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Molecule to Malady > Lecture 25 - Synovium in Health and Rheumatoid Arthritis > Flashcards

Lecture 25 - Synovium in Health and Rheumatoid Arthritis Flashcards

1
Q

Synovium

A

Thin membrane that extends from skeletal tissue at the interface between cartilage and bone, and lines the capsule of diarthroidal joints

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2
Q

Layers of synovium
1)
2)

A

1) Intima

2) Subintima

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3
Q 
Intima
1)
2)
3)
4)
A

1) Inner layer of synovium.
2) Made up of synoviocytes (type 1 and 2)
3) 1-3 cells deep
4) Interface between subintima and joint cavity

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4
Q

Subintima
1)
2)
3)

A

1) Lies between the joint capsule and intima
2) Becomes more dense as it approaches the joint capsule, bone, cartilage
3) Contains blood vessels, lymphatic vessels , nerves

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5
Q

Three different types of synovial tissue

A

1) Areolar
2) Fibrous
3) Fatty

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6
Q

Areolar synovial tissue
1)
2)
3)

A

1) Continuous layer of synoviocytes lining it
2) Capillaries immediately below intima
3) Contains small arterioles, venules, lymphatic vessels

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7
Q

Fibrous synovial tissue
1)
2)

A

1) Layer of cells on a ligament or tendon

2) Hard to distinguish histologically from fibrocartilage

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8
Q

Fatty synovial tissue
1)
2)

A

1) Mostly found in fat pads

2) Underlying intima is a network of capillaries in between adipocytes

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9
Q 
Functions of a healthy synovium
1)
2)
3)
4)
A

1) Facilitates movement
2) Produces synovial fluid
3) Supplies chondrocytes with nutrition
4) Type 1 chondrocytes phagocytose material

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10
Q

How does a healthy synovium facilitate joint movement
1)
2)
3)

A

1) Synovium is highly deformable and movable
2) Provides lubricants
3) Non-adherent

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11
Q

Lubricants secreted by synovium
1)
2)

A

1) Lubricin

2) Hyaluronan

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12
Q

Lubricin
1)
2)
3)

A

1) Mucin-like proteoglycan
2) Protects bone and cartilage surfaces from protein deposition and cell adhesion
3) Inhibits synovial cell overgrowth

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13
Q 
Hyaluronan
1)
2)
3)
4)
A

1) High molecular weight polysaccharide
2) Maintains synovial fluid viscosity
3) Effective shock absorber
4) Prevents leakage of synovial fluid

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14
Q

How do chondrocytes receive nutrition?

A

Solute diffusion through synovial fluid

Cartilage is avascular

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15
Q

Proportion of type A synoviocytes to type B in healthy synovium

A

20% type A, 80% type B

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16
Q

Type B synoviocytes
1)
2)
3)

A

1) Fibroblast-like synoviocytes
2) Produce lubricin and hyaluronan
3) Produce collagen and fibrin

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17
Q

Type A synoviocytes
1)
2)
3)

A

1) Macrophage-like synoviocytes. Tissue-resident macrophages
2) Clear debris from joint
3) Express FcgammaR

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18
Q

Surface marker used to identify type B synoviocytes

A

CD55

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19
Q

Surface marker used to identify type A synoviocytes

A

CD68

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20
Q

When in RA does synovial inflammation present?

A

Very early

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21
Q 
Characteristics of RA synovium
1)
2)
3)
4)
5)
A

1) Intima expands from 1-3 cells thick to 12 cells thick (hyperplasia)
2) Infiltration of inflammatory cells into subintima (T cells, B cells, neutrophils)
3) Neovascularisation
4) Ectopic lymphoid neogenesis
5) Deposition of fibrin in active disease

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22
Q

Pannus

A

In RA where the inflamed synovium creeps over the bone and cartilage

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23
Q 
Features of pannus
1)
2)
3)
4) 
5)
A

1) Differs histologically from inflamed synovium away from bone and cartilage
2) Rich in fibroblasts
3) Macrophages
4) Fewer immune cells than inflamed synovium away from bone and cartilage
5) Hypoxic micro-environment

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24
Q

What do cells within the pannus do?

