pathogenesis Flashcards
3 essential functions by which bacteria is able to cause perio
1) colonisation of host tissues
2) evading host defense mechanisms
3) toxins
what is direct vs indirect pathogenicity
direct is when bacteria produces virulence factors like exotoxins that enable them to induce tissue damage
indirect is when bacterial components eg endotoxins like LPS induce host inflammatory response, and dysregulated host responses lead to tissue damage and perio disease
how does calculus form
through calcification of microbial plaque
develops when non mineralised biofilms rich in oral bacteria become mineralised with calcium phosphate mineral salts
what does the natural hx of perio disease study tell us
it is a sri lankan & norwegian study by Loe et al 1986
sri lankan tea labourers with no dental care had mor rapid rate of progression vs
norwegian academics with good dental care had minimal inflammation
4 pieces of evidence that plaque causes perio disease
1) Beagle dogs (lindhe, hamp and loe 1973) cleaned baseline and plaque accumulation in experimental. compared to control, experimental group had signs of disease and the control had none
2) natural history of perio disease - Loe et al 1986, sri lankan tea labourers with no dental care had more rapid rate of progression vs norwegian academics with good dental care
3) experimental gingivitis in man (Loe 1965) dental students and personnel asked not to OH for 2-3 weeks and gingivitis happened in 14-21 days while reinstitution of OH resolves it in 7 days
4) clinical experiment on schoolchildren done by Axelsson and Lindhe 1974-1978, best study so far because followup of 30 years
- 2 groups, one received intensive treatment while the other received 6 monthly/yearly review
- experimental group had negligible gingivitis/ CALoss, no caries
- control group had gingivitis and 1.2mm CAL and new caries
how does diabetes cause perio
1) direct effect on microbial flora, vascular changes
2) impaired host response (altered PMN function like:
- impaired chemotaxis
- impaired adherence
- delayed neutrophil apoptosis hence increased retention of neutrophils in periodontal tissues and hence increased tissue damage by release of destructive enzymes including MMP and ROS by the neutrophils
3) altered CT metabolism (increased breakdown)
4) upregulated inflammatory response due to accumulation of AGEs (advance glycated end products)
- monocytes possess a receptor for AGEs, known as RAGE and binding of RAGE on monocytes to AGEs leads to activation of local immune and inflammatory responses
- cause release of pro inflamamtory cytokines (IL1, IL6, TNFa), increased oxidative stress,
- and disrupt RANKL/OPG axis to favour bone resorption
what is the evidence for perio worseninng diabetes
Kiran et al 2005:
- improve glycemic control following perio therapy
but Jones et al 2006, Wennstrom et al say ITS BS
Mechanism:
- perio is a gram negative infection that involves TNFa and other cytokines like IL1b producing insulin resistance syndrome,
- even initiating destruction of pancreatic beta cells
how does smoking contribute to perio
1) smokers harbour more pathogenic oral flora (Aa, Tf, Pg)
- even though rate of plaque formation compared to non is the same, but calculus formation is faster due to non biologically compatible rough root surfaces
- lower o2 tension in pockets vs non smokers
2) vascular changes (nicotine release epinephrine and has a vasoconstrictive effect)
- so negative effects on healing following non surgical/ surgical perio therapy
3) impaired collagen metab
- impaired gingival/ pdl fibroblast recruitment
- collagenolysis increases, collagen synthesis down
- PDL fibroblasts growth and attachment is inhibited by nicotine
4) smoking stimulates monocytes/ macrophages to release inflammatory mediators (IL1, IL6, TNFa, CRP)
5) Impaired host defence (poor neutrophil migration, chemotaxis)
