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Locomotor 2 > Normal and Abnormal joints pathogenesis of RA > Flashcards

Normal and Abnormal joints pathogenesis of RA Flashcards

1
Q

how many cells thick is the synovial membrane

A

1-3 cells thick

- synoviocytes make up the synovial membrane

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2
Q

What are the cells called that make up the synovial membrane

A

Synoviocytes

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3
Q

name the two types of synoviocytes and what they do

A

Type A bone marrow derived macrophage - immune surveillance - last check to make sure that the synovial fluid is aseptic

Type B fibroblast-like connective tissue cell - make hyaluronic acid

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4
Q

what is another word for synovial membrane

A

Synovium

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5
Q

describe the synovial membrane

A
  • 1-3 Synoviocytes cells thick
  • no basement membrane
  • subintima
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6
Q

describe the subintima

A

Contains dense network fenestrated capillaries - leaky capillaries that allow substances through

fat (loose areolar connective tissue)

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7
Q

What type of synoviocytes make hyaluronic acid

A

Type B= fibroblast-like connective tissue cell - make hyaluronic acid

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8
Q

what does the hyaluronic acid do to the synovial fluid

A
  • it makes it more viscous
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9
Q

what is the benefit of having no basement membrane in the synovial membrane

A

this means that there is no barrier for blood plasma that is coming out of the capillary network in the subintima to go into the joint , also means there is no barrier for the synovial fluid passing into the blood

Loose areolar connective tissue allows plasma to move through subintima

No basement membrane between subintima and synoviocytes allows plasma to flow through to joint cavity

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10
Q

synovial fluid is the …

A

ultrafiltrate with blood and added hyaluronic acid

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11
Q

describe the downside of having no basement membrane

A
  • the joint can be easily more damaged
  • fenestrated capillaries are already more leaky meaning immune cells can leave more easily and enter the joint meaning the joints are at a higher risk of infections and autoimmune problems
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12
Q

what does normal synovial fluid look like

A
  • Normal synovial fluid is colourless to pale yellow and clear therefore it is normal
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13
Q

what does it mean if the synovial fluid is yellow and cloudy

A
  • this is what it looks like in rheumatoid arthritis

- due to the amount of neutrophils that are present

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14
Q

what is present if the synovial fluid looks white/creamy and cloudy/shiny

A

crystals

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15
Q

What is present if the synovial fluid looks colourless to yellow and purulent (lumpy)

A

means that there is a bacterial infection present

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16
Q

what does if mean if the synovial fluid is red and brown

A
  • means that there is haemorrhage into joint which is the result of a direct acute injury
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17
Q

What is synovial fluid made out of

A
  • white blood cells = mainly phagocytes
  • hyaluronate
  • glucose
  • protein - albumin (60%) and globulin (40%)
  • Lubricin
  • lactate and the rions
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18
Q

What is the pH of synovial fluid

A

7.38

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19
Q

what does the hyaluronate with the protein form

A
  • they form a gel like substance that separates the articulating surface from each other
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20
Q

where is synovial fluid

A
  • small amount occupies all free spaces between articulating surfaces - approximately 50 micrometers
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21
Q

what else does synovial fluid do

A
  • seeps into articular cartilages
  • this helps nourish articular cartilage
  • it is called weeping lubrication
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22
Q

What is articular cartilage

A

Slippery weight-bearing film which reduces friction between cartilages

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23
Q

what part of the articular cartilage are compressible

A
  • as you compress down the peripheral zone and transitional zone compress
  • water moves out of these zones
  • the lower zone is not compressible due to the direction of the collagen fibres
24
Q

what happens to the hyaluronate as you move

A

as you move it becomes more thicker

  • gets thicker between the joints at movement as it becomes more tangled and integrated with the articular proteins
  • this acts as a shock absorber
25
Q

describe what happens to the synovial joint and fluid at rest compared to movement

