5. Periodontal Immunology Flashcards
The inflammatory cascade and its consequences
____: infectious agents, tissue damage (sterile inflammation) > ____: PRR, complement > ____: cytokines, chemokines, anaphylatoxins, eicosanoids > ____: immune cells/tissues
Consequences:
Physiological (homeostatic immunity, ____ defense controls infection) > ____ response (ideal scenario)
Pathological > tissue ____ > inflam ____ (perio/RA)
\_\_\_\_ inducers sensors mediators effectors
host
tissue-repair
damage
disease/autoimmunity
The Immune System from an Oral Perspective
Host defense mediated by ____ (contains ____ defense factors)
Adaptive immunity represented by ____
saliva
innate
S-IgA
- Periodontitis is a prevalent ____ inflammatory disease that compromises the integrity of the tooth-supporting tissues.
- These include the ____, ____ ligament and ____ bone, collectively known as the periodontium.
Almost ____% of adults have some form of Periodontal disease.
Most of them have a very modest form while ____% of the population have severe periodontitis.
chronic gingiva periodontal alveolar 50 10
Periodontal Diseases
Gingivitis
Swollen gingiva, bleed easily.
____ inflammation
Periodontitis
Destruction of the ____ ligament; loss of tissue attachment to the teeth.
Deepening of the gingival crevice / ____.
____ bone loss.
Gingivitis: affects ____ layers of gingiva
Destruction of underlying bone only present in perio, not gingi
reversible periodontal periodontal pocket alveolar superficial
Periodontal Diseases
____-induced gingivitis and ____ periodontitis are the most frequent forms of periodontal disease.
However, there over 40 different periodontal conditions according to a 1999 classification system.
Other conditions include ____ periodontitis, periodontitis as a manifestation of ____ disease, ____ periodontal diseases, abscesses of the periodontium, and periodontitis associated with ____ lesions.
biofilm (plaque) chronic aggressive systemic necrotizing endodontic
Bone loss and inflammatory tissue damage in chronic periodontitis
• Radiographic status of a patient with advanced chronic periodontitis.
Arrow indicates normal position of alveolar bone crest.
• Photomicrograph of section of a tooth root surface (1)
with calculus and plaque (2), periodontal pocket (3)
ulcerated pocket epithelium (4), and gingival epithelium (5).
Note the ____ inflammatory infiltrate
in the subepithelial connective tissue next
to the ulcerated pocket epithelium.
Bone should be at point where arrow is
Biofilm associated with ____ disease; ____ of gingival sulcus and presence of ____ cells
chronic
inflam
ulceration
inflam
Periodontitis-associated biofilm
Periodontitis is initiated by communities of ____ bacteria.
The first multispecies biofilm ever viewed by man (in 1683 by van Leeuwenhoek) was bacteria (‘animalcules’) from ____ scrapings
subgingival anaerobic
tooth
Bacteria are necessary to cause periodontitis but what is their exact role?
Enduring principles
• Bacteria: necessary but not ____.
• Tissue destruction / bone loss mediated by ____ response.
• Disease requires a ____ host.
Bacteria cannot directly inflict damage on perio tissue; inflam host response to microbial challenge is what mediates the damage
Not everyone gets perio disease > people who never brush teeth, no inflam/perio/bone loss > requires susceptible host
sufficient
host
susceptible
Bacterial complexes in dental biofilms (culture-based studies)
- Until fairly recently, the identities of the organisms associated with periodontal lesions or with periodontal health were limited to those that could be ____ in the laboratory.
- On the basis of association with different disease states, these organisms were divided into groups of differing potential pathogenicity.
These bacteria (circled in blue) are ____ associated commensals. You can see the ____ complex which includes P. Gingivitis, T. Forsythia, T. Denticola. These were supposed to be the most important bacteria that could be seen in ____. The ____ bacteria group were also believed to be involved in periodontal disease.
This is not actually wrong but many things have changed as the investigation of the oral bacteria involving
periodontitis has been improved through new molecular techniques that did not depend on using culture as many
bacteria are unculturable.
cultured health red periodontitis orange
Recent Microbiome Studies
• Recent human ____ and ____studies suggest that a more diverse periodontitis-associated microbiota than previously thought is involved in disease.
