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

8. Pathogenesis of RA - Lesley Robson Flashcards

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
Q

How much synovial fluid is present within a joint and why?

A

Not very much is present - this is because it is very effective at carrying out its job

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26
Q

What is the effect of the synovial fluid on articulating hyaline cartilage?

A

Keeps the articular cartilages away from each other by about 50 micro metres

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27
Q

How does the viscosity of the synovial fluid change?

A

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

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28
Q

What is the main property of synovial fluid?

A

It is viscoelastic

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29
Q

How can you test the health of synovial fluid?

A

Measure the viscosity of the synovial fluid - more viscous - the healthier it is

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30
Q

Outlines two tests used to measure the health of synovial fluid

A

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

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31
Q

How far apart is articulating hyaline cartilage kept from each other due to synovial fluid?

A

50 micrometres

32
Q

What is the main change that occurs at the synovial joint in RA?

A

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
Q

What leucocytes are present in RA?

A

Lymphocytes in the synovial membrane/synovium

Neutrophils enter the synovial fluid

34
Q

What happens to the synoviocytes in RA?

A

There is a proliferation of synoviocytes and they form many many layers (remember synovium is only meant to be 1-3 cells thick)

35
Q

Which cells proliferate in RA?

A

Synoviocytes - many layers of the synovium

Fibroblasts - hyperplasia of the ECM

36
Q

What is the role of oesteoclasts in RA?

A

Increasing numbers of oestoclasts produced - break down and damage the bone

37
Q

Where do the osteoclasts have the main impact in the synovial joint in RA and where else do they have an impact?

A

Main impact is on the synovial membrane

Have a lesser impact on the articular cartilage

38
Q

Why is the presence of neutrophils in synovial fluid a problem?

A

Synovial fluid should be acellular

39
Q

What cells are normally found in synovial fluid?

A

Synovial fluid should be acellular

40
Q

What is the main inflammatory cell orchestrating the inflammatory process in RA?

A

Th17 cell

CD4+ t-helper cell (17)

41
Q

What is produced by the Th17 cell in RA?

A

IL17

42
Q

Where are the effects of IL17 and what is it produced by in RA?

A

IL17 produced by Th17 cells

Very local effect

43
Q

What is the action of IL17 in RA and what is it produced by?

A

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
Q

What does IL17 result in the release of?

A 
IL6
IL23
TNF alpha x2
IL-1
RANKL
45
Q

What is the action of IL23?

A

Linked with the leaky gut epithelium

46
Q

What is the main action of TNF alpha in RA?

What are the other actions?

A

TNF-alpha is the main systemic pro-inflammatory cytokine in RA

Production of synovial fibroblasts, digestive enzymes - damage ECM of the cartilage

47
Q

What is meant by ‘systemic’?

A

Has actions throughout the whole body

48
Q

What is the main impact of RANKL in RA?

A

Impacts bone metabolism - signals to osteoclast precursors to proliferate and differentiate - these then attack the bone

49
Q

Which cells to TH17 cells interact with in RA?

A

B-cells

50
Q

What is the function of the B cells that interact with TH17 cells in RA?

A

Production of autoantibodies, rheumatoid factor

51
Q

What is the function of IL-6?

A

Stimulates immune response during infection and trauma

52
Q

What is IL-17 commonly associated with?

A

Allergic responses - production of many other cytokines

53
Q

Which cells would normally act to combat inflammation in a synovial joint?

A

T-regulatory cells - would be inhibitory

54
Q

Why can t-regulatory cells not carry out their function in RA?

A

These cells seem to be impaired in cases of RA

55
Q

What does the lymphocytic infiltration result in at the synovial joint?

A

Lymphocytic infiltration and proliferation

Very thick subintima - forms aggregates - loses shape
Synovium thickens - results in the formation of a PANNUS

56
Q

What is a pannus?

A

Thickened synovium due to lymphocytic infiltration and proliferation and fibroblast proliferation at the subintima and synovium

57
Q

Which structures are first destroyed by a growing pannus?

A

The pannus grows into the articular cartilage at one end and into the underlying subchondral bone at the other end

58
Q

What happens to the subchondral bone when there is pannus formation?

A

Results in areas of erosion in the subchondral bone

59
Q

What is eroded in RA?

A

Bone

Some articular cartilage

60
Q

What are the types of erosion that can occur in RA?

A

Subchondral erosion

Periarticular erosion

61
Q

What is subchondral erosion?

A

Erosion of the underlying subchondral bone

62
Q

What is periarticular erosion?

A

Erosion of the cortical bone - loss of the barrier between tissue and bone marrow

63
Q

What structure is formed within a pannus and how?

A

Lymphoid nodule:

CD4 (helper) lymphocytes collect around small blood vessels and form the lymphoid nodule

64
Q

What is the action of the pannus?

A

The pannus is destructive - secretion of cytokines and involved in the erosion of articular cartilage and bone - destruction to joint

65
Q

How can a pannus be recogised?

A

By it’s fingerlike projections

66
Q

What antibodies are produced by the b-cells in RA?

A

Anti-citrullinated protein antibodies (ACPA)

67
Q

What kind of immune condition is RA?

A

Autoimmune condition

68
Q

What is the action of ACPA?

A

Stimulate osteoclast differentiation and proliferation - erode the underlying subchondral bone

69
Q

What is the impact of TH17 in tissue where there are no osteoclasts eg. tendon sheathes and bursae

A

Cytokines induce the production of DKK-1

70
Q

What is the full name of DKK-1?

A

Dickkopf-related protein 1

71
Q

What is the action of DKK-1?

A

Induces sclerostin production - stimulates osteoblasts to switch off and there is further destruction of bone

72
Q

How does the induced secretion of sclerosin by DKK-1 result in the further destruction of bone?

A

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
Q

What cell is present in the normally acellular synovial fluid?

A

Neutrophils

74
Q

What is the action of neutrophils in synovial fluid?

A

Respiratory burst - this is their mechanism of action - results in production of free radicals

75
Q

What is a respiratory burst?

A

The rapid release of reactive oxygen species from different types of cells

76
Q

What is the impact of the respiratory burst in RA? x3

A

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
Q

What are the two reasons for pain occurring in RA?

A

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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