Pathogenesis of RA Flashcards
What does the synovial membrane contain?
- cuboidal synoviocytes
What are cuboidal synoviocytes?
- type A and B
- A = bone marrow derived macrophages (immune cells)
- B = fibroblast like CT cells (make up majority, produce hyaluronic acid)
What is the subintima?
- loose CT so fluid moves easily through
- dense fenestrated capillary network so synovial fluid leaves to enter cavity
- below synovial membrane, no basement membrane between
What is synovial fluid?
- ultrafiltrate of blood plasma from fenestrated capillaries + hyaluronic acid from type B synoviocytes
- flows in and out of joint cavity
- constantly replaced
What is the function of synovial fluid?
- nourishes cartilage cells and synoviocytes
- removes CO2
- reduces friction between cartilages
- forms reserve volume
What are the disadvantages of loose membrane?
- more easily damaged
- reduced immune surveillance (hard to remove material)
What does synovial fluid normally look like?
- colourless to pale yellow and clear
What does synovial fluid look like when there is a haemorrhage in the joint?
Red/brown colour
What does synovial fluid look like when there is inflammation?
Yellow and cloudy
What does synovial fluid look like in a bacterial infection?
Colourless to yellow and purulent
What does synovial fluid contain?
- WBC
- hyaluronate
- glucose
- protein (abumin and globulin)
- lubricin
- ions/lactate
How is synovial fluid hydrophobic?
- hyaluronate interacts with albumin and globulin
- more hyaluronate = more viscous
How is synovial fluid viscoelastic?
- thixotropic = viscosity not constant
- when resting viscosity is greater (more interaction between hyaluronate and proteins)
What are the 2 synovial fluid tests?
- string test
- mucin clot test
What is the string test?
- normally 4-6cm string per drop of synovial fluid from syringe
- inflammation = decreased viscosity so smaller string as hyaluronate is shorter sections
What is the mucin clot test?
- add acetic acid to synovial fluid
- normally forms a clot surrounded by clear fluid
- inflammation = clot soft and hyaluronate not formed
What structural changes to synovial fluid are there in rheumatoid arthritis?
- proliferation of synoviocytes
- infiltration of inflammatory cells (T cells, neutrophils into fluid, lymphocytes into membrane)
- proliferation of fibroblasts in subintima causes thickening
Why are synovial joints susceptible to inflammatory injury?
- rich fenestrated capillary network
- limited responses (pro-inflammatory cytokines induce proliferation and osteoclast differentiation)
What is pannus?
- end destructive synovial membrane
- joint erosion at joint margin
- makes joint unstable and destroys it
- due to inflammation and synovium proliferation
- grows over into cartilage and bone
- secretes cytokines
- syvonectomy to remove but will regrow as disease progress continues
What are ACPA?
Anti-citrullinated protein antibodies
- made by B cells
- directly stimulate osteoclast differentiation which produce IL8 to induce more osteoclasts via autocrine feedback
- leads to bone loss
What is the function of IL8?
- produced by osteoclasts to induce more osteoclasts via autocrine feedback
- sensitises nociceptors = increased pain
What is established RA characterised by?
- large bone erosions filled with inflamed synovial derived pannus tissues
What does synovitis lead to in RA?
- production of cytokines stimulating osteoclast prolif and diff.
- this induces RANKL expression enhancing bone erosion
What is a hallmark of RA pathogenesis?
Th17 cells
CD4+ T cell infiltration
What do Th17 cells do?
secrete lots of IL-17 which:
- induces RANKL on synovial fibroblasts
- stimulates local inflammation
- activates synovial macrophages to secrete proinflammatory cytokines -> induce Dkk-1 expression by synovial fibroblasts
What is Dkk-1?
- inhibits osteoblast differentiation
- induces sclerostin expression
How does synovial fluid change in RA?
- neutrophils most numerous cells
- produce superoxide anion radical = free radical damage
- less viscous as shorter hyaluronate strands
- increased volume as leaker vessels from cytokines release
What do B cells do?
- produce auto-antibodies (rheumatoid factor and ACPA)
What do T cells do?
- produce pro-inflammatory cytokines which orchestrate synovitis and systemic symptoms
What do macrophages do?
- produce pro-inflammatory cytokines
- can differentiate into osteoclasts