• Previously underappreciated species (e.g., F. alocis, P. stomatis, species from the genera Prevotella, Megasphaera, Selenomonas, & Desulfobulbus) exhibit at least as good a correlation with disease as traditional ____.
(Dewhirst et al 2010; Kumar et al, 2006; Griffen et al, 2012; Abusleme et al, 2013)
• The majority of virulence factors upregulated in the microbiome of periodontitis patients is primarily derived from previously ____ species that were not traditionally implicated in periodontitis
Not just a few select bacteria > it is now known that it is comprimised of a richer, more diverse pathogenic community
metagenomic
metatranscriptomic
“periopathogens”
underappreciated
Subgingival microbiome in health and periodontitis
- GRAY: present at equal prevalence and relative abundance in ____ and ____.
- GREEN: represents the core health-associated species, appearing at increased prevalence and relative abundance in ____ compared to disease.
- RED: represents the core ____ species, present at increased prevalence and relative abundance in periodontitis compared to health.
Doesn’t mean that all species in red compartment are found only in disease, but their ____ is much higher in disease than in health; and vice-versa
In middle: bacteria whose abundance doesn’t ____ much between perio health and perio disease
health periodontitis health periodontitis-associated abundance change
Recent microbiome studies confirm dramatic differences in the composition of the periodontal microbiota in health vs. disease.
This could be interpreted in two ways:
• # 1: Specific bacteria are involved in the etiology of periodontitis (i.e., the disease-associated microbiota contains ____ species acting as ____).
• # 2: The ecological shift from health to disease involves the emergence of ____ community members rather than appearance of novel species. Periodontitis is caused by ____.
• Recent evidence is consistent with interpretation ____
Newly-dominated > species at ____ abundance in perio health, but now for some reason numbers increase and they can cause perio disease; and vice-versa
novel
periodontal pathogens
newly-dominant
dysbiosis
low
Polymicrobial Synergy and Dysbiosis
• Periodontitis is not a ____ infection in the classical sense; no exogenous pathogen involved, not caused by a single or select few bacteria.
- Rather, periodontitis is the result of ____ polymicrobial synergy and ____ (PSD).
- PSD leads to disruption of tissue ____ and destructive inflammation in susceptible individuals.
- Different ____ or specific ____ within the microbial community fulfill distinct roles that converge to shape and stabilize a dysbiotic microbiota.
Does not conform to ____ postulates > no exogenous pathogen involved and is caused by a multitude of bacteria
bacterial
indigenous
dysbiosis
homeostasis
members
gene combinations
koch’s
Subgingival communities in health and periodontitis
- Periodontitis is not associated with novel species, but rather with increased relative abundance of certain species/genera (____).
- Conversely, certain taxa that dominate microbial communities in health display severely ____ abundance in periodontitis
dysbiosis
reduced
Dysbiosis:
A condition of ____ microbiota that is associated with disease, e.g., periodontitis or inflammatory bowel disease.
The dysbiosis of the periodontal microbiota represents an alteration in the relative ____ or influence of individual members of the polymicrobial community (relative to their abundance or influence in health) leading to ____ host-microbial interactions that mediate destructive inflammation and bone loss.
Numbers increase and reach a ____ at which they can become pathogenic > dysbiosis
imbalanced
abundance
dysregulated
What is ‘periodontal homeostasis’?
n Homeostasis: A condition of equilibrium or stability in a system, which is maintained by ____ physiological processes to ____ external changes, e.g., a ____ between a host tissue and the resident microbiota in ways that prevent destructive inflammation or disease.
n Periodontal health represents a dynamic balanced state where proinflammatory and antimicrobial activities are ____ to prevent unwarranted host reactions (homeostasis).
n Balance between the host and the microbiota (microorganisms of a particular site or habitat).
Opposite of dysbiosis
Dynamic condition
adjusting
counteract
balanced relationship
optimally regulated
Symbiosis
A close association of two different species (e.g., a microbe and a mammalian host) that live together without necessarily implying that either partner benefits.