6) shift neutrophil towards more destructive tendency hence more release of MMP
- nicotine can trigger PMN degranulation also
how does perio disease affect CVD
2 different pathways in which perio can affect atherosclerotic lesion formation
1) direct pathway
- perio give bacteremia then inflammation (IL1, IL6, TNFa)
- then blood vessel alteration
- vascular changes/ atherosclerosis
- then thrombus hence CVS
2) indirect pathway
- bacterial endotoxin/ pro inflammatory cytokines go into bloodstream then inflammation
- liver has acute phase response releasing CRP, fibrinogen, amyloid A proteins
- release of chemokines initiate leukocyte migration
- upregulation of macrophages which means increased risk of atherosclerosis because macrophages actively ingest and accumulate modified cholesterol and transform into foam cells, hence contributing to plaque growth
how does obesity affect perio
- adipocytes and macrophages in adipose tissue secrete TNFa and IL6, which increase osteoclast formation through upregulation of RANKL expression
then TNFa and IL6 stimulate production of acute phase proteins which impact the ability of perio tissues to respond appropriately to bacterial challenge, leading to enhanced tissue destruction
TNFa also increase host response to perio pathogens by recruitment of PMNs
what are interleukins and their roles
- is a type of cytokine
- serve as growth and differentiation factor for immune cells
- can either be pro or anti inflammatory
role of IL17
- enhances RANKL expression on osteoblast and CD4 T cell
- contributes to local inflammation by recruiting and activating immune cells, increasing IL1b and TNFa
how does the RANK RANKL system work, + OPG action
- RANK found in osteoclast precursor (receptor)
- RANKL found in osteoblast precursor (as well as fibroblasts, T and B cells)
- RANKL binds to RANK and causes osteoclast precursor to differentiate into active osteoclasts
- RANKL’s synthesis from osteoblasts, fibroblasts, t and b cells, is induced by pro inflammatory cytokines IL1b, TNFa
- osteoprotegerin (OPG) is a decoy receptor molecule which is produced by fibroblasts and endothelial cells
- OPG competes with RANK receptor for RANKL
- so RANKL on osteoblasts bind to OPG
- leads to reduced active osteoclast formation (because less RANKL bind to RANK on osteoclasts to activate them)
- leads to apoptosis of pre existing osteoclasts
- OPG production is upregulated by anti inflammatory cytokines (so these anti inflam cytokines want LESS bone resorption so less osteoclastic activity)
role of IL1
- potent pro inflammatory
- MAINLY produced by activated macrophage and lymphocytes
- but can be released by mast, fibroblast, keratinocytes and endothelial cells
- bacterial LPS is a potent activator of macrophage IL1 production
- IL1 and TNFa can activate production of IL1
role:
- activates T and B cells
- stimulates secretion of PGE2 and MMPs
- stimulates osteoclast proliferation, differentiation, activation
- IL1 is one of the most active stimulator of osteoclastic bone resorption
- IL1B gene polymorphism can result in heightened host immune response
role of TNFa
- produced by activated macrophages in response to LPS
- activates osteoclasts and stimulates bone resorption
- far less potent than IL1
what are chemokines
- produced by many cells in response to infection or physical damage
- activates and directs effector cells expressing the appropriate chemokine receptor to migrate to sites of tissue damage and regulate leukocyte migration to tissue
- hence chemokines are responsible for chemotaxis
- mainly produced by resident cells (epithelial cells, fibroblasts)
- CC chemokines: chemotactic for monocytes
- CXC chemokines: chemotactic for neutrophils
what are MMPs
- proteolytic/ collagenolytic zinc dependent endopeptidases capable of degrading ECM
- Involved in perio destruction by degrading ECM (collagen, gelatin, elastin).
