7. Acute Inflammation III Flashcards
Review: Systemic effects of Inflammation (Acute phase reaction)
TNF, IL1, IL6 on brain: ____
IL1, IL6 on liver: ____
TNF, IL1, IL6 on bone marrow: ____
fever
acute phase proteins
leukocyte production/release
____ > neutrophils, eosinophils, basophils
____ > monocytes, lymphocytes
Platelets are not cells, they’re remnants of the ____
Basophils are the blood-counterpart of tissue ____ , unknown ____
Neutrophils: \_\_\_\_ Eosinophils: \_\_\_\_ Basophils: \_\_\_\_ Monocytes: \_\_\_\_ Lymphocytes: \_\_\_\_
granulocytes round cells megakaryocytes mast cells function
50-70% 5% 1% 5-8% 20-40%
[TAKE A LOOK AT THE CELL IDENTIFICATION SLIDE]
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Neutrophil Kinetics
____ is present in bone marrow (of 100B), only ____ is not in the bone marrow and circulating/marginating (loosely adhering) throughout the body
\_\_\_\_ = neutrophils in circulation \_\_\_\_ = marginated neutrophils
93%
7%
3%
4%
Neutrophil Development
Nucleus gets smaller as you go from ____ to ____ (formation of granules) > myleocyte (more ____, and nucleus size is getting ____) > ____ (nucleus is becoming ____ shaped, the cytoplasm is increasing) > band (____ cell) > segmented/mature PMN
Blue background to yellow background > blue cells are all ____ (myeloblast, promyelocyte and myelocyte), and move to yellow (metamyelocyte, band, and segmented PMN) they stop ____ and mature into a neutrophil
Get into tissue and removed via ____; neutrophils are called ____ because they can only go one way > 1-2 hour they undergo apoptosis and removed via macrophages
Shift to the left > normally you do not expect to see ____ neutrophils, and if you do see a large amount > the reserve neutrophils in BM have been used up in the case of ____ for example
Regulated by ____ > released from fibroblasts and macrophages; when there is infection more of it is produced > causes more myeloblasts to enter the cycle and produce neutrophils and causes conversion of myelocytes into ____
myeloblast promyelocyte granules smaller metamyleocyte band ???
dividing
dividing
macrophages
end cells
band
infection
G-CSF
metamyleocyte
NEUTROPENIA
Neutropenia:
1500
500
NEUTROPENIA
- BONE MARROW PATHOLOGY:
- ____
- Malignancies
- ____
- Drugs (Anti-cancer antibiotics)
- Infection (____ and ____, ____)
- INEFFECTIVE PRODUCTION:
- ____
- Vitamin B12
ENHANCED DESTRUCTION:
» ____
» ____
congenital radiation hep A B measles
folic acid
septecemia
hypersplenism
NEUTROPENIA: ORAL MANIFESTATIONS
- Susceptible to ____ infection
- Middle ear, oral cavity, perirectal area
- ____ infection (PMN<500/mm3).
- Oral Cavity:(____, ____, ____ mucosa)
- ____ most affected (Ulceration)
- Premature bone loss/Exfoliation of Deciduous dentition
- Treatment and Prognosis
- ____
- Oral ____
- ____
bacterial pulmonary lip tongue buccal gingiva antibiotic hygiene G-CSF
CYCLIC NEUTROPENIA:
•
200
3-6
ulceration
affected
periodontal bone
recession mobility
Cyclic Neutropenia
- Mutation in ____ gene
- Arrest at ____
- ____
Diagnosis and Treatment • Sequential WBC count – \_\_\_\_ times/week for \_\_\_\_ weeks. • \_\_\_\_ for infection when PMN counts are low. • \_\_\_\_ • Oral \_\_\_\_
ELA2 > arrest promyelocyte > apoptosis > no neutrophil production
Can ____ test for mutation
Elastase (ELA2)
promyelocyte
apoptosis
2-3 8 antibiotics G-CSF hygiene
genetically
[TAKE A LOOK AT THE CASE REPORT]
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Agranulocytosis • \_\_\_\_, (\_\_\_\_ are absent) •Decreased production or increased destruction. •Some cases are \_\_\_\_. •\_\_\_\_ chemotherapeutic agents. •\_\_\_\_ infection often develops. •Deep oral ulcers: \_\_\_\_ mucosa, \_\_\_\_, \_\_\_\_, \_\_\_\_ (infection)
Treatment • If drug-induced, \_\_\_\_ ASAP • \_\_\_\_ for infection. • \_\_\_\_ • Oral \_\_\_\_
granulocytes PMNs idiopathic anticancer bacterial
buccal
tongue
palate
gingiva
discontinue
antibiotics
G-CSF
hygiene
Inflammation increased vascular permeability to proteins > ____ develops
As a result of inflammation > and the RBC clump > ____ (from fibrinogen, acute phase protein) > bigger, and they’re ____ on neutrophils, and then the neutrophil tumbles onto the surface of the endothelial cells and bounce off…
stasis
rouleaux
pushing
Neutrophil recruitment coincides with increased ____; even when there are not enough physical gaps, the neutrophils still ____ the endothelial cells > they produce their own gaps
[NOTES]
vascular permeability
transverse
Mast cell (he added)
[NOTES]
ADD HERE
Slowing of neutrophils mediated by selectins, and the ligands contain sugar molecules (carbohydrates)
L-selectin: L for ____, expressed on surface of leukocyte and ligand is on endothelial cells
P-selectin: present on surface of ____ and ____, and the ligand is on the leukocyte
