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BIOM30002 - M2M > Lecture 26 - Rheumatoid Arthritis - Synovium > Flashcards

Lecture 26 - Rheumatoid Arthritis - Synovium Flashcards

1
Q

What are the layers of healthy synovium?

A
  • Intima (internally)

* Subintima (externally)

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2
Q

Describe the intima

A
  • Interface between joint cavity and subintima
  • 1-3 cell layers deep
  • Made up of synoviocytes
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3
Q

Describe the subintima

A
  • Connective tissue
  • Becomes denser closer to the joint capsule
  • Contains blood vessels, lymphatics, and nerves
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4
Q

Describe the supply to the synovium

A

Subintima receives:
• Blood supply
• Lymphatic vessels
• Nerve innervation

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5
Q

What are the different types of synovial tissue?

A
  • Areolar
  • Fibrous
  • Fatty
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6
Q

Describe Areolar synovium

A
  • Intima
  • Continuous layer of lining cells
  • Often see villi formation
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7
Q

Describe fatty synovium

Where is it found?

A

• Mostly found in fat pads

  • Under the intima are adipocytes
  • Superficial net of capillaries among the adipocytes
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8
Q

Where is Fibrous synovium found?

A

Layer of cells on a ligament or tendon

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9
Q

What are the functions of healthy synovium?

A
  1. Facilitation of movement
    • Non-adherent
    • Provides lubricants that minimise wear and tear
  2. Synovial fluid production
  3. Chondrocyte nutrition
    • Solutes from synovial fluid diffuse to chondrocytes
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10
Q

What are the lubricants in the synovium?

A
  • Hyaluronan

* Lubricin

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11
Q

What is hyaluronan?

What are its functions?

A
  • Huge polysaccharide
  • Maintains synovial fluid viscosity
  • Shock absorption
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12
Q

What is Lubricin?

What are its functions?

A

• Mucin-like proteoglycan

  • Protects cartilage surfaces from protein deposition and adhesion
  • Inhibits synovial cell overgrowth
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13
Q

What are the cell populations in the healthy Intima?

A
  1. Type A synoviocyte
    • Macrophage-like
    • 20%
  2. Type B synoviocyte
    • Fibroblast-like
    • 80%
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14
Q

What are the functions of Type A synoviocytes?

A
  • Phagocytosis
  • Clearance of debris in joint
  • Recognition of immune complexes through expression FcγR
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15
Q

What are the functions of Type B synoviocytes?

A

Production of:
1. Cartilage
• Collagen
• Fibronectin

  1. Synovial fluid components:
    • Hyaluronan
    • Lubricin
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16
Q

What is the target for tissue inflammation in RA?

At what point in disease does it become inflamed?

A

The synovium

Becomes inflamed very early in disease

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17
Q

Describe the Intima when inflamed

A

• Hyperplasia of synoviocytes
→ up to 12 cells thick
• Proliferation of Type A synoviocytes (outnumber type B)

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18
Q

Describe the processes occurring in the synovium when inflamed

A
  • Hyperplasia of synoviocytes
  • Infiltration of inflammatory cells
  • Neovascularisation
  • Ectopic lymphoid neogenesis
  • Deposition of fibrin
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19
Q

Which inflammatory cells infiltrate the synovium in RA?

What brings about the infiltration?

Where do they infiltrate into?

A
  1. Which cells:
    • Macrophages
    • T cells
    • B cells

less commonly: neutrophils

  1. Recruitment:
    • Release of chemokines from inflamed synovial tissue
    • Expression of adhesion molecules to retain the cells
  2. Where:
    • Infiltrate into the Subintima
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20
Q

Where does neovascularisation occur in RA?

A

In the subintima

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21
Q

Describe ectopic lymphoid neogenesis

A

Occurs in synovitis in RA

Germinal centres form in the synovium

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22
Q

What is the Pannus?

Of what is it composed?

What does it do?

A
  • Inflamed synovial tissue
  • Creeps over the cartilage and bone tissue of the joint (v. important)

• Hypoxic microenvironment

Contains:
• Fibroblast-like cells
• Macrophages
• Fewer immune cells than peripheral inflamed synovial tissue

Function:
• Release of factors that destroy articular cartilage and bone

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23
Q

What is the oxygen status of the Pannus?

A

Hypoxic

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24
Q

What happens to the ratio of the various synoviocytes in RA inflammation?

