RA - L2 Flashcards
Describe healthy synovium
intima
subintima
20% macrophage like synoviocytes
80% fibroblast like synoviocytes
What are the 3 types of synovial tissue?
areolar
fibrous
fatty
What do FLS do?
produce lubricin and hyaluronan for joint lubrication
produce collage and fibronectin
Describe RA synovium
inflammation intima expands to 12 cells thick infiltration of inflammatory cells neovascularization deposition of fibrin
What is pannus?
inflamed synovial tissue that creeps over the cartilage and bone tissue of joint
Macrophage Like Synoviocytes in RA
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
Fibroblast like Synoviocytes in RA
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)
T cells in RA
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
B cells in RA
variable
production of RF & ACPA
source of RANKL
TNF
initially membrane-bound protein, subsequently cleaved to from a soluble form by TACE
TNFRI - constitutive expression
TNFRII expression is induced
predominate source is macrophages
IL-1
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
IL-1 roles
activates leukocytes, endothelial cells and synovial fibroblasts
induces expression of chemokines and cytokines
cartilage destruction by metalloproteinase
osteoclast differentiation factors
IL-6
membrane bound or soluble
receptor is gp130
main sources is FLS
IL-6 roles
increases acute phase response in liver
promotes TH17 production
cytokine production
RANKL production
GM-CSF
binds heterodimer of alpha and beta chains
GM-CSF role
supports differentiation of bone marrow precursor cells to mature granulocytes and macrophages
supports dendritic cell differentiation
potent activators of macrophages
JAK-STAT pathway
cytokine binds to receptor JAK autophosphorylates the receptor STAT binds JAK phosphorylates STAT STAT released and binds with another STAT initiates gene transcription
What does JAK and STAT stand for and how many of each are there?
Janus Kinase (JAK1-3) Signal Transducer & Activator of Transcription (STAT1-6)
JAK/STAT relevance in RA?
STAT3 phosphorylation increased in RA synovium promote cytokine expression suppress synovial fibroblast apoptosis promotes T cell survival promotes antibody production
What strain of mice used for CIA?
DBA/1
How is CIA induced?
immunisation of foreign source of type II collagen at base of tail
Pros of CIA
symmetrical arthritis
synovial inflammation
dependent on T & B cells
TNF, IL-1b, IL-6 and GM-CSF expression elevated
Cons of CIA
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)
hTNF.Tg mice model features
blocking TNF will reduce/block disease severity
dependent on IL-1/IL-1R expression & signalling
Pros of hTNF.Tg
reliable, robust arthritis
useful to assess TNF inhibition
Cons of hTNF.Tg
even though IL-1 essential to arthritis, this is a TNF driven model
arthritis not dependent of T and B cells