____ represents symbiosis in which one species benefits (increases its fitness) at the expense of the other species, whereas in
____ both species benefit.
____ represents symbiosis in which one species benefits without adversely affecting the other species.
parasitism
mutualism
commensalism
The presence of periodontal bacteria does not necessarily cause disease - Symbiosis
n Healthy human gingiva display a coordinated gradient of ____ and cell adhesion molecules (e.g., ____) that is topographically associated with the pathway of neutrophil migration from the vasculature to the gingival sulcus.
n A similar gradient exists for ____ expression.
n Healthy gingiva (epithelial cells and leukocytes in the junctional epithelium) also express an array of host-defense molecules, many of which are induced upon ____ stimulation by bacteria.
n This physiological inflammatory state or homeostatic immunity ( ____) can keep the bacteria at bay.
IL-8 ICAM-1 TLR TLR armed peace
When homeostasis fails…
n The host-microbe homeostasis that characterizes a healthy periodontal tissue could be potentially destabilized by host-related factors such as ____, antibiotics, ____, systemic disease, and ____ deficiencies.
n Moreover, perturbations to the host-microbe ecosystem could also be precipitated by increased expression of ____ that subvert the host immune response.
Certain bacteria can subvert host response > disrupts tissue ____ and promotion of ____
diet
smoking
immune
microbial virulence
homeostasis
dysbiosis
Polymicrobial synergy & dysbiosis
Constituent organisms contribute to disease ____ rather than ____…
Bacteria act collectively > when present as individuals they have no impact on host, but once they assemble in ____ they do have an impact
Controlled immuno-inflammatory state; PSD: certain communities of bacteria are ____ enough to lead to a destructive inflam response
collectively
individually
communities
pathogenic
Polymicrobial-induced disruption of homeostasis and dysbiotic inflammation in susceptible hosts
- The keystone pathogen ____ can subvert complement and TLRs and impair host defense.
- This leads to uncontrolled growth of the periodontal microbiota which becomes dysbiotic (altered ____ and higher ____).
- The dysbiotic microbiota causes destructive ____ and bone loss.
- Inflammatory tissue destruction reinforces dysbiosis by generating ____ for the bacteria
P. Gingivalis (original red complex bacteria) > important in pathogenic community > subverts by preventing signaling pathways that can ____ bacteria, where inflam response that are harmless to bacteria are upregulated > preferential outgrowth of bacteria (____, requires proteins/peptides) that take advantage of new conditions
Destruction of gingival tissue > release of ____, and the new bacteria can feed; or ____ compounds upon bleeding > rich source of iron
p. gingivalis composition counts inflammation nutrients
destroy
catalytic
peptides
heme-compounding
Definition of KP; numbers may not be ____, but has a community-wide impact bc it can regulate ____ response which benefits other bacteria thereby leading to disease
high
host
P. gingivalis tips the balance toward dysbiosis by altering the composition and the counts of the microbiota
Keystone pathogen
- ____ abundance
- ____-wide impact
Remove KP > whole community ____ > remaining bacteria will not be as ____ as it was before
Experiment > bacteria present in mice before infection > once P gingivalis was introduced: suppressed ____ immunity and increased ____, host cannot control bacteria that started outgrowing (ones that benefit from inflammation, ____ bacteria) > higher in number, and different types of bacteria that enhances inflammation > ____ disease (not p gingi by itself)
low
community
collapses
pathogenic
innate
inflammation
catalytic
periodontal
Why does Pg need complement C5a receptor (C5aR) to promote the overgrowth of the oral microbiota?
In order for PG to subvert > requires complement > ____
C5aR
P. gingivalis exploits the ____ to impair the killing capacity of macrophages …without affecting their ____ responses
When PG interacts with C5aR and activates ____ > cross-talk signalling > inhibits production of ____ (potent antimicrobial molecules that macrophages use to kill bacteria)
C5aR
inflammatory
TLR2
NO
P. gingivalis exploits complement ____ crosstalk signaling to inhibit bacterial clearance while promoting inflammation
In human neutrophils:
• Pg disarms a host-protective ____ pathway.
• Pg activates an alternate TLR2-Mal-PI3K pathway, which blocks ____ and promotes ____ inflammation.
