immunology Flashcards
- I. Gingivitis
– Plaque-induced
– Inflammation (edema/bleeding upon probing)
– No destruction of PDL and bone
– No apical migration of epithelial attachment
- II. Periodontitis
–Plaque-induced
–Inflammation (edema/bleeding upon probing)
–Destruction of bone
–Apical migration of epithelial attachment
–Not all cases of gingivitis progress to periodontitis
In other words, periodontitis is:
- Plaque-induced similar to gingivitis.
- Host-related (susceptible host).
- Each site is individualized or a specific environment.
- A % of affected population experiences severe destruction.
- The progression of the disease is probably (?)———–
Models of disease progression
- Continuous model (1900-1950’s)
- Progressive model (1940-1960’s)
- Random burst model (1980-2000’s)
- Asynchronous multiple burst model
(1980-2000’s)
- Asynchronous multiple burst model
- Continuous model (1900-1950’s)
– Continuous throughout life at same rate of
loss (i.e. Everyone gets perio disease.)
- Progressive model (1940-1960’s)
– Progressive loss over time of some sites
– No destruction in others
– Time of onset and extent vary among sites
– (i.e. Periodontal disease affects mainly posterior teeth.)
Random burst model (1980-2000’s)
– Activity occurs at random at any site
– Some sites show no activity
– Some sites have one or more bursts of activity
– Cumulative extent of destruction varies among sites
– (i.e. Periodontitis is different in various sites in the same individual and it is difficult to predict attachment loss.)
who doesnt show BOP?
smoking due to nic vasoconstriction
- Asynchronous multiple burst model
(1980-2000’s)
– Several sites have one or more bursts of activity during one period of life
– Prolonged period of inactivity; remission
– Cumulative extent of destruction varies among sites
– Some sites don’t develop attachment loss
– (asynchronous=not occurring at same time)
– Bursts due to Risk Factors
how long to form established gingivitis?
3 wks
Signs of Inflammation
- Rubor (redness)
- Calor (heat)
- Dolor (pain)
- Tumor (swelling)
- Functio Laesa (loss of function)
Inflammatory Response
- Inflammation is a vascular phenomenon
- Inflammation:
– Leukocyte migration
– Vasculitis: Dilation, Venous stasis (congestion), and Increased Permeability
– Transudate
– Exudate
innate immunity
1st defense
a. Innate (non-adaptive, genetic) (kills by
phagocytosis)
– PMNs
– Monocytes/Macrophages
adaptive immunity
2nd defense
b. Adaptive (production of immunoglobulins by
antibodies)
– highly specific
– B and T cells involved
– Plasma cells produce specific antibodies to
individual antigens
B cells and T cells**
c. B lymphocytes
– Activated B-cells become Plasma cells
– Plasma cells produce immunoglobulins
d. T lymphocytes
– developed in the thymus
– several functions (antigen presentation)
– help B-cells divide; can destroy virally infected cells;
can down-regulate immune response
t cells can dif into:
CD4 and CD8
CD 4
- CD 4 - MHC class II molecules
– T helper cells (TH0/TH1/TH2) - help B cells to divide
- control leukocyte development
- activate innate cell lining
- CD 8
- CD 8 - MHC class I molecules
– T cytotoxic - destroy virally infected target cells
. PMNs:
phagocytosis; produce lysosomal enzymes
Macrophages:
phagocytosis; process antigens; cytokine secretion
B-Lymphocytes
- Plasma cells: produce antibodies
T-Lymphocytes classes/functions
- T-helper (CD4):helps B-cells divide
- T-suppressor (CD8 & CD25): down-regulates T and B cells
- NK cell (natural killer-T cell) (CD56): kills virally-infected cells
- T-cytotoxic cell (CD8): destroys infected cells
- K (killer-T cell) (CD28): kills infected cells
Humoral immunity components
a. Antibodies
* IgM : first responder; largest in size
* IgG : second responder; most abundant; crosses
placenta
* IgA: salivary IgA; a dimer
* IgD : co-expressed with IgM (role?)