A

Type A outnumber Type B

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25
Q

Describe the phenotype of Type A synoviocytes in RA

A

“Activated phenotype”

• Expression of phagocytic markers
• Increased expression of MHC II → increased Ag presentation
• Production of:
- Pro-inflammatory cytokines
- Chemokines
• Possible transdifferentiation into osteoclasts

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26
Q

Which cells produce pro-inflammatory cytokines in inflamed synovium?
Which cytokines are they?

A

Activated Type A synoviocytes

  • TNF
  • IL-1
  • IL-6
27
Q

What is the function of osteoclasts?

A

Bone resorption

28
Q

Describe the role of Type B synoviocytes in RA

A 
Production of:
 • Pro-inflammatory cytokines
 • Chemokines
 • Matrix-metalloproteinases (MMP)
 • Factors that bring about bone destruction
 • Factors that inhibit bone formation
29
Q

Which cells produce chemokines in inflamed synovium?

A
  • Type A synoviocytes

* Type B synoviocytes

30
Q

What is the function of MMPs?

A

(Matrix-metalloproteinases)

• Degradation of the ECM

31
Q

Which factors bring about bone destruction?

A
  • TNF

* RANKL

32
Q

Which factors inhibit bone formation?

A
  • TNF
  • DKKs
  • sFRPs
33
Q

Which is the predominant lymphocyte in inflamed synovium?

A

Th17

34
Q

Describe the role of T cells in RA inflammation

A

Th17:
• Produce IL-17
• Express RANKL

Treg:
• Present, but non-functional
• Reduced expression of IL-10 and IL-4

35
Q

Which cytokine skews Th differentiation into Th17?

A

IL-6

36
Q

Which cytokine does Th17 produce?

What are the effects of this?

A 
1. IL-17
 • Matrix degradation
 • Activation of osteoclasts
Induces other cells to express:
 • RANKL
 • Pro-inflammatory cytokines
  1. IL-22
    • Activation of osteoclasts
37
Q

Describe the role of B cells in RA inflammation

Describe their presence

A

• Presence is variable (depends of stage of disease?)

Function:
1. Production of auto-antibodies:
 • ACPA
 • RF
 • anti-collagen type II antibodies
  1. Antigen presentation to CD4+ T cells
    → cytokine release
  2. RANKL secretion
38
Q

What type of molecule is RANKL?

A

Cytokine, member of the TNF superfamily

39
Q

Which general categories of molecules are release by cells in inflamed synovium?

A
  • Cytokines
  • Chemokines
  • Growth factors
40
Q

Where is TNF?

A
  • Initially membrane bound
  • Cleaved by TACE (TNF-alpha converting enzyme)
  • Now soluble
41
Q

What are the receptors for TNF?

Compare expression of these

A
  1. TNFRI:
    • Constitutive expression
  2. TNFRII:
    • Induced expression
42
Q

What are the sources of TNF in RA synovium?

A

Predominantly: Activated macrophages

  • Activated fibroblast-like synoviocytes
  • T cells
43
Q

What are the functions of TNF in RA?

A
  • Osteoclast activation
  • Osteoblast inhibition
  • Proinflammatory cytokine release
  • Recruitment of inflammatory cells
  • Angiogenesis
44
Q

What are the isoforms of IL-1?

Compare their locations

A
  1. IL-1α
    • Cytosolic form
    • Stored in cytoplasm
  2. IL-1β
    • Inducible form
    • Secreted and cleaved into active form by ICE
45
Q

Which molecule activates IL-1β?

A

ICE: IL-1 converting enzyme

IL-1β → active form

46
Q

Which molecules are important in the regulation of IL-1?

Describe how they function

A
  1. Soluble IL-1 receptors: sIL-1R
    • Act act decoy receptors
    • Bind soluble IL-1 in extra-cellular space, so that it can’t bind the real receptor
  2. IL-1 receptor antagonist: IL-1Ra
    • Binds the membrane bound IL-1R so that IL-1 can’t bind
47
Q

What are the sources of IL-1 in RA synovium?

A

• Macrophages

  • Type B synoviocytes
  • Endothelial cells
  • Neutrophils
  • Lymphocytes
48
Q

What are the roles of IL-1 in RA?