A

Movement

  • at movement pressure is pressed on the joint
  • decreases the peripheral and transitional zone of the articular cartilage
  • the hyaluronate becomes more entangled with proteins and therefore acts as a shock absorber and an energy store

Rest

  • at rest pressure is decreased in the joint
  • increased elongation of the peripheral and transitional zone back to normal on the articular cartilage
  • hyaluronate becomes less entangled and more viscous and energy is dissipated as viscous flow
26
Q

How do you test viscosity in the synovial fluid (hyaluronic acid)

A
  • measure the string that originates from the synovial fluid
  • the longer the string the less oedema fluid and the less hydrolysed the hyaluronic acid
  • normal string is between 4-6cm
  • the longer it is the more vicious it is and the better the result
  • normal synovial fluid is highly vicious
27
Q

What is the mucin clot test used to measure

A

measures the viscous property of the synovial fluid

28
Q

describe how to do the mucin clot test

A
  • add 2-5% acetic acid
  • normal synovial fluid will then from a clot surrounded by clear fluid
  • In RA - the hyaluronate is smaller and not as polymerised therefore clots less this means that the results would show a cloudy view with no clot
29
Q

What is Rheumatoid arthritis

A

Autoimmune condition that primarily damages the synovial membrane causing synovicitis

30
Q

What and the three things that happen microscopically with rheumatoid arthritis

A

proliferation of synoviocytes

infiltration of inflammatory cells

  • neutrophils - in the synovial fluid
  • lymphocytes in the subintima

proliferation of fibroblasts in the subinitima causing thickening

31
Q

Where are the neurtrophils and lymphocytes in an inflammatory reaction such as rheumatoid arthritis in the joint

A
  • neutrophils - in the synovial fluid

- lymphocytes in the subinitima

32
Q

describe the inflammatory cells that are associated with rheumatoid arthritis

A
  • the synovial fluid has infiltration of tissue inflammatory cells
  • B cells inflation which produce autoantibodies that we find in RA as it is an autoimmune condition
  • the B cells produce the two main autoantibodies associated with RA these are Rheumatoid factor and Anti-Citrullinated protein antibodies (ACPA)
  • Anti-Citrullinated protein antibodies (ACPA) is thought to be the main antibody associated with RA as they are present in higher quantities
  • there are also T cells present and mainly TH17
  • TH17 produces IL17 int eh synovium
  • IL-17 causes synonvitis
  • IL-1, TNF alpha and RANKL are also produced
  • TNF-alpha is more important peripherally = TNF alpha also helps produce synovial fibroblasts therefore we get proliferation of the synovial membrane
  • T regulatory cells that should be stopping the T and B cells from targeting our own cells are impaired and don’t recognise the problem so therefore do not act
  • The macrophages within the synovial membrane and the subitnma can swtich and become under the influence of cytokines and osteoclasts – make them switch to become bone destroyers
33
Q

what is the mechanism of action of how the autoimmune reaction happens in RA

A

Mechanism of action

  • Neurotrophils are the first responders and take-up an infection and this particular infection has antigens that look like self antigens
  • therefore our own self antigens are mistaken for the infections
  • therefore the B cells make antibodies against these self antigens
34
Q

What are the two antibodies that are associated with RA

A

Rheumatoid factor and Anti-Citrullinated protein antibodies (ACPA)
- Anti-Citrullinated protein antibodies (ACPA) is thought to be the main antibody associated with RA as they are present in higher quantities

35
Q

what T cell is more prelevant and what does is produce in RA

A
  • TH17 and IL-17
36
Q

What does IL-17 cause to happen

A

IL-17 causes synonvitis
- induces RANKL on synovial fibroblasts

  • stimulates local inflammation
  • activates synovial macrophages to secrete proinflammatory cytokines, such as TNF, IL-1 and IL-6.
37
Q

What does TNF alpha do

A

TNF alpha also helps produce synovial fibroblasts therefore we get proliferation of the synovial membrane