* IgE : on Mast cells, allergic reactions
b. Complement: part of both innate and adaptive
immunity systems. (A biochemical cascade that helps clear pathogens by lysis, opsonization, binding, and clearance of immune complexes).
Immunoglobulins**
4 proven risk factors of perio dx
plaque
smoking
DM
immunosuppresion
T suppressor cells
ow T-regulatory cells,
down-regulate T and B cells (CD8 ,CD25expression); prevent autoimmune dx
K (Killer) cells
K (Killer) cells - mononuclear cells that kill cells sensitized with antibody (via Fc receptors) (CD28cells which were signaled by CD8 cells)
NK (Natural Killer) cells
kill virally infected and transformed target cells that have not been previously sensitized (CD56 cells)
is dx progression consistent throughout mouth?
no, may be variable
Monocytes (%)
(5%) - activation in connective tissue
►will become macrophages*
Neutrophils (%)
Neutrophils (> 70%)* - 48 hours lifespan in
blood with migration to sites for phagocytosis
Eosinophils (%)
Eosinophils (2-5%) - cause damage by
exocytosis (eg: histamine release)
Mast cells
Mast cells - contain mediators of inflammation
(histamine, prostaglandins, leukotrienes and
cytokines)-involved in allergic reactions
Basophils (< %) -
Basophils (< 0.5%) - are in some ways
functionally similar to mast cells
Cytokines Definition:
soluble, locally active polypeptides; regulate cell growth, differentiation, function;
Produced by cells of immune system
- Specific cytokines may have different
biologic properties dependent on:
– Their concentration
– The cells that produce them
– The cells being attracted and acted upon
– Presence and extent of extracellular matrix
Important Cytokines
IL-6,IL-8,IL-1, TNF, PGE2
IL-1
Pro-inflammatory: stimulates osteoclasts, fibroblasts, macrophages
MOST IMPORTANT IN PERIO, can be tested for its presence
IL-6
IL-6 Pro-inflammatory: stimulates T and B cells
IL-8
Pro-inflammatory: attracts and activates
PMNs
TNF
TNF Pro-inflammatory: activates osteoclasts
PGE2 functions
Vasodilation
Pyrogenic
mast cells degranulation
Cell-mediated cytotoxicity
which cell is IgE on?
mast cells
TGF
TGF Stimulates epithelial cells and fibroblasts
PDGF
PDGF Stimulates fibroblasts
EGF
EGF Stimulates epithelial cells
FGF
FGF Stimulates fibroblasts
keystone pathogen of perio dx
p. gingivalis, can reprogram cell to evade host immune cells
Histologic/Immunologic Phases of Periodontal Disease
Clinically Healthy Gingiva**
* cells present in connective tissue
* cells migrating through the JE
* collagen destruction?
* epithelial barrier?
* Gingival crevicular fluid?
* Appears?
- Some neutrophils and macrophages are present in
connective tissue - A few neutrophils are migrating through the JE
- No collagen destruction
- Intact epithelial barrier
- Gingival crevicular fluid is present
- Appears clinically healthy (Color, Contour, Consistency)
Inflammatory Response Modifiers
- Mechanical (plaque retention factors)
- Systemic
- Genetic
Inflammatory Response Modifiers
* Mechanical (plaque retention factors)
a. Calculus
b. Caries
c. Restorations: defective margins, subgingival margins, overcontoured margins
d. Prosthesis
e. Tooth Anatomical Factors
* i.e. Palatogingival Grooves, Furcations
Inflammatory Response Modifiers
* Systemic
– Uncontrolled/controlled diabetes**
– PMN defects
– Hematological
– Hormonal: Puberty, Pregnancy**
– Immune disturbances
– HIV/AIDS
– Medications*
– Nutrition deficiencies
Inflammatory Response Modifiers
* Genetic
– Agranulocytosis
– Neutropenias
– Lazy Leukocyte
– Leukocyte adhesion deficiency (LAD)
– Down’s syndrome
– Papillon-Lefevre
– Hypophosphatasia
– Chediak-Higashi
– Ehlers-Danlos syndrome
Initial Lesion
* Develops in?