A
  1. Cell activation:
    • Leukocyte activation
    • Endothelial activation
    • Fibroblast activation
  2. Proinflammatory expression of cytokines and chemokines
  3. MMP production by chondrocytes and synovial fibroblasts
  4. Production of factors required for osteoclast differentiation
    → bone resorption
49
Q

Describe the location and mode of action of IL-6

A

• Present in extra-cellular space in soluble form

1. Binds:
 • Membrane bound IL-6R
 • Soluble IL-6R
2. IL-6:IL-6R associate with gp130 homodimer
3. Response in cell
50
Q

What are the sources of IL-6 in RA synovium?

A

• Type B synoviocytes

  • Macrophages
  • T cells
51
Q

High levels of pro inflammatory cytokines in RA are detectable in…

A
  • Synovial fluid
  • Serum

(IL-6, TNF, IL-1)

52
Q

What are the roles of IL-6 in RA?

A
  • Acute phase response in liver → systemic inflammation
  • B cell Ig production
  • Differentiation into Th17
  • Pro-inflammatory cytokine production in fibroblasts and macrophages
  • Osteoclast differentiation via RANKL
53
Q

What does the acute phase response in the liver bring about?

What brings about this response

A

IL-6 → Acute phase Response → Systemic inflammation

54
Q

Which animal models are used to research RA?

What have animal models told us?

A

Murine models:
• CIA
• h.TNF.Tg

Why:
• Hard to study RA pathogenesis in humans

What murine models have shown us:
• Identification of cellular and molecular mechanisms driving RA
• Enables pre-clinical studies
• Validation of therapeutic targets for the treatment of RA

55
Q

What is the CIA model?

Describe how it is performed and the progression to disease

A

Collagen-induced arthritis

Day 0: Immunisation of foreign source of Type II collagen / FCA (by intradermal injection)

→ Systemic activation of lymphocytes
→ anti-collagen Ab production

Day 21: booster injection at base of tail

→ Local synovitis
→ Inflammatory infiltrate into synocium

Day 30:
→ Significant local synovitis
→ Destruction of cartilage and bone

56
Q

What is FCA?

A

Freunds Complete Adjuvant

Part of the solution used to immunise mice against collagen in the CIA rodent model

57
Q

What are the pros and cons of the CIA model?

A 
1. Pros:
 • Symmetrical arthritis affecting knees and paws
 • Synovitis
 • Dependent on B and T cells
 • TNF and IL-1 expression elevated
 • RF reported to be produced
  1. Cons:
    • Disease susceptibility dependent on expression of certain classes of MHC class II
    → Only certain mice are susceptible: DBA/1
    • Anti-collagen Ab produced, unlike in humans
    • Timing of disease onset is variable, large experiment groups required
58
Q

What is the hTNF.Tg mouse?

What does the mouse experience?

What does this tell us about RA?

A

Genetic mouse model of RA

Mouse over expresses human TNF

  • Arthritis of knees and paws
  • Synovial hyperplasia
  • Inflammatory cell infiltrate
  • Full blown arthritis by 10 weeks
  • Pannus formation
  • Cartilage destruction
  • Focal bone erosion
  • System bone loss
  • Disease severity reduced with TNF blockage
  • KO of IL-1 or IL-1R results in no disease!

Conclusions:
• RA disease process driven by TNF

59
Q

What are the pros and cons of the hTNF.Tg mouse?

A
  1. Pros:
    • Reliable, robust arthritis
    • Arthritis is chronic
    • Allowed investigation of TNF inhibition in treatment
  2. Cons:
    • TNF dependent, but the other cytokines are not so important in this model
    • Not dependent on T and B cells
60
Q

In general what are the pros and cons of rodent models of RA?

A
  1. Pros:
    • Pre-clinical identification
    • Validation of therapeutics targets
  2. Cons:
    • Most animal models are dependent on IL-1

IL-1 is not so important in human disease:
→ mAb against IL-1 not so effective, but this may have just been an issue with the mAb
→ TNF blockade very powerful

61
Q

Which molecule prevents protein deposition on articular cartilage?

A

Lubricin

62
Q

Which mouse strain is most susceptible to RA disease in the CIA model?

A

DBA/1

63
Q

Which cells make the synovial fluid?

A

Synovial membrane, specifically, the type B synoviocytes

64
Q

Drawbacks of murine models of RA:

“Most animal models are dependent on … expression”

A

IL-1

BIOM30002 - M2M (36 decks)

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