A

Release factors that destroy articular cartilage and bone

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25
Q 
Type A synoviocytes in RA synovium
1)
2)
3)
4)
5)
A

1) Outnumber type B synoviocytes
2) Express active phenotype (high phagocytic marker expression, high MHCII expression)
3) Release pro-inflammatory cytokines (TNFa, IL-1, IL-6)
4) Release chemokines
5) Might trans-differentiate into osteoclasts

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26
Q 
Type B synoviocytes in RA synovium
1)
2)
3)
4)
5)
6)
A

1) Mediators in inflammation in RA joint
2) Release pro-inflammatory cytokines (TNFa, IL-1, IL-6)
3) Chemokine release
4) Release matrix-degrading enzymes that break down cartilage (EG: matrix-metalloproteinases)
5) Release factors that lead to bone destruction (TNF, RANKL)
6) Release factors that inhibit bone reformation (TNF, DKKs, sFRPs)

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27
Q

Predominant lymphocyte in RA synovium

A

CD4+ T cell

28
Q

Role of Th17 in RA
1)
2)

A

1) Express RANKL

2) IL-17 induces release of other pro-inflammatory cytokines, and RANKL release

29
Q

What induces Th17 differentiation in RA?

A

IL-6 release

30
Q

Role of Treg in RA
1)
2)

A

1) Present in synovial tissue, but non-functional

2) Don’t release IL-14, IL-10

31
Q 
Role of B cells in RA
1)
2)
3)
4)
5)
A

1) Variable presence in RA patients
2) Local production of autoantibodies (RF, ACPA)
3) Source of RANKL
4) Can present antigens to CD4+ T cells
5) Produce antibodies in response to T cell activation by APCs

32
Q

Cytokines that play a critical role in RA pathogenesis

A

IL-1, IL-6, TNFa

33
Q

How is TNFa released?
1)
2)
3)

A

1) Initially a membrane-bound protein
2) Cleaved from cell membrane by TNFa converting enzyme (TACE)
3) Both membrane-bound and soluble forms are active

34
Q

Types of TNFa receptors
1)
2)

A

1) TNFRI - Constitutively expressed

2) TNFRII - Induced expression

35
Q 
Roles of TNFa in RA
1)
2)
3)
4)
5)
6)
7)
8)
A

1) Pro-inflammatory cytokine release
2) Hepcidin production
3) Osteoclast activation
4) Chondrocyte activation
5) Angiogenesis
6) Leukocyte accumulation
7) Endothelial cell activation
8) Chemokine release

36
Q 
Pro-inflammatory cytokines induced by TNFa in RA
1)
2)
3)
4)
A

1) IL-1
2) IL-6
3) IL-23
4) GM-CSF

37
Q

What are hepricidins?

A

Acute phase proteins made in the liver

EG: C-reactive protein

38
Q

What does TNFa induce chondrocytes to do in RA?

A

Produce matrix-metalloproteinases –> Leads to cartilage destruction

39
Q

What does TNFa make leukocytes do in RA?

A

Increase MHCII expression

40
Q

Two isoforms of IL-1

A

IL-1alpha, IL-1beta

41
Q

IL-1alpha

A

Cytosolic form of IL-1

Stored in cytophasm of some cells

42
Q

IL-1beta
1)
2)

A

1) Inducible form

2) Secreted, then cleaved into active form by IL-1 converting enzyme (ICE)

43
Q

How is IL-1 activity regulated?

A

By endogenous inhibitors

44
Q

IL-1 endogenous inhibitors
1)
2)

A

1) Soluble IL-1 receptors (act as decoy receptors)

2) IL-1 receptor antagonist (competes for IL-1R binding with IL-1)

45
Q

What determines the effect of IL-1 signalling?

