L7.PerioImmunology

Question 1

Are bacteria alone enough to cause periodontal disease? If not, what else is required?

Answer 1

Bacteria are NECESSARY but NOT SUFFICIENT to cause periodontitis, which is mediated by the HOST INFLAMMATORY RESPONSE

Question 2

What human immune cell type predomintes during each of the following stage of periodontal infection?

1. Incipient Gingivitis (acute periodontitis)
2. Initial mature (early) lesion, more pathogenic plaque
3. Established lesion

Answer 2

1. Neutrophils - acute response
2. Macrophages and Lymphocytes (mostly B-cells)
3. Plasma cells and Lymphocytes (T-cells)

Question 3

Periodontal disease seems to be caused by Dysbiosis. What is this?

Answer 3

It is the shift in the dominant species of an environment. If this shift results in dominant pathogens, disease, such as periodontitis, may result.

Question 4

How does P. gingivalis act to promote periodontitis?

Answer 4

P. ginigivalis acts in an unexpected way. Instead of directly causing periodontitis it inhibits the hosts immune system by inhibiting complement system & TLRs thus, allowing other more pathogenic bacteria to proliferate and cause periodontal disease

Question 5

What are 3 ways that bacteria like P. gingivalis, T. denticola, & T. forsythia act to incapacitate host defenses?

Answer 5

1. Degrade complement components
2. Manipulate chemokine expression
3. Block TLR-dependent killing

Question 6

Specifically, what are 3 ways that P. gingivalis disrupts host homeostasis leading to Dysbiosis?

Answer 6

1. Proactively inhibits IL-8 chemoattraction of Neutrophils.
2. Expression of an atypical LPS molecule (present on all Gram- bacteria) avoids detection by or inhibits TLR4. This TLR4 antagonist inhibits Beta-defensin expression.
3. Exploits C5a receptor to inhibit leukocyte killing while increasing inflammation leading to bacterial overgrowth and dysbiosis.

Question 7

Can stable gingivitis be a positive thing?

Answer 7

Yes, stable gingivitis means that your body is fighting potential bacterial pathogens without progressing beyond a normal immune response

Question 8

What are Pathobionts? How do keystone species play a role in ‘activating’ pathobionts?

Answer 8

Pathobionts are commensalit organisms at host homeostasis but have the ability to be pathogenic under dysbiotic conditions. Keystone species, such as P. gingivalis, have the ability to circumvent/disrupt the host immune system to disrupt homeostasis by inducing increased inflammation.

Question 9

Leukocyte Adhesion Defects (LAD I-III) disrupt interaction of leukocyte (neutrophils) with vascular endothelium so that the leukocytes can never reach the site of bacterially infected tissue. What is the mechanism by which LAD I, II, & III each disrupt this process?

Answer 9

1. LAD I: Is caused by a deficiency in Beta2 integrins (stops neutrophil from rolling, allowing it to migrate out of bloodstream through endothelium = Diapedesis)
2. LAD II: Defective glycosylation of selectin ligands (‘catch’ neutrophils from bloodstream and start them rolling to the Beta2 integrins)
3. LAD III: Dysfunction of signaling intermediates that affect integrin activation.

Question 10

Explain why aging might increase the risk for periodontitis? Use Del-1, IL-17 model.

Answer 10

In mice models, Del-1 expression decreases with age while IL-17 expression remains stable. This is important b/c Del-1 and IL-17 are antagonistic genes that control the inflammatory response. Specifically, Del-1 inhibits the inflammatory response by lowering the # of cytokines, while IL-17 is an osteoclastic inflammatory inducer. Thus as we age Del-1 expression decreases allowing IL-17 expression to predominate and thus inflammation & bone loss increase resulting in periodontitis.

Question 11

What osteoclastic activator ligand is upregulated during the inflammatory response?

Answer 11

RANKL

Question 12

During homeostasis RANKL is in balance with what signalling molecule?

Answer 12

OPG

Question 13

What role do RANKL and OPG play in bone renewal? What happens during periodontitis?

Answer 13

• RANKL is an activating ligand that binds to osteoclasts and activates them (allows them to form large multinucleated cells). Thus, upregulating bone loss.
• OPG binds to RANKL and keeps it from binding to RANK receptors. Thus, keeping bone loss in check ensuring that osteoblasts can keep up with osteoclasts.
• During periodontitis, inflammation cytokines upregulate RANKL and downregulate OPG. Thus, if inflammation is chronic RANKL will overwhelm OPG and more bone loss than production occurs leading to periodontal disease related bone loss

Question 14

Prostaglandin E2 (PGE2) is a biochemical marker for and a contributor to the pathogenesis of periodontitis.

• How is it activated during the inflammatory response?
• What are the 2 affects PGE2 has that increase periodontitis?

Answer 14

• PGE2 is upregulated during inflammatory responses when macrophages produce IL-1, TNF, & cause an increase in [COX-2].
• 1. PGE2 causes increase in vasodilation & vasopermeability, leading to redness & edema
     
     2. PGE2 also induces matrix metalloproteinases (MMPs), which lead to degradation of connective tissue and alveolar bone destruction

Question 15

What T cell is responsible for mediating innate immunity & inflammation? Overexpression of this cell results in what?

Answer 15

Th17. Produce IL-17 & TNF-alpha.

-Overexpression leads to Autoimmunity.

Question 16

Increased production of IL-17 by Th17 can increase bone loss by increasing production of what?

Answer 16

RANKL