ic10 inflammation

Question 1

What is a tendon, ligament and bursae?

Answer 1

Tendon
Fibrous connective tissue
Connect muscle to bone

Ligament
Connect bone to bone to form a joint
Limit joint dislocation, restrict improper hyperextension and hyperflexion

Bursae
Cushions between bones and tendons, muscles around a joint

Question 2

How does inflammation occur?

Answer 2

1. DAMP (damage associated molecular patterns) released by stressed cells eg. ATP, S100, HMGB1
2. Innate immunity eg. APC, T cells, Macrophages recognise DAMP, increase cytokine / chemokine expression and cause immune cell recruitment to site of injury

Question 3

What cells are activated first during tissue injury? followed by?

Answer 3

Neutrophils (within hrs)

Monocytes and Macrophages (1-3 days)

T cells (1-2 week)
Adaptive immune response

Question 4

What determines whether there is scarring or regeneration?

Answer 4

Depends on secretion of IL4 or IL10

IL4
Activates Pro-fibrotic macrophage which activates Scar forming Myofibroblast

IL10
Activates Anti-inflammatory anti-fibrotic (AIAF) macrophage
AIAF macrophage inhibits scarring
Insulin Growth Factor IGF-1 causes angiogenesis

Question 5

Pathophysiology of Osteoarthritis (4 points)

Answer 5

1) Cartilage, meniscus damage causes production of DAMPs (eg. degraded cartilage matrix constituents, alarmins etc.)
2) DAMPs will activate innate immune system eg. macrophages to produce proinflammatory cytokines cytokines eg. IL1B, IL8, TNF, Chemokines
3) PRR (Pattern Recognition Receptors) will recognise DAMPs, activate the complement pathway
4) This leads to synovitis (inflammation of joint) and chondrocyte activation. Synovial space becomes smaller than before, more cartilage erosion.

Question 6

Pathophysiology of RA (3 points)

Answer 6

1) Macrophage secretes TNF
2) TNF is the most important cytokine in inflammation, stimulate synovial fibroblast to secrete other cytokines and MMP (Matrix Metalloproteinase)
3) MMP and Neutrophils will break down cartilage, cause bone destruction

Question 7

Pathophysiology of Gout

Answer 7

1) Monosodium Urate Crystals are DAMPs, activate Inflammasome
Inflammasome activate Caspase-1, enzyme that catalyse maturation of pro-IL1B to IL1B.

2) Caspase 1 also cleave Gasdermin D, form N-terminal cleavage product which triggers Pyroptosis (cell death). IL-1B leaves cell via Pyroptotic pore
(Anakinra is an IL-1 receptor antagonist, prevent IL-1 from activating immune response)

3) Potassium efflux occurs, Mitochondria produces ROS (reactive oxygen species)
After IL1B leave cells, bind to receptors on endothelial cells and synoviocytes

4) This triggers phosphorylation downstream, eventually cause transcription of cytokines and chemokines → increase inflammation and neutrophil recruitment
Neutrophils try to phagocytose MSU crystals…

Question 8

Role of Canakinumab and Anakinra

Answer 8

Canakinumab - IL1B inhibitor

Anakinra - IL1 receptor inhibitor

Question 9

Function of Osteoblasts, Osteoclasts, Osteocytes

Answer 9

Osteocytes
Osteoblasts that become incorporated into calcified bone matrix
Respond to changes, send messages to Osteoblasts and
Osteoclasts
Produce RANKL and Sclerostin

Osteoblasts
Responsible for bone matrix synthesis

Osteoclasts
Resorption of mineralised tissue

Question 10

how does glucocorticoid cause osteoporosis

Answer 10

Decreases osteoblast differentiation, increase death of osteoblasts and osteocytes