In neutrophils, same cross-talk used by PG:
Pathway downstream of TLR2 (MYD88): important in immune clearance of bacteria (but here it degrades MYD88 and nothing happens downstream) > gives bacteria chance to grow because neutrophils are ____; the pathway is also pre-inflammatory (bacteria need food from inflammation); same cross-talk activated MAL (terminal adaptor) > leads to ____ response (keeps inflammation going, thereby feeding the bacteria) and also inhibits ____ (important for neutrophil phagocytosis)
Inflammation only aids bacteria that can withstand ____
TLR2-MyD88
phagocytosis
dysbiotic
incapacitated
inflammatory
actin polymerization
inflammation
The presence of P. gingivalis does not necessarily precipitate disease
- P. gingivalis is ____, albeit with decreased frequency, in periodontally healthy individuals.
- Might be explained by the considerable ____ diversity within the population structure of P. gingivalis.
- Key virulence factors of this P. gingivalis (e.g., ____ and ____) are regulated by ____ environmental conditions, which may differ among individuals.
- There might be individuals who can resist the conversion of a symbiotic microbiota into a dysbiotic one by virtue of their ____ status (e.g., alterations in signalling pathways required for immune subversion by P. gingivalis).
- P. gingivalis as a ____ rather than cause.
Heterogenity in PG; some strains may be more ____
Gingipains activate ____; environmental conditions differ from one individual to another, same strains, but one may be more pathogenic due to ____ condition
Genetic: PM/SNP in the molecular downstream pathway, PG may not be able to affect the pathway
detectable strain gingipains lipid A phosphatases local
intrinsic immuno-inflammatory status
risk factor
pathogenic
C5aR
environmental
Polymicrobial-induced disruption of host homeostasis and inflammation
- In addition to P. gingivalis, other periodontal bacteria, such as, T. denticola, T. forsythia, P. intermedia have various ways to incapacitate host defense mechanisms.
- For instance, they can degrade ____ components, manipulate ____ expression, and block ____-dependent killing.
- These immune subversion mechanisms could protect also otherwise susceptible ____ species, thus promoting the survival of the entire microbial community.
complement
chemokine
TLR
bystanders
Functional ____ of community participants, has given rise to several newly-appreciated designations within the commensal-to-pathogen spectrum.
specialization
Accessory pathogen: inherently ____ in a particular microenvironment, nonetheless enhances the ____ or metabolic activity of pathogens
Keystone pathogen: exert its influence at ____ abundance by manipulating ____ responses and modulating the composition and levels of ____ participants
Pathobionts: exploit disrupted host homeostasis to flourish and promote ____ disease
Feedback loop is ____ , inflammation increase dysbiotic microbiota > won’t stop w/o ____ intervention; may underlie the chronicity of period disease
commensal colonization low host community inflammatory
self-sustained
therapeutic
Periodontitis-associated bacteria love inflammation (‘inflammophilic’)
n Periodontal bacterial communities have evolved in ways that allow them to not only ____ inflammation but also ____ inflammation for promoting their survival and, collaterally, causing periodontal tissue injury.
n The inflammatory exudate (GCF) contains tissue-breakdown products (____ & ____ compounds), that serve the nutritional needs of periodontitis-associated bacteria.
In effort to be fed > causes ____ (inflammation)
endure
exploit
collagen peptides
heme-containing
Implications
Periodontitis can be prevented by interfering with the ____ factors driving the selection and ____ of disease-provoking bacterial communities, rather than by attacking the bacteria directly.
Use of ____ agents.
Do not need to directly target bacteria > use anti-inflammatory agents > prevents ____ destruction but also controls ____ bacteria
environmental enrichment anti-inflammatory tissue dysbiotic
Inflammation as a Game Changer:
Inflammatory environmental conditions alter community dynamics
Something has to occur between incipient dysbiosis and full-blown dysbiosis > some factor induces this transition (____/____/____ factors), and the induction of ____ (immune subversion)
genetic
systemic
environmental
KP
Host-intrinsic factors that can disrupt periodontal homeostasis
- ____ or ____ host immune deficiencies or ____ defects.
- Systemic diseases such as ____ and obesity.
- ____ factors, such as smoking, diet, and stress, and ____ modifications in response to environmental changes.
