Lecture 26 - Synovium in health and RA

Question 1

What is the synovium?

Answer 1

thin membrane that extends from skeletal tissue at interface of cartilage and bone and lines the capsule of diarthrodial joints

Question 2

The first layer f the synovium is

Answer 2

Intima

tissue between the joint cavity and subintima
1-3 cell layers deep (cells=synoviocytes)

Question 3

The second later of synovium is..

Answer 3

Subintima

connnective tissue that becomes denser closer to the joint capsule

contains BV, Lymph.Vs, and nerves

Question 4

The Areolar section is bit _____ from the joint, the Fibrous section is where the ____ is and is difficult to distringuish from ______

The Fatty section is mostly in fat pads,

Answer 4

Areolar section is bit further from the joint, the Fibrous section is where the joint is and is difficult to distringuish from fibrocartilage

all have Subintima and Intima

Question 5

What are the functions of the synovium?

Answer 5

Facilitiates movement

Question 6

What provision of lubricants exist to to minimuse “wear and tear: on joint tissues?

Answer 6

Hyaluronan - shock absorbtion, prevents fluid loss

Lubricin - proteoglycan, protects cartilage surfaces from protein desposition and cell adhesion, and inhibits cell overgrowth

The “Grease” within your joints

Question 7

___ of cells are Macrophage-like synovocytes in intima

Answer 7

20% - phagocytic capability

others are Fibroblast-like synoviocytes

Question 8

Which type of synoviocytes produces Hyaluronan and Lubricin?

Answer 8

Fibroblast-like synoviocytes

Question 9

___is when the inflamed synovial tissue is next to cartilage

Answer 9

pannus

Question 10

True or False

RA inflammation; you will see neutrophils in synovial fuid

Answer 10

False

Question 11

There will be infiltration of infalmmatory cells into the sublining, as well as formation of new…

Answer 11

blood vessels (neovascularisation)

Question 12

True or False

Inflammationof the synovium occurs late in disease

Answer 12

False

happens early

Question 13

Cells present within the inflammed synovial tissue secrete factors which:

Answer 13

1 ) attract inflammatory cells into the joint (chemokines)

2) retain the cells there (adhesion molecules)

Question 14

Pannus is..

Answer 14

the inflammed synovial tissue that “creeps’ over the cartilage and bone tissue of the joint

Question 15

True or False

Pannus contains macrophages but fewer T/B cells than the peripheral inflammed synovial tissue

Answer 15

true

Question 16

Cells within the pannus release factors which..

Answer 16

destroy articular cartilage and bone

Question 17

In RA Type _ (macrophage) synoviocytes outnumber type _ (fibroblast-ike) cells

Answer 17

In RA Type A (macrophage) synoviocytes outnumber type B (fibroblast-ike) cells

usually type A are only 20%

Question 18

There will be high expression of _____ markers and ______ from type A synovioocytes

Answer 18

There will be high epression of phagocytic markers and MHC II from type A synovioocytes

Question 19

Synovial macrophages may trans-differentiate” to a ____ -resorbing osteoclast

Answer 19

bone

Question 20

Type B cells respond to infammation with ____

Answer 20

cytokines including IL-1, TNF, IL-6

chemokines

MMPs

factors that promote local bone destruction

Question 21

What factors promote local bone destruction?

Answer 21

TNF and RANKL

Question 22

___are the most prominant CD4+ T cells

Answer 22

TH17 - express IL-17

Question 23

___ _____T cells are most prevalent in RA synovium

Answer 23

Cd4+ helper T cells

Question 24

TH17 cells are recreited and differentiate upon signalling by..