38
Q

Why are synovial joints susceptible to inflammatory injury

A
  • Presence of rich network of fenestrated capillaries that are more leaky to begin with
  • limited ways that it can respond - pro-inflammatory cytokines induce proliferation and or direct osteoclast differentiation
39
Q

What is a Pannus

A
  • Synovial membrane at the end of proliferation that is abnormal
  • grows over the surface of joints and covers the cartilage
40
Q

describe what a pannus results in

A
  • Pannus contains osteoclasts
  • the osteoclasts erode and remove bone
  • therefore they erode the cartilage that the Pannus overhangs
  • they cause the cartilage to soften and the chondrocytes to become stressed and produce a tide mark
  • the pannus also secretes cytokines
  • CD4 T helper lymphocytes collect around small blood vessels and form lymphoid nodules
41
Q

What happens if you remove the Pannus

A
  • if you remove the Pannus it will regrow
42
Q

What does anti-citrullinated protein antibodies stimulate

A
  • osteoclast differentiation from monocytes leading to intimal bone loss
43
Q

describe the autocrine feedback of osteoclasts

A
  • Osteoclasts produce IL 8 that induces more osteoclasts by autocrine feedback
  • IL 8 also sensitises nociceptors and may contribute to increased pain
44
Q

what contributes to the pain felt in RA

A
  • IL 8 also sensitises nociceptors and may contribute to increased pain
45
Q

what does synovitis lead to

A

Synovitis at start of clinical disease leads to production of cytokines, which stimulate osteoclast proliferation and differentiation
- causes the production of RANKL this enhances osteoclast differentiation and causes more bone erosion

46
Q

what molecule does synovitis lead to the expression of

A

RANKL

47
Q

Describe what established RA looks like

A
  • Large bone erosions filled with inflamed synovial derived pannus tissue
48
Q

What is Citrullination

A

changing arginine to citrulline by deamination by peptidyl arginine deiminase occurs during apoptosis

49
Q

what is the hallmark of RA pathogenesis

A

CD4+T-cell infiltration is a hallmark of RA pathogenesis (TH17 cells)

50
Q

what does inflammation within synovial tissue induces

A
  • Osteoclast proliferation and differentiation

- causes increased expression of RANKL by pro inflammatory cytokines which synergies with RANKL

51
Q

what do cytokine induce

A

Cytokines induce expression of Dkk-1 by synovial fibroblasts which inhibits directly osteoblast differentiation

52
Q

What does DKK-1 do

A

inhibits directly osteoblast differentiation

- induces the expression of sclerotin by osteocytes which inhibits osteoblasts therefore reducing osteoblast activity

53
Q

how is synovial fluid affected in RA

A
  • increased amount of neutrophils
  • synovial fluid is less viscous due to shorter hyaluronic acid strands
  • increased volume due to leakier vessels from the release of cytokines
54
Q

what is the most numerous cells in inflammatory synovial effusion

A

Neutrophils

55
Q

describe how much fluid expands in the knee in RA

A

Normal knee 2 ml in RA can remove 20ml from knee

56
Q

what do neutrophils do in the synovial fluid

A

Direct damage

  • present in the early or active stages of the disease
  • they produce superoxide anion free radical
  • therefore there is free radical damage which directly damages hyaluronic acid

Indirect damage

  • they also secrete B cell activating factor
  • this activates the B cell to produce more antibody
  • B cells stimulate osteoclasts
57
Q

describe the difference between RA and OA in synovial fluid analysis

  • colour
  • clarity
  • viscosity
  • white cell count
  • neutrophils
  • crystals
  • bacteria
A

OA

  • colour - colourless
  • clarity - clear
  • viscosity - high to medium (1-2cm string)
  • white cell count - 100-2000
  • neutrophils - <5
  • crystals - 5% have pyrophosphate crystals
  • bacteria - no

RA

  • colour - yellow
  • clarity - cloudy
  • viscosity - low, less than 1cm
  • white cell count - 2000-50,000
  • neutrophils- 30-80
  • crystals - no
  • bacteria - no

Locomotor 2 (30 decks)

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