- ____ is associated with a decline in immune regulation and function, which in turn can predispose to increased susceptibility to periodontitis.
- These factors– ____ or in ____– can contribute to unfavorable tipping of the homeostatic balance.
congenital
acquired
immunoregulatory
diabetes
enviornmental
epigenetic
aging
alone
combination
Experimental gingivitis in human volunteers
Gingival inflammation and plaque accumulation develops upon cessation of oral hygene. This is a ____ condition as the inflammation resolves within ____ days after resuming oral hygiene.
reversible
7
Gingivitis does not necessarily lead to periodontitis
- Although dental plaque accumulation causes gingivitis, gingivitis in turn does not necessarily lead to periodontitis.
- In fact, stable gingivitis may represent a ____e host response (‘____ immunity’) that does not ____ transition to periodontitis.
- In this regard, there are cases of individuals who remain free of ____ despite massive dental plaque accumulation.
protective
homeostatic
allow
periodontitis
Susceptible hosts:
Several factors can tip the balance from symbiosis to dysbiosis
Factors ____ or in ____, determines whether someone is or is not susceptible to periodontitis
alone
combination
Gingivitis does not necessarily lead to periodontitis
- In cases in which gingivitis can transition to periodontitis, gingival inflammation progressively exerts selective pressure for the development of a ____ and ____ microbiota.
- The severity of the ensuing periodontitis may depend, in great part, on host-related parameters (e.g., ____, ____, ____, or ____-related factors) that influence the host’s immune, inflammatory, and regenerative responses.
dysbiotic
inflammophilic
congenital
environmental
epigenetic
age
Periodontal host-microbe interactions in the subgingival environment lead to ____ activation
Humans w/ perio disease: ____ activation; analyze GCF > abundance of ____ products (higher in ____ patients)
complement
complement
complement-activation
Complement: a double-edged sword in health and disease
Normally, complement - in cooperation with other immune systems – acts to maintain ____ functions and clear ____ after injury or infection.
However, massive triggering or dysregulation of complement can lead to ____ state that can exacerbate damage and cause more harm than the initial insult.
barrier
pathogens
hyper-inflammatory
Periodontal Disease & Complement
n Activated complement components are abundantly found in ____ inflamed gingiva or in ____ of patients; undetected or at lower levels in healthy control samples.
n In animal models, complement is involved in both the ____ transformation of the periodontal microbiota (see earlier slides) and the ____ response that mediates tissue destruction.
n The activation of ____ (central complement component) in the human GCF increases with increasing pocket depth.
n Induction of experimental gingivitis in humans correlates with progressive ____ of complement cleavage products.
n Experimental periodontitis studies in mice and non-human primates show that complement mediates inflammatory ____. The condition is reversed by complement ____.
chronically
GCF
dysbiotic
inflammatory
C3
elevation
bone loss
inhibitors
Immunohistological features of dental plaque-induced periodontal disease
- Incipient gingivitis is thought to be a ____-dominated inflammatory response (however, neutrophils also play a role in ____ periodontitis).
- As plaque matures and becomes more pathogenic, the host inflammatory response evolves from acute to chronic, with additional participation of antigen- presenting cells and ____.
• Initially, the lymphocyte infiltrate is mostly ____, whereas in the established lesions, ____ cells predominate
Early lesion (7 days): \_\_\_\_ and macrophages
Established lesion (>7 days): Contain \_\_\_\_ cells and \_\_\_\_ cells (produce ab's); all three stages refer to \_\_\_\_
Conversion to perio > advanced lesion > hallmark: ____
neutrophil chronic lymphocytes T cells B cells/plasma cells B cells plasma cells
gingivitis
bone loss
Neutrophils constitute the majority of inflammatory cells in the gingival crevice
95% of leukocytes present in crevice are ____
Wall of neutrophils > accumulate in a position with plaque biofilm > making a ____ so bacteria cannot invade periodontal tissues
neutrophils
physical wall
Neutrophils play both protective and destructive roles in periodontal disease
Protective
Individuals suffering from neutrophil disorders
(e.g., ____, Chédiak-Higashi syndrome,
____) have increased susceptibility to and severity of periodontal tissue destruction.
Destructive
Neutrophil-derived matrix ____ (e.g., MMP-2, MMP-9), ____ burst, and ____ cytokines (e.g., IL-1β, TNF) contribute to periodontal tissue breakdown.