Answer 24

IL-6 (from the macrophage)

Question 25

Th17 are large sources of

Answer 25

RANKL - bone destruction

Question 26

In RA ___ cells are not functoin - leading to reduced expression of IL-10 and IL-4

Answer 26

T regs

Question 27

True or False The presence and distribtion of B cells is fixed among RA patients

Answer 27

False - it is varialbe May depend on stage of disease

Question 28

What is responsible for the antibodu production in response to T cell cativation and production of autoantibodies (eg. RA factor and anti-CCP)

Answer 28

B cells

Question 29

Moleules belonging to the categories of cytokines chemokines growthfactors are all released in

Answer 29

RA synovium and contribute to RA pathogenesis

Question 30

TNF is.. family of _____ Initially membrane bound, is cleaved by ___ (both forms are active)

Answer 30

Tumour necrosis factor family of cytokines Initially membrane bound, is cleaved by TACE (both forms are active)

Question 31

what are the 2 receptors for TNF and how are they expressed?

Answer 31

TNFR1 | TNFR2 - expression is induced (particularly in inflammatory situations)

Question 32

TNF can have local and ___ actions

Answer 32

systemic

Question 33

What role does TNF play in RA?

Answer 33

Proinflammatory cytokine release Hepcidin induction PGE Osteoclast activation Chondrocyte activation (cartilage destruction) Angiogenesis Leukocyte accumulator Endothelial cell activation Chemokine release

Question 34

IL-1has two forms..

Answer 34

IL-1 aplha - cytosolic form IL-1 beta - inducible form, secreted and then cleaved into its active form by ICE

Question 35

Il-1 activity is tightly regulated by ______ inhibitors

Answer 35

endogenous inhibitors

Question 36

IL-1 receptor antagonist called ____ competes with IL-1 for binding to IL-1 receptor

Answer 36

IL-1ra It is the balance of the cytokine and the inhibitor that determines the effect of IL-1 signalling

Question 37

What is IL-1's role in RA

Answer 37

activation of leukocytes, endothelial cells and synovial fibroblasts induce expression of chemokines and cytokines Induce MMP production by chondrocytes Induce expression of osteoclasts

Question 38

IL-6 is responsible for

Answer 38

increasing acute phase response in liver Induces Ig production in B cells promotes differentiation of TH17 cells induces cytokine production by synovial fibroblasts and macrophages promote osteoclasts (RANKL)

Question 39

The most common model for screening therapeutic compounds is ___

Answer 39

Collagen induced arthritis (CIA)

Question 40

What are the pros of Rodent collagen-induced arthritis models?: ____arthritis affecting knee and paws ______ inflammation dependent on __ cells ___ and __-beta expression is elevated (inhibition of either of these cytokines, _____ arthritis onset and severity) __ factor reported to be produced

Answer 40

symmetrical arthritis affecting knee and paws synovial inflammation Dependent on T/B cells (also requires the expression of MHC II alleles) TNF and IL-beta expression is elevated (inhibition of either of these cytokines, reduces arthritis onset and severity) RF factor reported to be produced

Question 41

What are the cons of Rodent collagen-induced arthritis models?: Disease susceptibily is depends on expression of certain classes of _____ only certain mouse strains are susceptible (_____ most susceptible) _____ of disease onset and severity of disease can be variable unlike RA patients Collagen _____ are produced

Answer 41

Disease susceptibily is depends on expression of certain classes of MHC II - only certain mouse strains are susceptible (DBA/1 most susceptible) - limits utility Timing of disease onset and severity of disease can be variable unlike RA patients Collagen antibodies are produced

Question 42

Mouse that have been genetically engineered to over-express human TNF (hTNF.Tg ) are quite good in the human-like onset and

Answer 42

blocking TNF will reduce/block disease severtity Is dependent on the IL1 receptor expression and signalling (used extensively

Question 43

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

Answer 43

Pros reliable arthritis, chronic useful to assess effect of TNF inhibition Cons. even though IL-1 is essential to arthritis it is a TNF driven model Arthritis not dependent on T or B cells

Question 44

Process of inflammation and bone loss is similar with ___and ____ and ____ playing a dominant role

Answer 44

Process of inflammation and bone loss is similar with TNF and IL-1 and RANKL playing a dominant role