the relative
abundance of individual components of the bacterial community compared
to their abundance in health, leading to alterations in the host–microbe
crosstalk sufficient to mediate destructive inflammation and bone loss.

87. Synergism among periodontal bacteria
 P. gingivalis can provide a source of free glycine and isobutyric acid for T.
denticola growth, while T. denticola produces succinic acid which enhances
growth of P. gingivalis.
 S. gordonii and A. actinomycetemcomitans interact on a number of levels. S.
gordonii produce lactate as an end product of metabolism, and A.
actinomycetemcomitans displays resource partitioning to favor lactate as a
carbon source even in the presence of alternative carbon sources such as glucose
or fructose.

88. Interactions between bacterial communities and
epithelial cells
 A consortia of P. gingivalis and Fusobacterium nucleatum invade gingival
epithelial cells in higher number than either organism alone.
 F. alocis and P. gingivalis also exhibit synergistic infection of epithelial
cells, and dual species invasion elicits a distinct pattern of host cell
responses.

89. Manipulation of host immunity
 P. gingivalis and certain other periodontitis‐associated bacteria can suppress
complement activation through the action of specific proteolytic enzymes.
 Polymicrobial synergy and dysbiosis drive periodontitis in a susceptible
host.
 Dysbiosis involves specialized accessory and keystone pathogens and
pathobionts.

90. Contemporary model- Chapple 2015
 It is based upon a circular relationship between the periodontal biofilm and
the inflammatory immune response.
 Inflammation also contributes to the biofilm structure and function and there
is a need for metagenomic studies to start defining what functional
characteristics of the biofilm render it pathogenic as opposed to health
promoting.
 Pathogenic roles for viruses are emerging, either as priming agents of host
immune cells or as co-infectors alongside bacteria, conspiring together to
deregulate host-defence systems.
 The key features of immune disruption in periodontitis include excessive
inflammation that fails to resolve and becomes chronic and self-destructive
in nature, generating an environment that favours pathogenic bacteria.

93. MODIFIERS OF PERIODONTAL DISEASE
PATHOGENESIS
 Diabetes
 Smoking
 Stress
 Allergy
 HIV infection
 Osteoporosis
 Anemia

94. LINKING PATHOGENESIS TO CLINICAL SIGNS OF
DISEASE
 Increased infiltration ofinflammatory cellss, particularly neutrophils, results in
development of collagen- depleted areas below the epithelium and as a result, the
epithelium proliferates to maintain tissue integrity.
 Antimicrobial peptides, termed defensins, are expressed by epithelial cells, and
gingival epithelial cells express two human β defensins( Hbd-1 and hBD-2)
 Antimicrobial peptides are important in determiing the outcomes of the host-
pathogen interactions at the epithelial barrier.

95.  Neutrophils release their potent lysosomal enzymes, cytokines, and reactive
oxygen species extracellularly causing tissue damage.
 The very first steps in the development of the pocket result from a
combination of factors, including detachment of cells at the coronal aspect
of the junctional epithelium as those at the apical aspect migrate apically
into collagen- depleted areas and intraepithelial cleavage within the
junctional epithelium.

96. Alveolar Bone Resorption
 This is a protective mechanism to prevent bacterial invasion of the bone, but
it ultimately leads to tooth mobility and even tooth loss.
 Factors that determine whether bone loss will occur
 The concentration of inflammatory mediators in the gingival tissues must be
sufficient to activate pathways that lead to bone resorption
 The inflammatory mediators must penetrate to within a critical distance of
the alveolar bone.

97.  It has also been demonstrated that bone resorption ceases when there is at
least a 2.5 mm distance between the site of bacteria in the pocket and the
bone.
 Osteoclasts are stimulated by proinflammatory cytokines and other
mediators of inflammation to resorb the bone, and the alveolar bone
“retreats” from the advancing inflammatory front.
 Other mediatos that also stimulate bone resorption include LIF, oncostatin
M, bradykinin, thrombin, and various chemokines.

98. Receptor Activator of Nuclear Factor- κB Ligand/
Osteoprotegrin
 A key system for controlling bone turnover is the receptor activator of nuclear
factor- кB (RANK)/RANK ligand (RANKL)/ osteoprotegrin (OPG) system.
 RANK is acell surface receptor expresses by osteoclast progenitor cells as well
as mature osteoclasts.
 RANKL is a ligand that binds to RANK and is expressed by bone marrow
stromal cells, osteoblasts, fibroblasts.
 Binding of RANKL TO RANK results in osteoclast differentiation and
activation and thus bone resorption.

99.  Another ligand that binds to RANKL is OPG that has the opposite
effect.
 Levels of RANKL are higher and levels of OPG are lowe insites with
active periodontal breakdown compared to sites with healthy gigiva.
 GCF RANKL: OPG ratios are higher in periodontitis tha health.

100. RESOLUTION OF INFLAMMATION
 Resolution of inflammation is an active process that results in a return to
homeostatis, and is mediated by specific molecules including a class of
endogenous proresolving lipid mediators, the lipoxins, resolvins, and
protectics.
 These molecules are actively synthesised during the resolution phases of
acute inflammation, they are inflammatory , and they inhibit neutrophil
infiltration.
 They are also chemoattractants but do not cause inflammation

101. 1. LIPOXINS
 Lipoxins are lipoxygenase derived eicosanoids and are generated from
arachidonic acid.
 Lipoxins include lipoxin A4 (LXA4) and lipoxin B4 ( LXB4).
 They are highly potent, possessing biologic activity at very low
concentrations, and inhibit neutrophil recruitment, vhemotaxis, and
adhesion.
 Signal macrophages to phagocytose the remnants of apoptotic cells at sites
of inflammation, without generating an inflammatory response.
 Pro- inflammatory cytokines such as IL- 1 released durig acute
inflammation can induce expression of lipoxins, which promote resolution
of the inflammatory response.

102. 2. RESOLVINS
 They are derived from omega-3 fatty acids eicosapenraenoic acid and
docosahexaenoic acid and are classified as the E series resolvins (RvE) and
D series resolvins (RvD), respectively.
 Resolvins inhibit neutrophil infiltration and transmigration, they inhibit the
production of proinflammatory mediators, and they have potent
antiinflammatory and immunoregulatory effects.
 They are highly potent and have shown to reduce neutophill transmigration
by around 50% at concetrations as low as 10nM,

103. 3. PROTECTINS
 Protectins are derived from DHA.
 Produced by glial cells and reduce cytokine expression.
 Inhibit neutrophil infiltration.
 The release of endogenous proresolving molecules that “switch off”
inflammation and acts as a braking signal for neutrophil activity indicates
that control of inflammation is an active process.
 Inadequate resolution of inflammation is likely to be an important
component of the pathogenesis of periodontitis.

104. REFERENCES
 Newman, Takei, Klokkevold, Carranza.Carranza’s Clinical Periodontology
for South Asia. 11th Edition
 Lindhe J, Lang N P. Clinical Periodontology and Implant Dentistry. 6th
Edition
 Pereira V A, Pai B S J , Pattanshetty R S A. A Review on Models of
Pathogenesis in Periodontitis. Int. J. Adv. Res.2017: 5(12), 1115-1124.
 Preshaw PM, Seymour RA, Heasman PA. Current concepts in periodontal
pathogenesis. Dent update. 2004 ;31 (10):570-8.
 Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways
in the pathogenesis of periodontal disease. Periodontol 2000. 2014;64(1):57-80.
 Meyle J, Chapple I. Molecular aspects of the pathogenesis of periodontitis.
Periodontol 2000. 2015;69(1):7-17.

105. THANK YOU