* Cells present
* GCF flow
* Start of what formation
- Develops in 2 to 4 days
- Cells of acute inflammation present
- Increased GCF flow
- Start of pseudopocket formation
– Remember:
Acute = PMNs
Chronic = Lymphocytes
Increase in chronicity ►►►Plasma cells
The Initial Lesion plaque
Plaque is deposited on the tooth
Bacterial byproducts are released into the periodontal tissues (virulence factors)
Can we then accurately predict which patients with gingivitis are going to develop periodontitis?
Today: NO (?)
One can only identify risk factors such as:
- Habits: Smoking
- Systemic disorders: HIV and Diabetes
- Patients with risk factors are more likely to have attachment loss!!!
- The answer is in the host’s immune system/genetics
Virulence factors types
– Stimulation of the host defense systems
– Degradation of the host tissues
– Stimulation of the host defense systems
- Stimulates cells to release cytokines (ie: IL-1, TNF and PGE) and chemoattractant factors (IL-8)
- Attracts inflammatory cells (example of LPS causing chemotaxis of PMNs)
– Degradation of the host tissues
- Done with Enzymes
– Collagenase
– Trypsin-like enzymes
– Keratinase
– Phospholipase A
Poor plaque control result
Bacterial byproducts are released into the periodontal tissues (virulence factors)
Stimulation of epithelial cells and fibroblasts to release IL-8 into the CT which attracts and activates PMNs
PMNs are present in the connective tissue
PMN’s are attracted to and near JE and sulcular epithelium
Plaque accumulation result (after poor control)
Bacterial byproducts are released into the periodontal tissues (virulence factors)
Stimulation of inflammatory cells to release cytokines into the CT
PMN’s attracted near and to the JE and sulcular epithelium
Attraction inflammatory cells
p gingivalis main VF
collagenase
Aa main VF
leukotoxin
do all bac make same VF
no
Clinical Features of Initial Lesion
* I GCF flow
* Sulcus depth
* Alveolar bone on radio
- Increased GCF flow
- Sulcus increases from 0→3 mm by formation of a pseudopocket
- Alveolar bone is normal on the radiograph
PMN Diapedesis
which cytokines?
molecules playing a role?
e
Selectins
Selectins“slow” the PMNs and cause them to “roll”.
Cytokines activate ICAM receptors on endothelial cells for PMN attachment
Early Lesion
* time
*result of?
GCF flow? pocket?
* Cells that appear/dominate?
* loss of/ what enzyme actives?
- 4-7 days
- Acute inflammation persists (initial lesion►►), increased GCF, pseudopocket formation
- Cells of chronic inflammation appear and then dominate
- (chronic→shift to T lymph. from PMNs) Collagen loss continues**
MMPs Activation begins**
How is collagen lost diagrammed
microbial factors?
cytokines involved?
enzyme?
IL-1 and 6
Matrix Metalloproteinases
(MMPs)
The MMP family includes 28 metal-dependent endopeptidases (proteases) with activity against most, if not all, extracellular matrix macromolecules. (used for normal tissue remodeling)
Early Lesion Histopathology
1. Collagen loss up to%*
2. cause?
- Collagen loss up to 70%*
- What causes collagen destruction?
PMN’s products, Cytokines, MMPs are included, so a combination of bacterial products and host’s defense system cause the destruction.
Early Lesion Histopatholgy
2. PMNs accumulation in?
3. PMNs accumulation in?
4. Cells of _______ inflammation accumulate
and predominate– called?