E-selectin: present on ____, and the ligand is on the leukocyte
Normally, selectins are not ____ on surface of endothelial cells
leukocyte plasma cell endothelial cells endothelial cells expressed
P-selectin is pre-synthesized and stored in ____; and ____ from mast cells causes the redistribution of P-selectins from WP bodies from cytoplasm onto the surface of the endo cell
____ contributes to initial adherence of leukocytes to endo cells**
Cytokines (IL1, TNFalpha) induce expression of ____, takes longer than P-selectin (pre-synthesized), and induces ligand for ____
Following all this, interaction is ____ (bt neutrophils and endo cells) and is not sufficient to bring neutrophils to a halt on surface of endo cells; “slow brakes” on your car
Next: ____, mediated by different set of molecules
webel-palade bodies (WP bodies)
histamine
histamine
E-selectin
L-selectin
low-affinity
firm adhesion
FIRM ADHESION OF NEUTROPHIL ON ENDOTHELIAL SURFACE
Integrins are receptors and LFA-1 contains two subunits (____), Mac1 (____), p150,95 (____)
All three have common subunit = ____, LFA-1 in all ____ cells, Mac-1 > most granulocytes, but mostly ____ and ____, p150,95 > more on ____ than monocytes
Ligands are present on endo cells > ____ > upon interaction > firm adhesion of neutrophil
Only occurs when ____ is present
CD11a/CD18
CD11b/CD18
CD11c/CD18
CD18
immune
macrophages monocytes
macrophages
ICAM1
inflammation
FIRM ADHESION OF NEUTROPHILS ON ENDOTHELIAL SURFACES
Normally: no ICAM-1, add ____ (IL1, TNFalpha) during inflammations > induction of ICAM-1 > this induction is not sufficient for firm adhesion; neutrophils must be ____
Integrins are activated by ____ (chemotactic cytokines, produced from macrophages during infection/irritation, bind to PG on endothelial (???) cells; captures chemokines near where they are produced) > bind receptor on neutrophil there is activation of neutrophil > integrins become ____, and they have higher ____ for ICAM-1 > firm adhesion
Integrins are always ____ on neutrophils, but only once ____ the integrins align properly and interact with ICAM-1
cytokines
activated
chemokines
clustered
affinity
present
activated
TRANSMIGRATION / EXTRAVASATION / DIAPEDESIS
Neutrophils are crossing endothelial cells and are being recruited extravascularly
Second group of adhesion molecules > ____ (expressed both on ____ and on ____; upregulated on neutrophils by ____; upregulated sequentially after ____ takes place)
PECAM-1 neutrophils endothelial cells chemokines firm adhesion
Type of emigrating leukocytes depend on the nature of the etiology
• Most acute inflammation:
– Neutrophils first ____ h
– Monocytes ____ h
• Pseudomonas organisms:
– ____ several days
• Viral infection:
– ____
• Allergic asthma
– ____
6-24
24-48
neutrophils
lymphocytes
eosinophils
Type of emigrating leukocytes depend on the age of the inflammatory response
Left: myocardial infarct; neutrophil firmly adhered to surface of BV > neutrophil removes dead tissue
Firstly, ____, then ____ recruitment, and then the recruitment of ____
Neutrophils > larger in number
Monocytes > smaller in number, expression of ____ molecules is smaller, they become macrophages and remain in the ____ tissue
[REWATCH]
edema
neutrophil
monocytes/macrophages
adhesion
EV
Leukocyte Adhesion Deficiency (LAD-I)
• Etiology and Pathogenesis:
• Deficient expression of the integrins containing
____ (mutation in ____ gene, CD18)
• Decrease in ____ to the endothelium
• Clinical Manifestations
• Delayed separation of the ____ (Normal,
7-10 days; LAD-I ____ days)
• Recurrent ____ infection (skin/mucosal surfaces)
• ____ (later in life)
• Impaired ____ healing
• ____ (10,000 - 40,000/mm3)
Similar clinical representation to ____; neutrophils cannot be recruited to where they’re required because they cannot adhere and cannot transverse in the EV space
CD18
ITGB2
firm adhesion
umbilical cord >30 bacterial gingivitis/periodontitis wound leukocytosis
neutropenia
Leukocyte Adhesion Deficiency (LAD-I)
Delayed separation of the ____
____/____
____
Impaired ____
Stump of umbilical cord > irritant > neutrophil recruited > inflammation > removed and heals; if LAD-1 > no number with total number of neutrophils, but no inflammatory response (the earliest sign of LAD-1 deficiency) > develop into ____
umbilical cord omphilitis septicemia gingivitis/periodontitis healing
omphilitis/septicemia
LEUKOCYTE ADHESION DEFICIENCY-I (LAD-I)
Diagnosis: • Clinical presentation, history • Reduced expression of \_\_\_\_ (CD11a and CD11b) on neutrophils (\_\_\_\_). • Elevated \_\_\_\_ count • \_\_\_\_ testing
Treatment:
• ____
• Ustekinumab? (____)
CD18
flow cytometry
neutrophil
genetic
antibiotics
stelara
LAD1 Case Report
• A 19-year-old man with LAD1 (mutation in ____ gene, CD18) presented for evaluation of severe periodontal disease.
