8. Pathogenesis of RA - Lesley Robson Flashcards
What is the main part of the joint involved in RA?
The synovial fluid
What is the synovium?
Synovial membrane
How thick is the synovium?
Thin layer - 1-3 cells thick
What are the cell types found in the synovium?
Synoviocytes:
Type a - bone marrow derived macrophage
Type b - fibroblast-like connective tissue cell
What is the function of type a synoviocytes?
Type a - bone marrow derived macrophage
Immune surveillance
Ensures that the joint capsule is aseptic and the synovial fluid contains no pathogens or bacteria - part of immune surveillance
What is the function of type b synoviocytes? x2
Type b - fibroblast-like connective tissue cell
These produce the ECM and the hyaluronic acid for the composition of synovial fluid
Where do the synoviocytes sit?
These sit on the subintima - there is no basement membrane
Does the synovium have a basement membrane?
No
What is the structure of the subintima?
Contains dense network of fenestrated capillaries - very dense blood supply
Loose areolar connective tissue
What is the composition of synovial fluid?
Ultrafiltrate of blood (same composition as the blood plasma) with added hyaluronic acid and lubricin
Where is synovial fluid located?
Forms a thin film over articular surfaces
What is the vasculature of the subintima?
Subintima contains many blood vessels inside - contains many fenestrated capillaries
What is the shape of synoviocytes?
Cuboidal cells
Why are the capillaries of the subintima fenestrated?
Allows the blood plasma to leak out of the capillaries whilst containing the cellular component so that synovial fluid can be formed from just the blood plasma
Why is the ECM composed of loose areolar connective tissue?
To allow the blood plasma to leak from the fenestrated capillaries through teh ECM to the joint cavity
When are the type a synoviocytes active?
These are not active in a healthy joint - they are quiescent
Only become activated when required
Why do synovial joints have reduced immune surveillance and protection?
Fenestrated capillaries and loose areolar tissue - bacteria and pathogens can pass from the blood vessels into the joint along with the blood plasma
What is the normal appearance (colour) of synovial fluid?
Colourless to pale yellow and clear - should be able to read text behind it
What does red/brown synovial fluid indicate?
Haemorrhage into the joint
What does yellow/cloudy synovial fluid indicate?
Inflammation - cloudy due to presence of WBCs
What does white/creamy and cloudy/shiny synovial fluid indicate?
Presence of crystals
What does colourless to yellow and purulent (lumpy) synovial fluid indicate?
Bacterial infection
What is the effect of the hyaluronic acid on the viscosity of the synovial fluid?
Increases the viscosity and causes the synovial fluid to be thick and gloopy
What are the microcomponents responsible for the viscosity of synovial fluid and why? x3
Albumin and globulin proteins and hyaluronic acid
These form tangles with the hyaluronic acid and this increases the viscosity
How much synovial fluid is present within a joint and why?
Not very much is present - this is because it is very effective at carrying out its job
What is the effect of the synovial fluid on articulating hyaline cartilage?
Keeps the articular cartilages away from each other by about 50 micro metres
How does the viscosity of the synovial fluid change?
Changes upon movement
At rest - forms a gel
Upon movement, gel complex (tangles are) is broken down and you get a more free moving composition
What is the main property of synovial fluid?
It is viscoelastic
How can you test the health of synovial fluid?
Measure the viscosity of the synovial fluid - more viscous - the healthier it is
Outlines two tests used to measure the health of synovial fluid
String test - pipette synovial fluid out of a pipette and the longer the string, the better quality the hyaluronic acid and the fluid
Place the hyaluronic acid in vinegar - if good quality should form a solid clump of the acid and vinegar and leave the remaining solution colourless
If no solid clot and not colourless - do not have a very good quality hyaluronic acid or synovial fluid
How far apart is articulating hyaline cartilage kept from each other due to synovial fluid?
50 micrometres
What is the main change that occurs at the synovial joint in RA?
There is an infiltration of lymphocytes into the synovial membrane meaning that there is no longer a loose areolar structure of the ECM - results in fibrosis
What leucocytes are present in RA?
Lymphocytes in the synovial membrane/synovium
Neutrophils enter the synovial fluid
What happens to the synoviocytes in RA?
There is a proliferation of synoviocytes and they form many many layers (remember synovium is only meant to be 1-3 cells thick)
Which cells proliferate in RA?
Synoviocytes - many layers of the synovium
Fibroblasts - hyperplasia of the ECM
What is the role of oesteoclasts in RA?
Increasing numbers of oestoclasts produced - break down and damage the bone
Where do the osteoclasts have the main impact in the synovial joint in RA and where else do they have an impact?
