RA - L2

Question 1

Describe healthy synovium

Answer 1

intima
subintima
20% macrophage like synoviocytes
80% fibroblast like synoviocytes

Question 2

What are the 3 types of synovial tissue?

Answer 2

areolar
fibrous
fatty

Question 3

What do FLS do?

Answer 3

produce lubricin and hyaluronan for joint lubrication

produce collage and fibronectin

Question 4

Describe RA synovium

Answer 4

inflammation
intima expands to 12 cells thick
infiltration of inflammatory cells
neovascularization
deposition of fibrin

Question 5

What is pannus?

Answer 5

inflamed synovial tissue that creeps over the cartilage and bone tissue of joint

Question 6

Macrophage Like Synoviocytes in RA

Answer 6

outnumber FLS in RA
activated phenotype
   high expression of MHC II
significant sources of pro-inflammatory cytokines (TNF, IL-1, IL-6, GM-CSF)
may trans-differentiate to osteoclast

Question 7

Fibroblast like Synoviocytes in RA

Answer 7

prevalent mediators of inflammation
produce cytokines (IL-1, TNF, IL-6), chemokines, matrix degrading enzymes (MMPs)
produce TNF & RANKL (promote bone destruction)
produce factors that inhibit bone formation activity (TNF, DKKS, sFRPs)

Question 8

T cells in RA

Answer 8

TH17 cells
recruitment and differentiation induced by IL-6
express RANKL
express IL-17
T reg cells
normally suppress inflam response, but not functional in RA

Question 9

B cells in RA

Answer 9

variable
production of RF & ACPA
source of RANKL

Question 10

TNF

Answer 10

initially membrane-bound protein, subsequently cleaved to from a soluble form by TACE
TNFRI - constitutive expression
TNFRII expression is induced
predominate source is macrophages

Question 11

IL-1

Answer 11

2 isoforms
IL-1a: cytosolic form
IL-1b: inducible form, secreted and then cleaved into its active form by ICE
IL-1 is tightly regulated by soluble IL-1 receptors (decoy) and IL-1ra
main source is macrophages

Question 12

IL-1 roles

Answer 12

activates leukocytes, endothelial cells and synovial fibroblasts
induces expression of chemokines and cytokines
cartilage destruction by metalloproteinase
osteoclast differentiation factors

Question 13

IL-6

Answer 13

membrane bound or soluble
receptor is gp130
main sources is FLS

Question 14

IL-6 roles

Answer 14

increases acute phase response in liver
promotes TH17 production
cytokine production
RANKL production

Question 15

GM-CSF

Answer 15

binds heterodimer of alpha and beta chains

Question 16

GM-CSF role

Answer 16

supports differentiation of bone marrow precursor cells to mature granulocytes and macrophages
supports dendritic cell differentiation
potent activators of macrophages

Question 17

JAK-STAT pathway

Answer 17

cytokine binds to receptor
JAK autophosphorylates the receptor
STAT binds
JAK phosphorylates STAT
STAT released and binds with another STAT
initiates gene transcription

Question 18

What does JAK and STAT stand for and how many of each are there?

Answer 18

Janus Kinase (JAK1-3)
Signal Transducer & Activator of Transcription (STAT1-6)

Question 19

JAK/STAT relevance in RA?

Answer 19

STAT3 phosphorylation increased in RA synovium
promote cytokine expression
suppress synovial fibroblast apoptosis
promotes T cell survival
promotes antibody production

Question 20

What strain of mice used for CIA?

Answer 20

DBA/1

Question 21

How is CIA induced?

Answer 21

immunisation of foreign source of type II collagen at base of tail

Question 22

Pros of CIA

Answer 22

symmetrical arthritis
synovial inflammation
dependent on T & B cells
TNF, IL-1b, IL-6 and GM-CSF expression elevated

Question 23

Cons of CIA

Answer 23

disease susceptibility dependent on certain MHC class II type (DBA/1 mice)
timing of disease variable
anitbodies to collagen produced (doesnt happen in human RA)

Question 24

hTNF.Tg mice model features

Answer 24

blocking TNF will reduce/block disease severity

dependent on IL-1/IL-1R expression & signalling

Question 25

Pros of hTNF.Tg

Answer 25

reliable, robust arthritis

useful to assess TNF inhibition

Question 26

Cons of hTNF.Tg

Answer 26

even though IL-1 essential to arthritis, this is a TNF driven model
arthritis not dependent of T and B cells