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Year 2 Loco > 8. Pathogenesis of RA - Lesley Robson > Flashcards

8. Pathogenesis of RA - Lesley Robson Flashcards

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1
Q

What is the main part of the joint involved in RA?

A

The synovial fluid

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2
Q

What is the synovium?

A

Synovial membrane

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3
Q

How thick is the synovium?

A

Thin layer - 1-3 cells thick

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4
Q

What are the cell types found in the synovium?

A

Synoviocytes:
Type a - bone marrow derived macrophage
Type b - fibroblast-like connective tissue cell

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5
Q

What is the function of type a synoviocytes?

A

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

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6
Q

What is the function of type b synoviocytes? x2

A

Type b - fibroblast-like connective tissue cell

These produce the ECM and the hyaluronic acid for the composition of synovial fluid

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7
Q

Where do the synoviocytes sit?

A

These sit on the subintima - there is no basement membrane

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8
Q

Does the synovium have a basement membrane?

A

No

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9
Q

What is the structure of the subintima?

A

Contains dense network of fenestrated capillaries - very dense blood supply
Loose areolar connective tissue

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10
Q

What is the composition of synovial fluid?

A

Ultrafiltrate of blood (same composition as the blood plasma) with added hyaluronic acid and lubricin

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11
Q

Where is synovial fluid located?

A

Forms a thin film over articular surfaces

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12
Q

What is the vasculature of the subintima?

A

Subintima contains many blood vessels inside - contains many fenestrated capillaries

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13
Q

What is the shape of synoviocytes?

A

Cuboidal cells

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14
Q

Why are the capillaries of the subintima fenestrated?

A

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

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15
Q

Why is the ECM composed of loose areolar connective tissue?

A

To allow the blood plasma to leak from the fenestrated capillaries through teh ECM to the joint cavity

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16
Q

When are the type a synoviocytes active?

A

These are not active in a healthy joint - they are quiescent

Only become activated when required

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17
Q

Why do synovial joints have reduced immune surveillance and protection?

A

Fenestrated capillaries and loose areolar tissue - bacteria and pathogens can pass from the blood vessels into the joint along with the blood plasma

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18
Q

What is the normal appearance (colour) of synovial fluid?

A

Colourless to pale yellow and clear - should be able to read text behind it

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19
Q

What does red/brown synovial fluid indicate?

A

Haemorrhage into the joint

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20
Q

What does yellow/cloudy synovial fluid indicate?

A

Inflammation - cloudy due to presence of WBCs

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21
Q

What does white/creamy and cloudy/shiny synovial fluid indicate?

A

Presence of crystals

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22
Q

What does colourless to yellow and purulent (lumpy) synovial fluid indicate?

A

Bacterial infection

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23
Q

What is the effect of the hyaluronic acid on the viscosity of the synovial fluid?

A

Increases the viscosity and causes the synovial fluid to be thick and gloopy

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24
Q

What are the microcomponents responsible for the viscosity of synovial fluid and why? x3

A

Albumin and globulin proteins and hyaluronic acid

These form tangles with the hyaluronic acid and this increases the viscosity

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25
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
26
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
27
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
28
What is the main property of synovial fluid?
It is viscoelastic
29
How can you test the health of synovial fluid?
Measure the viscosity of the synovial fluid - more viscous - the healthier it is
30
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
31
How far apart is articulating hyaline cartilage kept from each other due to synovial fluid?
50 micrometres
32
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
33
What leucocytes are present in RA?
Lymphocytes in the synovial membrane/synovium Neutrophils enter the synovial fluid
34
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)
35
Which cells proliferate in RA?
Synoviocytes - many layers of the synovium | Fibroblasts - hyperplasia of the ECM
36
What is the role of oesteoclasts in RA?
Increasing numbers of oestoclasts produced - break down and damage the bone
37
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
38
Why is the presence of neutrophils in synovial fluid a problem?
Synovial fluid should be acellular
39
What cells are normally found in synovial fluid?
Synovial fluid should be acellular
40
What is the main inflammatory cell orchestrating the inflammatory process in RA?
Th17 cell CD4+ t-helper cell (17)
41
What is produced by the Th17 cell in RA?
IL17
42
Where are the effects of IL17 and what is it produced by in RA?
IL17 produced by Th17 cells Very local effect
43
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
44
What does IL17 result in the release of?
``` IL6 IL23 TNF alpha x2 IL-1 RANKL ```
45
What is the action of IL23?
Linked with the leaky gut epithelium
46
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
47
What is meant by 'systemic'?
Has actions throughout the whole body
48
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
49
Which cells to TH17 cells interact with in RA?
B-cells
50
What is the function of the B cells that interact with TH17 cells in RA?
Production of autoantibodies, rheumatoid factor
51
What is the function of IL-6?
Stimulates immune response during infection and trauma
52
What is IL-17 commonly associated with?
Allergic responses - production of many other cytokines
53
Which cells would normally act to combat inflammation in a synovial joint?
T-regulatory cells - would be inhibitory
54
Why can t-regulatory cells not carry out their function in RA?
These cells seem to be impaired in cases of RA
55
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
56
What is a pannus?
Thickened synovium due to lymphocytic infiltration and proliferation and fibroblast proliferation at the subintima and synovium
57
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
58
What happens to the subchondral bone when there is pannus formation?
Results in areas of erosion in the subchondral bone
59
What is eroded in RA?
Bone Some articular cartilage
60
What are the types of erosion that can occur in RA?
Subchondral erosion | Periarticular erosion
61
What is subchondral erosion?
Erosion of the underlying subchondral bone
62
What is periarticular erosion?
Erosion of the cortical bone - loss of the barrier between tissue and bone marrow
63
What structure is formed within a pannus and how?
Lymphoid nodule: | CD4 (helper) lymphocytes collect around small blood vessels and form the lymphoid nodule
64
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
65
How can a pannus be recogised?
By it's fingerlike projections
66
What antibodies are produced by the b-cells in RA?
Anti-citrullinated protein antibodies (ACPA)
67
What kind of immune condition is RA?
Autoimmune condition
68
What is the action of ACPA?
Stimulate osteoclast differentiation and proliferation - erode the underlying subchondral bone
69
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
70
What is the full name of DKK-1?
Dickkopf-related protein 1
71
What is the action of DKK-1?
Induces sclerostin production - stimulates osteoblasts to switch off and there is further destruction of bone
72
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
73
What cell is present in the normally acellular synovial fluid?
Neutrophils
74
What is the action of neutrophils in synovial fluid?
Respiratory burst - this is their mechanism of action - results in production of free radicals
75
What is a respiratory burst?
The rapid release of reactive oxygen species from different types of cells
76
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
77
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

Year 2 Loco (31 decks)

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