Main impact is on the synovial membrane
Have a lesser impact on the articular cartilage
Why is the presence of neutrophils in synovial fluid a problem?
Synovial fluid should be acellular
What cells are normally found in synovial fluid?
Synovial fluid should be acellular
What is the main inflammatory cell orchestrating the inflammatory process in RA?
Th17 cell
CD4+ t-helper cell (17)
What is produced by the Th17 cell in RA?
IL17
Where are the effects of IL17 and what is it produced by in RA?
IL17 produced by Th17 cells
Very local effect
What is the action of IL17 in RA and what is it produced by?
IL17 produced by Th17 cell
Interacts with dendritic cell - release of IL6 and IL23, TNF-alpha
Interacts with macrophages - type a synoviocytes and others - production of pro-inflammatory cytokines IL-1, TNF-alpha, RANKL
What does IL17 result in the release of?
IL6 IL23 TNF alpha x2 IL-1 RANKL
What is the action of IL23?
Linked with the leaky gut epithelium
What is the main action of TNF alpha in RA?
What are the other actions?
TNF-alpha is the main systemic pro-inflammatory cytokine in RA
Production of synovial fibroblasts, digestive enzymes - damage ECM of the cartilage
What is meant by ‘systemic’?
Has actions throughout the whole body
What is the main impact of RANKL in RA?
Impacts bone metabolism - signals to osteoclast precursors to proliferate and differentiate - these then attack the bone
Which cells to TH17 cells interact with in RA?
B-cells
What is the function of the B cells that interact with TH17 cells in RA?
Production of autoantibodies, rheumatoid factor
What is the function of IL-6?
Stimulates immune response during infection and trauma
What is IL-17 commonly associated with?
Allergic responses - production of many other cytokines
Which cells would normally act to combat inflammation in a synovial joint?
T-regulatory cells - would be inhibitory
Why can t-regulatory cells not carry out their function in RA?
These cells seem to be impaired in cases of RA
What does the lymphocytic infiltration result in at the synovial joint?
Lymphocytic infiltration and proliferation
Very thick subintima - forms aggregates - loses shape
Synovium thickens - results in the formation of a PANNUS
What is a pannus?
Thickened synovium due to lymphocytic infiltration and proliferation and fibroblast proliferation at the subintima and synovium
Which structures are first destroyed by a growing pannus?
The pannus grows into the articular cartilage at one end and into the underlying subchondral bone at the other end
What happens to the subchondral bone when there is pannus formation?
Results in areas of erosion in the subchondral bone
What is eroded in RA?
Bone
Some articular cartilage
What are the types of erosion that can occur in RA?
Subchondral erosion
Periarticular erosion
What is subchondral erosion?
Erosion of the underlying subchondral bone
What is periarticular erosion?
Erosion of the cortical bone - loss of the barrier between tissue and bone marrow
What structure is formed within a pannus and how?
Lymphoid nodule:
CD4 (helper) lymphocytes collect around small blood vessels and form the lymphoid nodule
What is the action of the pannus?
The pannus is destructive - secretion of cytokines and involved in the erosion of articular cartilage and bone - destruction to joint
How can a pannus be recogised?
By it’s fingerlike projections
What antibodies are produced by the b-cells in RA?
Anti-citrullinated protein antibodies (ACPA)
What kind of immune condition is RA?
Autoimmune condition
What is the action of ACPA?
Stimulate osteoclast differentiation and proliferation - erode the underlying subchondral bone
What is the impact of TH17 in tissue where there are no osteoclasts eg. tendon sheathes and bursae
Cytokines induce the production of DKK-1
What is the full name of DKK-1?
Dickkopf-related protein 1
What is the action of DKK-1?
Induces sclerostin production - stimulates osteoblasts to switch off and there is further destruction of bone
How does the induced secretion of sclerosin by DKK-1 result in the further destruction of bone?
Presence of sclerostin - the bone thinks that it is fine - the bone does not try to repair itself and instead continues to destroy itself
What cell is present in the normally acellular synovial fluid?
Neutrophils
What is the action of neutrophils in synovial fluid?
Respiratory burst - this is their mechanism of action - results in production of free radicals
What is a respiratory burst?
The rapid release of reactive oxygen species from different types of cells
What is the impact of the respiratory burst in RA? x3
Free radicals damage the structure of the articular cartilage and also of any exposed bone
Damages hyaluronic acid - shorter string and less viscous
Results in increased synovial fluid due to increased leakage from vessels
What are the two reasons for pain occurring in RA?
One - nerve endings are irritated by the inflammation occurring at the joint
Two - stretching of the capsule due to swelling of the joint
