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