5. Fibroblasts?
6. Rete pegs ?
Early Lesion Histopatholgy
2. PMNs accumulation in gingiva
3. PMNs accumulation in sulcus
4. Cells of chronic inflammation accumulate and predominate– T-cell lesion
5. Fibroblasts show cell damage
6. Rete pegs proliferation of JE into CT
early lesion diagram
Clinical Features of Early Lesion
1. Edema of what tissue?
2. GCF flow?
3. Loss of what on gingiva?
4. Erythema of what part of gingiva?
5. migration of JE attachment?
6. Alveolar bone lost?
7. Reversible?
Clinical Features of Early Lesion
1. Edema of gingiva
2. Increased GCF flow
3. Loss of gingival stippling
4. Erythema of gingival margin
5. No migration of JE attachment
6. Alveolar bone is normal-no bone loss
7. Reversible
Host Defenses of the established lesion
- Inhibit Dramatic Plaque Growth thus it Prevents infection from becoming dramatically worse, but a Stand-off exists, since plaque is unable to be eliminated and there is a Shift to a B-Cell/Plasma Cell lesion
The Established Lesion
inflamm
time frame
what cell activates?
PMN wall?
- Acute inflammation persists
-After 2-3 weeks early lesion shifts to established lesion (a stable lesion)
-Chronic inflammation dominates
* Activated B-lymphocytes → Plasma cells - PMN “wall”: host tries to contain the infection
**-Micro-ulcerations of pocket epithelium= BOP **
-More proliferation of JE
-More elongation of epithelial rete pegs into connective tissue - Bystander Damage
- Two-edged “sword” of immune system**
The Established Lesion-Disease Activity
processes occurring?
dominate cell?
vascular?
conn tissue app?
- Two processes
– Damage: Bacterial and Immunological
– Repair - Shift to activated B-cell►plasma cell lesion
- Highly vascular
- Immature connective tissue with new collagen forming
Effect on the Ground Substance in established lesion
- Bacterial Enzymes produce:
a. Proteases
b. Hyaluronidase - Fibroblasts, Macrophages, PMN’s produce:
a. Gelatinase
b. Stromelysin
both create destruction, majority caused by host cells
loss of collagen in established lesion, affected rates?
- Decreased rate of synthesis
- Increased rate of breakdown
The Established Lesion
* Connective Tissue Repair
1. Attempts to minimize?
2. Fibroblasts are _______-regulated
* Synthesis of?
3. Recruitment of ?
* regulated by?
* Chemotactic?
4. ”The shut-off mechanism”?
- Attempts to minimize tissue damage
- Fibroblasts are cytokine-regulated
* Synthesis of extracellular matrix - Recruitment of new cells
* Cytokine regulated (TGF-beta, PDGF)
* Chemotactic collagen and elastin fragments - Tissue Inhibitors of Metalloproteinases (TIMP)-”The shut-off mechanism”
Established lesion diagram
The Established Lesion
* Histopathology of the established lesion
1. Cellular damage of?
2. change to Collagen loss?
3. Micro-ulcerations of?
4. Persistence of?
5. Marked numbers of what cell in pocket?
6. Degradation of?
7. infiltrate?
8. JE proliferation and extension?
9. Elongation of ?
- Cellular damage of fibroblasts, epithelium
- Collagen loss increases
- Micro-ulcerations of pocket epithelium
- Persistence of acute inflammation
- Marked numbers of PMN’s in pocket
- Degradation of extracellular matrix
- Dense T-cell, B-cell, Plasma cell infiltrate
- JE proliferation and extension into CT
- Elongation of rete peg ridges
The Established Lesion
* Clinical Features
1. Edema?
2. Erythema?
3. Bleeding?
4. Gingival changes?
5. bone loss?