LAD
cyclic neutropenia
metalloproteinases
oxidative
pro-inflammatory
Bystander tissue damage by neutrophils
Formation of ____ and ____ > tissue degradation
ROS
MMP
Neutrophil homeostasis and periodontitis
- The homeostasis of neutrophils is tightly regulated through coordinated ____ production, release into the circulation, ____ to and activation in peripheral tissues, and clearance of ____ neutrophils.
- Dysregulation of any of these homeostatic mechanisms at any age can cause severe ____.
- Both ____ and ____ neutrophil activity (in terms of numbers or immune function) can precipitate periodontitis.
- Neutrophil defects of congenital origin (e.g., ____, leukocyte adhesion deficiency, and ____) are associated with cutaneous and systemic infections and ____-onset forms of periodontitis affecting both the ____ and ____ dentitions of children.
bone marrow
transmigration
senescent
periodontitis
imparied
excessive
congenital neutropenia CHS early primary permanent
Conditions that affect neutrophil homeostasis precipitate periodontitis
Key events in the life cycle of the neutrophil include ____, release into the circulation, ____ to the endothelium and ____ migration to tissues, antimicrobial function, and apoptotic cell clearance. Shown are congenital and other disorders that interfere with the indicated functions leading to development of severe forms of periodontitis.
Can be destructive even if not present in tissue:
Can see different genetic disease associated with periodontitis:
____: neutrophils cannot do bacterial killing (same as PL); cannot extravasate
____: neutrophils cannot adhere to endothelial surface
____: produce neutrophils in BM but cannot be released into the circulation (none in peripheral tissues)
All have ____ form of perio disease
granulopoiesis
adhesion
chemotactic
CHS
LAD1
WHIM
aggressive
Leukocyte adhesion deficiencies (LAD): defective interaction of leukocytes with vascular endothelium. Limited capacity of these cells to attach to the endothelium and migrate into the tissues.
LAD is a group of inherited disorders: n LAD I is caused by deficiency in ____
integrins.
n LAD II is due to defective glycosylation of ____ ligands.
n LAD III involves dysfunction of signaling intermediates that affects ____ activation.
Mutation in gene CD18 (LAD1)
In order to firmly adhere: LFA-1 (B2 integrin) binds ICAM-1 > LAD1: no LFA-1 integrin, neutrophils accumulate in circulation but never transmigrate
LAD2: before firmly adhering, neutrophils slow down and there much be interaction between selectin ligands and selectins on endothelium > if absent: cannot slow down
LAD3: have B2 integrin (LFA-1), but cannot activate them, thereby cannot adopt the clumping conformation
All these patients do produce neutrophils, but they cannot travel to peripheral tissues
B2
selectin
integrin
Children with neutrophil disorders with respect to ____ (e.g., cyclic neutropenia) or ____ (e.g., leukocyte adhesion deficiencies) have increased susceptibility to and severity of periodontitis.
numbers
trafficking
LAD-I periodontitis is caused by dysregulated local overproduction of ____ and ____
No neutrophils > overgrowth of bacteria (not absolutely true)
Neutrophils when present in tissue > have regulatory action
Absent from tissue > macrophages overexpress IL-23 (part of ____ cascade) > overexpresses IL-17 and G-CSF (required for granulopoesis) > produces a lot of neutrophils in BM > enter circulation but cannot transmigrate > and cannot shut down the overexpression
The tissue senses lack of neutrophil, produces more indefinitely, and the loop never closes
IL-17 is an ____ cytokine > has antimicrobial activity > too much: activate downstream osteoclasts resulting in ____ > lose both ____ and ____ teeth
IL17
IL23
granulopoietic
osteoclastogenic
bone resorption
baby
adult
Treated LAD patients with ____ (treated ____, approved for systemic use by FDA)
14 months: gingival condition was improved
antibodies
locally
Aging and periodontal homeostasis
• Aging is another factor thought to be associated with a decline in ____ regulation and function, which in turn can predispose to increased susceptibility to ____.
immune
periodontitis
Aging and periodontal homeostasis
- Del-1 is a protein that is secreted by ____ cells and homeostatically regulates ____ extravasation.