- there is strong evidence suggesting involvement in bone resorption and inflammatory mediated destruction of perio tissues
- produced by neutrophils, macrophages, fibroblasts, epithelial cells, osteoblasts, osteoclasts
- in response to certain growth factors and cytokines (IL1, TNFa, TGFa)
- regulated by tissue inhibitors of metalloproteinases (TIMPs)
- increased MMP level found in GCF and tissue of diseased sites
- higher MMP 1,3,8 and TIMP1 in diseased samples
histology of gingivitis
aka incipient dysbiosis
initial (0-4 days) - clinically increased GCF
- acute inflammation limited to JE and most coronal part of CT
- vasculitis of vessels subjacent to JE
- exudation of fluid from gingival sulcus
- increased migration of leukocytes (mainly neutrophils) into JE and gingival sulcus
- lose peri vascular collagen
- presence of serum proteins especially fibrin extravascularly
early (4-8 days) - clinically got BOP, erythema
- proliferation of basal cells of JE
- accumulation of lymphoid cells (mainly lymphocytes) immediately subjacent to JE at the site of acute inflammation
- loss of collagen fiber network supporting marginal gingiva
how does gingivitis progress to periodontitis
- in susceptible patients (eg overactive IL1, neutropenia), incipient dysbiosis triggers inappropriate and excessive host response (hence got more cytokines, MMPs)
- this overwhelms antagonists like TIMPs
- collateral perio tissue damage is caused, increasing collagen degradation
- body will attempt to heal but the rich nutritional environment created by angiogenesis sustains dysbiosis and pathogenic biofilm
- failure of innature inflammation resolving mechanisms result in chronic inflammatory lesions
- macrophages become activated and enhance inflammatory response + immune response initiated
- activated macrophages produce chemokines which recruit more monocytes + lymphocytes to the area
- MMPS produced by neutrophils, macrophages, fibroblasts, epithelial cells, osteoclasts and osteoblasts
- cytokines produced by macrophages, monocytes, t helper cells and these promote collagen degradation
- reduced collagen synthesis by local fibroblasts: apical migration of JE, loss of CT attachment with degraded collagen and start of bone resorption
HIStology of periodontitis (established and advanced lesions)
established (14-21 days) - changes in colour, size, texture
- persistence of acute inflammation
- predominantly plasma cells
-presence of immunoglobulins extravascularly in CT and JE
- continuing loss of CT
- proliferation and apical migration and lateral extension of JE
- no appreciable bone loss yet (technically established lesion is not perio yet)
advanced lesion - deep PPD, BOP, suppuration, surface ulceration, mobility
- predominantly plasma cells
- persistence of features above
- extension of lesion into alveolar bone and PDL - significant bone loss, continued loss of collagen
- formation of perio pockets
- periods of quiescence and exacerbation
- widespread manifestation of inflammatory and immunopathologic tissue reactions
how does biofilm form
adhesion of microorganisms to the tooth surface is a complex process involving initially weak, long range electrostatic attractive forces, followed by specific strong short range molecular interactions between bacterial adhesions and receptors adsorbed to the surface
extracellular polysaccharides contribute to the plaque matrix, along with proteins, lipids and eDNA
fusobacteria act as a bridge between early and late colonising bacteria
criteria for defining perio pathogens
1) association
- high numbers in perio disease, absence in periodontally healthy subjects
2) host response
- elevated antibodies in serum, saliva and GCF to the putative pathogen
3) virulence factors
- organism demonstrates in vitro production of virulence factors
4) animal studies
- inoculation of organism into the gingival crevice of an animal model leads to perio disease
5) elimination
- elimination of organism from lesion should result in clinical improvement
ecology of perio pocket
- highly anaerobic
- pathogens like T forsythia and P gingivalis are obligate anaerobes
- anaerobic bacteria lack or have low levels of superoxide dismutase that destroy superoxide by converting it into oxygen and h2o2
- perio pocket consists of mostly proteolytic bacteria living which raise the pH to alkaline levels (pH 7.4-7.8) compared to neutral values in health
- increased pH promotes growth of bacteria eg P gingivalis
smoker classification
what is current, former, occasional, moderate and heavy
current is within 12 months by right
but if quit recently but not 5 years yet, its known as recent quitter
if quit for 5 years or more, its former smoker
occasional: less than 10 sticks a day
moderate: 11-19 sticks a day
heavy smoker: 1 pack/ 20 sticks a day
