Lecture 26 - Synovium in health and RA Flashcards
What is the synovium?
thin membrane that extends from skeletal tissue at interface of cartilage and bone and lines the capsule of diarthrodial joints
The first layer f the synovium is
Intima
tissue between the joint cavity and subintima
1-3 cell layers deep (cells=synoviocytes)
The second later of synovium is..
Subintima
connnective tissue that becomes denser closer to the joint capsule
contains BV, Lymph.Vs, and nerves
The Areolar section is bit _____ from the joint, the Fibrous section is where the ____ is and is difficult to distringuish from ______
The Fatty section is mostly in fat pads,
Areolar section is bit further from the joint, the Fibrous section is where the joint is and is difficult to distringuish from fibrocartilage
all have Subintima and Intima
What are the functions of the synovium?
Facilitiates movement
What provision of lubricants exist to to minimuse “wear and tear: on joint tissues?
Hyaluronan - shock absorbtion, prevents fluid loss
Lubricin - proteoglycan, protects cartilage surfaces from protein desposition and cell adhesion, and inhibits cell overgrowth
The “Grease” within your joints
___ of cells are Macrophage-like synovocytes in intima
20% - phagocytic capability
others are Fibroblast-like synoviocytes
Which type of synoviocytes produces Hyaluronan and Lubricin?
Fibroblast-like synoviocytes
___is when the inflamed synovial tissue is next to cartilage
pannus
True or False
RA inflammation; you will see neutrophils in synovial fuid
False
There will be infiltration of infalmmatory cells into the sublining, as well as formation of new…
blood vessels (neovascularisation)
True or False
Inflammationof the synovium occurs late in disease
False
happens early
Cells present within the inflammed synovial tissue secrete factors which:
1 ) attract inflammatory cells into the joint (chemokines)
2) retain the cells there (adhesion molecules)
Pannus is..
the inflammed synovial tissue that “creeps’ over the cartilage and bone tissue of the joint
True or False
Pannus contains macrophages but fewer T/B cells than the peripheral inflammed synovial tissue
true
Cells within the pannus release factors which..
destroy articular cartilage and bone
In RA Type _ (macrophage) synoviocytes outnumber type _ (fibroblast-ike) cells
In RA Type A (macrophage) synoviocytes outnumber type B (fibroblast-ike) cells
usually type A are only 20%
There will be high expression of _____ markers and ______ from type A synovioocytes
There will be high epression of phagocytic markers and MHC II from type A synovioocytes
Synovial macrophages may trans-differentiate” to a ____ -resorbing osteoclast
bone
Type B cells respond to infammation with ____
cytokines including IL-1, TNF, IL-6
chemokines
MMPs
factors that promote local bone destruction
What factors promote local bone destruction?
TNF and RANKL
___are the most prominant CD4+ T cells
TH17 - express IL-17
___ _____T cells are most prevalent in RA synovium
Cd4+ helper T cells
TH17 cells are recreited and differentiate upon signalling by..
IL-6 (from the macrophage)
Th17 are large sources of
RANKL - bone destruction
In RA ___ cells are not functoin - leading to reduced expression of IL-10 and IL-4
T regs
True or False
The presence and distribtion of B cells is fixed among RA patients
False - it is varialbe
May depend on stage of disease
What is responsible for the antibodu production in response to T cell cativation and production of autoantibodies (eg. RA factor and anti-CCP)
B cells
Moleules belonging to the categories of
cytokines
chemokines
growthfactors
are all released in
RA synovium and contribute to RA pathogenesis
TNF is..
family of _____
Initially membrane bound, is cleaved by ___ (both forms are active)
Tumour necrosis factor
family of cytokines
Initially membrane bound, is cleaved by TACE (both forms are active)
what are the 2 receptors for TNF and how are they expressed?
TNFR1
TNFR2 - expression is induced (particularly in inflammatory situations)
TNF can have local and ___ actions
systemic
What role does TNF play in RA?
Proinflammatory cytokine release
Hepcidin induction
PGE
Osteoclast activation
Chondrocyte activation (cartilage destruction)
Angiogenesis
Leukocyte accumulator
Endothelial cell activation
Chemokine release
IL-1has two forms..
IL-1 aplha - cytosolic form
IL-1 beta - inducible form, secreted and then cleaved into its active form by ICE
Il-1 activity is tightly regulated by ______ inhibitors
endogenous inhibitors
IL-1 receptor antagonist called ____ competes with IL-1 for binding to IL-1 receptor
IL-1ra
It is the balance of the cytokine and the inhibitor that determines the effect of IL-1 signalling
What is IL-1’s role in RA
activation of leukocytes, endothelial cells and synovial fibroblasts
induce expression of chemokines and cytokines
Induce MMP production by chondrocytes
Induce expression of osteoclasts
IL-6 is responsible for
increasing acute phase response in liver
Induces Ig production in B cells
promotes differentiation of TH17 cells
induces cytokine production by synovial fibroblasts and macrophages
promote osteoclasts (RANKL)
The most common model for screening therapeutic compounds is ___
Collagen induced arthritis (CIA)
What are the pros of Rodent collagen-induced arthritis models?:
____arthritis affecting knee and paws
______ inflammation
dependent on __ cells
___ and __-beta expression is elevated
(inhibition of either of these cytokines, _____ arthritis onset and severity)
__ factor reported to be produced
symmetrical arthritis affecting knee and paws
synovial inflammation
Dependent on T/B cells (also requires the expression of MHC II alleles)
TNF and IL-beta expression is elevated
(inhibition of either of these cytokines, reduces arthritis onset and severity)
RF factor reported to be produced
What are the cons of Rodent collagen-induced arthritis models?:
Disease susceptibily is depends on expression of certain classes of _____
only certain mouse strains are susceptible (_____ most susceptible)
_____ of disease onset and severity of disease can be variable
unlike RA patients Collagen _____ are produced
Disease susceptibily is depends on expression of certain classes of MHC II
- only certain mouse strains are susceptible (DBA/1 most susceptible)
- limits utility
Timing of disease onset and severity of disease can be variable
unlike RA patients Collagen antibodies are produced
Mouse that have been genetically engineered to over-express human TNF (hTNF.Tg ) are quite good in the human-like onset and
blocking TNF will reduce/block disease severtity
Is dependent on the IL1 receptor expression and signalling
(used extensively
What are the pros and cons of the hTNF.Tg mouse model?
Pros
reliable arthritis, chronic
useful to assess effect of TNF inhibition
Cons.
even though IL-1 is essential to arthritis it is a TNF driven model
Arthritis not dependent on T or B cells
Process of inflammation and bone loss is similar with ___and ____ and ____ playing a dominant role
Process of inflammation and bone loss is similar with TNF and IL-1 and RANKL playing a dominant role