• Had delayed umbilical cord separation, otitis, and skin infections in early childhood.
• ____ at 4 years of age, which led to the diagnosis of LAD1. Prophylactic treatment with trimethoprim–
sulfamethoxazole.
• Since then, recurrent oral ____ (treated with steroids), frequent skin infections and several cases of pneumonia.
• Severe periodontitis began in his early ____ and chronic non-healing wound
• On admission, the patient had severe periodontitis with generalized gingival inflammation and severe periodontal bone loss.
The patient’s CD18 expression ____ of the control (moderate LAD1).
• Biopsy of gingival and chronic cutaneous wound tissue; lymphocyte infiltrate and ____, ____
ITGB2
appendicitis
ulcers
teens
~34%
IL17, IL23
____ > apoptotic neutrophils phagocytosed by macrophages in the wound
Infection > more ____ > more neutrophil production in BM
Efferocytosis > negative feedback on production of cytokines > no ____
…
In LAD-1; neutrophil cannot get out BV > no efferocytosis, so no feedback inhibition of ____ (macrophages have nothing to phagocytose)
TURN-OFF SIGNAL > not transverse migration of neutrophils, nothing for macrophage to phagocytose
IL17 > involved in oral ____, ____ wound, ____ and ____
Stelara/Ustekinumab > monoclonal ab binds to ____ subunit of ____ (IL-12 may participate in periodontal disease) > prevents production of ____ and ____
efferocytosis
G-CSF
IL23/17
cytokines
ulceration
chronic
gingivitis
periodontitis
P40
IL-23/IL-12
IL17
G-CSF
Inflammation: Gingiva
Upon treatment with Ustekinumab/Stelara…
____ decreases upon treatment
Also had severe ____> would treatment regress the bone loss > in this patient, no change in ____
Chronic inflammation > ____ destruction > won’t regrow the tissue, but will treat the other issues
bleeding
bone loss
bone growth
tissue
LEUKOCYTE ADHESION DEFICIENCY-II (LAD-II)
- Etiology and Pathogenesis:
- Absence of ____
- ____ deficiency
- Neutrophils do not bind to ____ on EC
- Defective ____
- Clinical Manifestations
- Less severe than ____
- No ____ in umbilical cord separation
- ____ infection not life threatening
- ____
sialyl lewis X-modified glycoprotein
GDP-fucose transporter
selectins
rolling
LAD-I
delay
bacterial
periodontitis
LEUKOCYTE ADHESION DEFICIENCY-II (LAD-II)
- Diagnosis:
- ____ Stature, mental/growth ____
- ____ (neutrophils, 10,0000 – 40,0000/mm3)
- Absence of ____ expression (____)
- Treatment
- ____ (children)
- ____
- ____ supplementation
short retardation leukocytosis SLeX flow cytometry
antibiotic prophylaxis
periodontitis
fucose
LEUKOCYTE ADHESION DEFICIENCY-III (LAD-III)
• Etiology and Pathogenesis:
• Defect in integrin ____ by chemokines
• Mutation in the gene for the adapter protein ____ (which binds to beta ____, ____, and ____)
• Reduced ____
• Dysfunctional platelet ____
- Clinical Manifestations
- Similar to ____
- ____ at birth
- ____ disorders
Kindlin-3 protein is also found in ____, the mutation is global which results in hemorrhage
activation kindlin-3 1 2 3 integrins firm adhesion aggregation
LAD-I
cerebral hemorrhage
bleeding
platelets
LEUKOCYTE ADHESION DEFICIENCY-III (LAD-III)
- Diagnosis:
- Intact integrin ____ but impaired ____
- ____(neutrophils, 10,0000 – 40,0000/mm3)
- ____ analysis for mutation in Kindlin-3
- Treatment:
- ____ or ____ cell transplantation
- Prognosis poor unless treatment in early ____
expression
activation
leukocytosis
genetic
bone marrow
hematopoietic
infancy
[REVIEW LAD TABLE]
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