The Established Lesion
* Clinical Features
1. Edema
2. Erythema
3. Bleeding on probing (BOP)
4. Gingival changes:
* color, contour, consistency
5. No bone loss
Stages of gingivitis diagrammed
time frame
dominate cell
collagen loss
sulcular epi
clinical findings
e
establioshed lesion progression
- The established lesion is the final stage of
“pure” gingivitis - This lesion can remain stable for weeks,
months, or even years until/if it progresses to
periodontitis - The mechanisms that cause the change from
gingivitis to periodontitis are not well
understood: Host factors? - Difficult to predict which patients will develop
periodontitis –but one can identify the risks
groups (smokers, diabetics, etc.)
The Advanced Lesion
* Features of periodontal breakdown
1. Pocket?
a. PDL?
b. JE?
c. Bone?
2. Model of progression (?)
3. Bystander damage
4. Host balance of ?
The Advanced Lesion
* Features of periodontal breakdown
1. Pocket formation
a. PDL destruction
b. Apical migration of JE
c. Bone resorption
2. Asynchronous Multiple Burst Model (?)
a. Short bursts of disease activity
b. Long periods of quiescence
3. Bystander damage
4. Host balance of damage/repair is upset
The Advanced Lesion
5. Alveolar bone resorption
a. Activation of?
b. Ruffled border produced (active site)
c. enzymes released?
d. Cytokines?
e. Prostaglandins?
f. Leukotrienes?
a. Activation of osteoclasts
b. Ruffled border produced (active site)
c. Hydrolytic enzymes released
d. Cytokines released: IL-1, IL-11, TNF
e. Prostaglandins produced: PGE 2
f. Leukotrienes produced (inflammatory mediators and involved in allergic reactions)
Advanced lesion: Mechanisms of bone loss diagrammed
Histopathology of the Advanced Lesion
1. cells present
3. infiltrate?
4. Extension of lesion into?
5. Loss of collagen?
6. altered plasma cells?
7. pocket formation?
8. phases?
Histopathology of the Advanced
Lesion
1. PMNs
2. B-cells, plasma cells dominate
3. Inflammatory infiltrate
4. Extension of lesion into PDL and bone
5. Loss of collagen continues
6. Cytopathologically altered plasma cells
7. Progressive pocket formation
– Attachment loss
8. Quiescence & exacerbation
Clinical Features of Advanced
Lesion
1. Periodontal pocket?
2. ulceration where?
3. Radiographic bone loss?
4. Bleeding?
5. Changes in gingival?
6. Attachment Loss?
7. Mobility?
Clinical Features of Advanced
Lesion
1. Periodontal pocket formation
2. Pocket epithelium ulceration
3. Radiographic bone loss
– 50% of volume/density needs to be lost before
detection on radiograph
4. Bleeding on probing
5. Changes in gingival color, contour, consistency
6. Attachment Loss
7. Mobility
Immune cells Overview
* Initial lesion
* Early lesion
* Established lesion
* Advanced lesion
- Initial lesion
– PMNs, macrophages - Early lesion
– PMNs, macrophages, T-lymphocytes - Established lesion
– PMNs, macrophages, T-lymphocytes, B-lymphocytes,
plasma cells - Advanced lesion
– PMNs, macrophages, T-lymphocytes, B-lymphocytes,
plasma cells
Treatment
* Gingivitis
Treatment
* Gingivitis
– Reversible
* Method
– Suppression of microflora for plaque-induced
gingivitis
* Scaling
* Polishing
* Patient’s daily removal of plaque
Treatment
* Periodontitis
– Irreversible
– There is no cure for periodontitis, only control
* Method
– Suppression of microflora
* Scaling and root planing
– (SRP + Antibiotics (?))
– Reeval
* Surgery
* Maintenance
– Modulation of host
* Low Dose Doxycycline- collagenase inhibitor
Does everybody that has gingivitis because of poor long-term plaque control eventually develop periodontitis?
no
Primary etiology of periodontal
disease is
bacterial plaque in a susceptible host
Plaque Dysbiosis
everybody develops gingivitis but only __________ patients will develop
periodontitis
only susceptible patients will develop
periodontitis
