Inflammation & Resolution workshop Flashcards
1
Q
Different stages of inflammation.
A
- Vasodilation
- Margination - binding of macrophages, phagocytes
- Migration - phagocytes & mø force into tissue
- Phagocytosis
- tissue repairing/Resolution - by resolvins or lipoxins
2
Q
Vasodilation occurs how?
A
- Compliment system, C3A, C5A activate mast cells.
- mø/ mast cells react to tissue damage & release inflammatory mediators inc. histamine, kinin, prostaglandin, leukotrienes.
- These act on endothelial cells, causing separation from nearby capillaries.
- endothelial cells release nitric oxide = vasodilation.
- Capillary more permeable.
3
Q
Cytokines role?
A
- activate cells in local environment & allow immune cells to enter the environment & attack intruding toxin/pathogen
- growth factors
- endogenous pyrogens - drive immune response & change body temp.
- induce acute phase protein in liver
- Eg? IL1, IL6, chemokines: CCL8- attract neutrophils, CCL5 - attract mø,
4
Q
Process leading to fever?
A
- macrophage ingests the toxin
- broken down in vacuole.
- endotoxins released so mø release IL1.
- IL1 goes into blood stream. hypothalamus.
- IL1 induces production of prostaglandins which increase body’s thermostat.
5
Q
Margination?
A
- adhesion molecules roll down with phagocytes/leukotrienes
- force themselves between the endothelial cells
- squeeze into site via emigration.
- chemotaxis guide them through tissue
6
Q
vascular stage of inflammation
A
- arterioles & venules near site of injury constrict briefly then dilate.
- dilation = congestion , capillary permeability
7
Q
Phagocytosis - cellular stage?
A
- leukotrienes engulf & degrade bacteria & cellular debris.
* products/ exudates cause swelling & pain
8
Q
Exudates are?
A
- serous fluid
- RBC
- fibrinogen
- tissue debris
- WBC breakdown products
9
Q
pain how?
A
brady kinins increase capillary permeability and stimulate pain receptors
10
Q
Cytokines eg
A
- Pro-inflammatory TNF, IL-1, IL6 etc
- Chemokines – CXCL-8, CCL2, CCL5 etc
- Growth factors – M-CSF, GM-CSF etc
- Adhesion molecules – VCAM-1, ICAM-1
• Matrix metalloproteinases - MMP-1, 2, 9 - changes extracellular matrix to allow cells to migrate
- Clotting factors -
- Prostaglandins – local
11
Q
What are acute phase proteins?
A
- made by hepatocytes in liver
- made in response to pro-inflammatory cytokines
- fluctuate due to infections & tissue injury
- eg. C reactive protein, fibrinogen, complement factors eg opsonin, haptoglobin, ferritin
12
Q
Acute phase protein eg?
A
- C reactive protein
- Fibrinogen
- serum amyloid A
- complement factors - chemotaxis, opsonin
- haptoglobin, ferritin
13
Q
C reactive protein fn?
A
opsonin - labels pathogen so immune cells can detect it easily
14
Q
fibrinogen fn?
A
• coagulation factors - stops bleeding
15
Q
serum amyloid A fn?
A
- cell recruitment & MMP/matrix metalloid proteoids inducer.
- allows cells to move through extracellular matrix.
- allows tissue to change
16
Q
Haptoglobin & ferritin fn?
A
bind Hb or Fe - blood cells.
17
Q
Role of adhesion molecules in inflammation
A
- Cells travelling high speed due to BP.
- Endothelial cells release MCP-1 & IL8, which attracts leukocytes.
- Selections slow down leukocyte.
- Adhesion molecules ICAM1 VCAM1 cause them to adhere onto endothelial cells.
- adhesion molecule & leukocyte roll along vessel wall to site.
- PCAM1 and CD99 are responsible for taking the leukocyte down into the site of inflammation.
18
Q
PCAM1 & CD99 are?
A
responsible for taking leukocyte down into site of inflammation
19
Q
endothelial cells release MCP-1 & IL8 which?
A
Attracts leukocytes.
20
Q
adhesion molecule eg?
A
ICAM1 & VCAM1
21
Q
How is NFkB activation in inflammation?
A
- NFkB controls cytokines, chemokine & their receptor, adhesion molecules, MMPs, growth factors and acute phase proteins.
- normally found in cytoplasm, bound to inhibitor IkB.
- IkB kinase protein activated by sensing pro-inflammatory cytokines, bacterial components, viruses, DNA damaging agents.
- IkB kinase phosphorylates IkB into smaller molecules. NFkB released & migrates into nucleus
- NFkB binds to DNA & transcribes RNA.
- RNA translates to proteins involved in apoptosis. inflammation, eg adhesion molecules etc
22
Q
how NFkB released?
A
- bound to inhibitor IkB
- IkB kinase activated by sensing pro-inflammatory cytokines, etc.
- IkB kinase phosphorylates IkB into smaller molecules.
23
Q
NFkB controls?
A
cytokines, chemokine & their receptor, adhesion molecules, MMPs, growth factors and acute phase proteins.
24
Q
NFkB found in?
A
cytoplasm, bound to inhibitor IkB.
25
Mediators in resolution & fn?
* Cytokines such as TGFß, IL4,
* IL10 - regulates release of TH2 cells, can slow down & stop mø so that they cant differentiate & engulf cells.
* Soluble adhesion molecules - cover the cells & leukotrienes cant bind to adhesion molecules on the membrane anymore.
* TIMPS - inhibit metallomatrix proteins/MMP
* Lipoxins/resolvins - counteract inflammatory mediators which are present in the blood.
* Internal opioids - counteract pain by increasing blood flow.
26
Mediators in resolution list
* Cytokines TGFß, IL4, IL10
* . soluble adhesion molecules
* TIMPS
* lipoxins, resolvins
* i nternal opioids
27
Events that drive autoimmune diseases
* Genetics MHC2 gene
* failure of self tolerance/ central tolerance system
* sustained infection/ inflammation
* environmental triggers,
* ongoing acute to chronic
* high levels of auto antibodies
28
Why central & peripheral tolerance?
* Central = thymus & bone marrows
* peripheral = regulated auto-reactive cells in circulation.
* In central lymphoid organs/ peripheral tolerance, not all self antigens are expressed thus may not undergo negative selection
* maintaining T cell tolerance = B cell tolerance to same antigen
* T cell only activated by foreign molecule.
* If both central tolerance not there then both cant target correct antigens.
29
conventional immune disease treatments?
* Anti-inflammatory drugs: corticosteroids, aspirin and ibuprofen. NSAIDS. Block TNF & IL1.
* Immunosuppressants - inhibit proliferation of lymphocytes and ciclosporin-A (to flood inflammatory response)
* Non-specific control of autoantibodies.
* Infusion of IV immunoglobulin (IV-IG): antibodies of multiple specificity from a group of healthy donors, how it works = not clear
* Plasmapheresis - remove circulating antibodies, short term
* Organ specific:
* Insulin in diabetes
* Acetylcholinesterase inhibitor in Myasthenia gravis