- Aging-associated decline of ____ expression in the periodontal tissue of humans and mice.
- Aging-related Del-1 deficiency in mice causes unrestrained recruitment of ____ cells and promotes ____.
- Del-1 and IL-17 (bone-resorptive cytokine) are ____.
Del-1: when young you express in ____ amounts, and as you age you produce less
Expressed by endothelial cells and blocks interaction between ____ and ICAM-1 > will not completely block neutrophils, but it will regulate the amount (if the number of neutrophils is too high)
KO Del-1 > too many ____ in perio tissues > periodontitis
Aging: Del-1 decreases and more IL-17 > a lot of ____ and ____
endothelial neutrophils Del-1 inflammatory periodontitis antagonistic high LFA1 neutrophils neutrophils bone resorption
Disrupted homeostasis and inflammatory bone loss
- When periodontal homeostasis is disrupted, a ____ cell infiltrate may accumulate in the connective tissue.
- Inflammatory cytokines are produced in abundance and act on several cell types to promote ____, in great part via ____ interactions
RANKL: osteroclast activation/differentiation
heavy inflammatory
osteoclastogenesis
RANKL-RANK
Osteoclastogenesis
Osteoblasts and lymphocytes (T and B cells) express receptor activator of ____ ligand (RANKL), which binds to its receptor, RANK, on the surface of osteoclast ____. This promotes the differentiation of precursors into multinucleated cells (____) which can mediate bone resorption.
Osteoprotegerin (OPG) is secreted by ____ and osteogenic ____ cells and inhibits excessive bone resorption by binding to ____ and thus blocking its interaction with RANK.
In periodontitis, there is high ____ ratio (too much RANKL and/or too little OPG)
OPG: ____ receptor; negative regulator of osteoclastogenesis
NF-kB
precursors
osteoclasts
osteoblasts
stromal stem
RANKL
RANKL/OPG
decoy
The osteoclast
Secrete ____ > resorb organic substrate of the bone and secretes > ____ that can demineralize the calcium phosphate
cathepsin K
HCl
What is the role of T cells in periodontitis?
Naïve CD4+ Th cells differentiate into diverse lineages depending on the ____ milieu during activation. They may be involved in different pathological conditions. What is their role in periodontitis?
TH17 will produce different cytosine like IL17 (this is how they got their name). They are important ____ immunity
and inflammation and can control eitraccelulate pathogens like bacteria and fungi.
TH1 is important in cell ____ immunity and thats why they are important for controlling killing
intracellular pathogens like bacteria and viruses
TH2 is important in ____immunity. They help B cells make ____ and its important in intracellular
pathogens, parasites and bacteria.
These are the good things that the T helper cells can do. But each of these subset is also associated with certain diseases. For example, TH17 has been associated with ____ disease
and ____
TH1 results in ____ hypersensitivity. TH2 since they express cytokines like IL4 and IL5 have been
associated with ____. But what is their role in periodontal disease?
innate
medaited adaptive
humoral adaptive
antibodies
inflammatory
autoimmunity
delayed type
allergy
T cells in periodontal disease
n The role of T cells in periodontitis is poorly understood.
n Initially research focused on the roles of Th1 and Th2 but results have been inconclusive.
n The recent discovery of the Th17 subset may lead to a more nuanced understanding of periodontitis.
____ > more important in perio disease
Th17
TH17 cells and IL-17 are involved in bone immunopathology:
Involved in rheumatoid arthritis, perhaps also in periodontitis
• IL-17-producing T helper cells (TH17) constitue an ____ TH cell subset.
• TH17 cells secrete IL-17, which induces ____ on synovial fibroblasts.
• IL-17 also stimulates local inflammation (TNF, IL-1 and IL-6).
• These cytokines activate osteoclastogenesis by directly acting on ____
cells or by inducing ____ on synovial fibroblasts.
• TH17 cells also express ____, which contributes to the enhanced osteoclastogenesis.
