Lecture 25 - Synovium in Health and Rheumatoid Arthritis Flashcards Preview

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Flashcards in Lecture 25 - Synovium in Health and Rheumatoid Arthritis Deck (65):
1

Synovium

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

2

Layers of synovium
1)
2)

1) Intima
2) Subintima

3

Intima
1)
2)
3)
4)

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

4

Subintima
1)
2)
3)

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

5

Three different types of synovial tissue

1) Areolar
2) Fibrous
3) Fatty

6

Areolar synovial tissue
1)
2)
3)

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

7

Fibrous synovial tissue
1)
2)

1) Layer of cells on a ligament or tendon
2) Hard to distinguish histologically from fibrocartilage

8

Fatty synovial tissue
1)
2)

1) Mostly found in fat pads
2) Underlying intima is a network of capillaries in between adipocytes

9

Functions of a healthy synovium
1)
2)
3)
4)

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

10

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

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

11

Lubricants secreted by synovium
1)
2)

1) Lubricin
2) Hyaluronan

12

Lubricin
1)
2)
3)

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

13

Hyaluronan
1)
2)
3)
4)

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

14

How do chondrocytes receive nutrition?

Solute diffusion through synovial fluid
Cartilage is avascular

15

Proportion of type A synoviocytes to type B in healthy synovium

20% type A, 80% type B

16

Type B synoviocytes
1)
2)
3)

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

17

Type A synoviocytes
1)
2)
3)

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

18

Surface marker used to identify type B synoviocytes

CD55

19

Surface marker used to identify type A synoviocytes

CD68

20

When in RA does synovial inflammation present?

Very early

21

Characteristics of RA synovium
1)
2)
3)
4)
5)

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

22

Pannus

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

23

Features of pannus
1)
2)
3)
4)
5)

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

24

What do cells within the pannus do?

Release factors that destroy articular cartilage and bone

25

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

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

26

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

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)

27

Predominant lymphocyte in RA synovium

CD4+ T cell

28

Role of Th17 in RA
1)
2)

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

29

What induces Th17 differentiation in RA?

IL-6 release

30

Role of Treg in RA
1)
2)

1) Present in synovial tissue, but non-functional
2) Don't release IL-14, IL-10

31

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

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

Cytokines that play a critical role in RA pathogenesis

IL-1, IL-6, TNFa

33

How is TNFa released?
1)
2)
3)

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

Types of TNFa receptors
1)
2)

1) TNFRI - Constitutively expressed
2) TNFRII - Induced expression

35

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

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

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

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

37

What are hepricidins?

Acute phase proteins made in the liver
EG: C-reactive protein

38

What does TNFa induce chondrocytes to do in RA?

Produce matrix-metalloproteinases --> Leads to cartilage destruction

39

What does TNFa make leukocytes do in RA?

Increase MHCII expression

40

Two isoforms of IL-1

IL-1alpha, IL-1beta

41

IL-1alpha

Cytosolic form of IL-1
Stored in cytophasm of some cells

42

IL-1beta
1)
2)

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

43

How is IL-1 activity regulated?

By endogenous inhibitors

44

IL-1 endogenous inhibitors
1)
2)

1) Soluble IL-1 receptors (act as decoy receptors)
2) IL-1 receptor antagonist (competes for IL-1R binding with IL-1)

45

What determines the effect of IL-1 signalling?

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

46

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

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

47

IL-1 roles in RA
1)
2)
3)
4)

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

Unsuccessful RA treatment that targeted IL-1R

Anakinra (IL-1R antagonist)

49

IL-6 receptors

Either soluble or membrane-bound

50

How does IL-6 induce effects?

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

51

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

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

52

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

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

Why is the study of human RA pathogenesis limited?

Only observe people with active disease.

54

Most common animal model of RA

Collagen-induced arthritis

55

How is collagen-induced arthritis induced?

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

56

How do genetics affect collagen-induced arthritis?

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

57

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

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

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

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

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

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

Transgenic mouse for RA model

hTNF.Tg mouse
Human TNF transgenic mouse

61

hTNF.Tg mouse features
1)
2)
3)
4)

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

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

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

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

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

Cons of hTNF.Tg mouse model
1)
2)

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

Common issue with animal RA models

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