A

Balance between IL-1, and IL-1 inhibitors (soluble IL-1 receptors, IL-1 receptor antagonist)

46
Q 
Sources of IL-1 in RA
1)
2)
3)
4)
5)
A

1) Macrophages
2) Type B synoviocytes
3) Endothelial cells
4) Lymphocytes
5) Neutrophils

47
Q 
IL-1 roles in RA
1)
2)
3)
4)
A

1) Activates leukocytes, synovial fibroblasts, endothelial cells
2) Induces expression of chemokines, cytokines
3) Induce metalloproteinase production by type B synoviocytes
4) Induce expression of RANKL

48
Q

Unsuccessful RA treatment that targeted IL-1R

A

Anakinra (IL-1R antagonist)

49
Q

IL-6 receptors

A

Either soluble or membrane-bound

50
Q

How does IL-6 induce effects?

A

IL-6/IL-6R complex bind to gp130 homodimer on cell surface

51
Q

IL-6 sources in RA
1)
2)
3)

A

1) Macrophages
2) Type 2 synoviocytes
3) T cells

52
Q 
IL-6 effects in RA
1)
2)
3)
4)
5
A

1) Increases acute-phase protein release from liver
2) Increases Ig release by B cells
3) Promotes Th17 differentiation
4) Increases cytokine production by type B synoviocytes, macrophages
5) Induces RANKL

53
Q

Why is the study of human RA pathogenesis limited?

A

Only observe people with active disease.

54
Q

Most common animal model of RA

A

Collagen-induced arthritis

55
Q

How is collagen-induced arthritis induced?

A

Immunise mouse with foreign source of collagen II, Freund’s complete adjuvant at base of tail

56
Q

How do genetics affect collagen-induced arthritis?

A

A lot.
DBA/1 mouse strain most susceptible.
Inducible in C57B6, but less severe disease

57
Q

Rodent collagen-induced arthritis timeline
1)
2)
3)

A

1) Day 0 - Intradermal injection at base of tail with foreign type II collagen, Freund’s complete adjuvant.
Leads to systemic B cell, T cell activation, collagen Ab production
2) Day 21 - Booster of foreign type II collagen, Freund’s complete adjuvant.
Leads to local synovitis, invasion of synovium with inflammatory cells
3) Day 30+ - Significant local inflammation within affected joint, destruction of bone and cartilage

58
Q 
Pros of collagen-induced arthritis model
1)
2)
3)
4)
5)
A

1) Symmetrical inflammation affecting knees and paws.
2) Synovial inflammation leading to destruction of bone and cartillage
3) B and T cell infiltration, high expression of MHCII
4) TNFa, IL-1b levels elevated. If either of these are inhibited, reduces symptoms
5) Rheumatoid factor is produced

59
Q

Cons of collagen-induced arthritis
1)
2)
3)

A

1) Susceptibility is dependent on certain HLA types. Therefore only certain mouse strains can be used
2) Timing to disease is variable. Therefore large numbers of mice are required
3) Anti-collagen antibodies are produced, which aren’t normally present in RA

60
Q

Transgenic mouse for RA model

A

hTNF.Tg mouse

Human TNF transgenic mouse

61
Q 
hTNF.Tg mouse features
1)
2)
3)
4)
A

1) Genetically-engineered to overexpress human TNF
2) Develops arthritis spontaneously, affecting knees and paws
3) Blocking TNF reduces disease severity
4) Dependent on IL-1/IL-1R expression

62
Q

Timeline of hTNF.Tg mouse disease
1)
2)
3)

A

1) 3-4 weeks of age - Synovial hyperplasia, inflammatory cell infiltrates
2) 10 weeks - Arthritis
3) Inflammation, pannus formation, cartilage destruction, focal bone erosion, systemic bone loss

63
Q

Pros of hTNF.Tg mouse model
1)
2)
3)

A

1) Chronic arthritis
2) Reliable, robust development of arthritis (synovial inflammation, cartilage, bone loss)
3) Useful to test effect of TNF inhibition on bone loss

64
Q

Cons of hTNF.Tg mouse model
1)
2)

A

1) Even though IL-1 is essential to arthritis, this is a TNF-driven model. Could discount the effects of other cytokines
2) Arthritis not dependent on T or B cells, which are important in RA

65
Q

Common issue with animal RA models

A

Very dependent on IL-1 expression.

IL-1 inhibition in animals has been very effective at controlling RA, but less effective in humans.

Molecule to Malady (35 decks)

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