• At least in animal models of periodontitis, ____ drives inflammatory bone loss.
Contributes to destructive inflammation, and treating with ____ to IL17 is protective
osteoclastogenic RANKL osteoclast precursor RANKL RANKL IL-17 antibodies
Biological functions of interleukin-17 and their role in periodontitis
By inducing granulocyte ____ and ____ chemokines, IL-17 orchestrates bone marrow production and release of neutrophils and their chemotactic recruitment to the periodontium.
Additionally, IL-17 inhibits endothelial cell production of ____, which restrains neutrophil extravasation.
IL-17 can promote the destruction of both ____ and the underlying ____ by stimulating the production of matrix ____(MMPs) and ____ from the indicated stromal cell types.
IL-17 can also induce the production of epithelial cell- derived ____l molecules.
The current burden of evidence from human and animal model studies suggests that the net effect of IL-17 signaling promotes ____ development.
Function of IL17 (the bad): Osteoblasts > RANKL Macrophages > inflam cytokines Fibroblasts > MMP > tissue damage Inhibit production of Del-1 > low levels, cannot regulate recruitment
Can do good things: Stimulate epithelial cells to produce anti-microbial peptides Activate neutrophils (antimicrobial function)
GCSF CXC Del-1 connective tissue bone metalloproeinases RANKL antimicrobial disease
Malocclusion worsens periodontal bone loss: Why?
Vertical bone loss at sites with occlusal interferences or premature contacts with opposing teeth
Mechanical damage induces ____ leading to increased numbers of ____ cells, an osteoclastogenic cell subset.
Rectify malocclusion > bone ____
Was believed that malocclusion will not do anything but it will exasperate it
IL6
Th17
returns
B-lineage cells appear late in the periodontal lesion but ultimately comprise the ____ of leukocytes
B and T lymphocytes are the primary sources of ____ in the bone resorptive lesion of periodontal disease
Established: majority of cells is ____ cells
majority
RANKL
b/plasma
Role of B-lineage cells in periodontitis
Plasma cell-derived antibody that diffuses into the gingival sulcus or remains in the connective tissue may inhibit the bacterial ____.
However, clinical studies have shown that the antibody response is not associated with protection against ____.
B-lineage cells are recruited to the ____, where locally produced ____ promote the survival, proliferation, and maturation of B cells into antibody-secreting plasma cells.
B cells and plasma cells express ____ cytokines, matrix metalloproteinases, and ____.
B-lineage cells thus ____ and ____ participate in the degradation of the soft and hard tissue components of the periodontium.
Plasma/B cells can be protective via ab production > no correlation however
Activated B cells > rich source of RANKL production > overactivate osteoclast precursors > formation of mature osteoclasts > bone resorption and ____
challenge
periodontitis
periodontium
cytokines
proinflammatory
RANKL
directly
indirectly
periodontitis
Polymicrobial synergy and dysbiosis
- Periodontal disease is the result of a ____community-induced perturbation of the host homeostasis leading to inflammation in ____ individuals.
- Bacterial constituents of these communities often exhibit ____ interactions that will enhance colonization, persistence or virulence, and some bacteria may be involved in the breakdown of ____ whereas other may trigger destructive ____ once homeostasis is disrupted.
polymicrobial susceptible synergistic homeostasis inflammation
Inflammation & Dysbiosis reinforce each other
Implication: Host modulation therapies can potentially
- Inhibit destructive inflammation & promote ____.
- Control ____
Feed forward loop
Control inflammation > control of outgrowth of ____ bacteria
resolution
dysbiosis
dysbiotic
Role of T cells in periodontal disease
____ may be implicated as major driver of perio disease (production of ____)
Th17
IL17
Host susceptibility in periodontitis
The susceptibility to periodontal disease (PD), i.e, whether the infection will be contained in the gingiva, or will propagate apically and result in tissue destruction, is determined at multiple levels:
§ At the microbial level, based on the presence of a pathogenic microbial community capable of ____ disruption.
§ At the host level, based on ____ predispositions that may contribute to ____-inflammatory, destructive responses
§ At the level of ____ exposures that may further modify the response to the microbial challenge in either ____.
homeostasis genetic hyper environmental direction
