Synovium in Health and in RA Flashcards
What is the synovium?
It is a thin membrane that extends from the skeletal tissue at the interface of cartilage and bone. It also lines the capsule of synovial joints. It consists of two layers:
- Intima
- 1-3 cell layers deep
- Cells: synoviocytes
- Sub-intima
- contains blood vessels, lymphatic vessels, and nerves
- few cells
Recall the function of the synovium.
It facilitates the movement between non-deformable structures within a joint (e.g. bone/cartilage surfaces). The synovium itself is highly deformable and freely mobile. It has non-adherent properties (doesn’t stick to bone and cartilage).
Recall the function of synovial cells.
- produce collagens and fibronectin - contribute to the structural framework of synovial interstitium
- provides nutrients for cartilage/chondrocytes via synovial fluid (cartilage is avascular)
- produce lubricants that minimise wear and tear of joints
- Hyaluronan: high MW polysaccharide that maintain fluid viscosity - provides shock absorption and fluid loss under loading
- Lubricin: protects cartilage surfaces from protein deposition and cell adhesion; inhibits synovial cell overgrowth
Recall the 2 distinct cell populations in the healthy intima of synovium.
- Type B synoviocytes (fibroblast-like synoviocytes)
- mesenchymal of origin
- produce lubricin and hyaluronan (joint lubrication)
- produce collagen and fibronectin (ECM important for cell adherence)
- Type A synoviocytes (macrophage-like synoviocytes)
- effectively resident macrophages - derived from blood mononuclear cells
- involved in clearance (phagocytosis) of debris in joints
- recognise immune complexes (via Fc receptors)
- present antigen, initiate inflammatory responses (cytokine release)
Recall the mechanism of inflammation of the synovium in RA.
Occurs very early in disease
- Intima expands => up to 12 cells
- cell proliferation (hyperplasia)
- infiltration of inflammatory cells into the sub0intima: macrophages, T and B cells, neutrophils (less common)
- formation of new blood vessels (neovascularisation)
- Ectopic lymphoid neogenesis
- Deposition of fibrin in active disease - citrullinated fibrinogen may contribute to localized ACPA
What is a “pannus” in RA?
Pannus refers when the inflamed synovial tissue “creeps” over the cartilage and bone tissue
- differs histologically from inflamed synovial tissues away form bone/cartilage
- rich in fibroblasts-like cells
- contains macrophages
- contains fewer immune cells than the peripheral inflamed synovial tissue
- hypoxic micro-environment
- cells within the pannus release factors => destroys articular cartilage and bone
Describe the response of Type B synoviocytes in RA.
It is the prevalent mediator of inflammation within the RA joint. It responds to inflammation by producing:
- Cytokines (IL-6, IL-8, macrophage migration inhibitory factor (MIF), M-CSF, GM-CSF, TNF)
- Chemokines to attract inflammatory cells (CCL2, CCL5, CCL8, CXCL5, CXCL10)
- Matrix degrading enzymes such as MMPs which lead to cartilage degradation
- Factors that promote local bone destruction (RANKL)
- Factors that inhibit bone formation activity (DKKs, sFRPs)
Recall the role of Type A synoviocytes in RA inflammation.
“Activated phenotype”:
- Increased expression of phagocytic markers
- High expression of MHC class II molecules (required for the presentation of peptide antigens to CD4+ T cells)
- May “trans-differentiate” to bone-resorbing osteoclast
Major source of:
- Cytokines (TNF, IL-1ß, IL-6, IL-18, MIF)
- Chemokines to attract inflammatory cells
Recall about the cross-talk between synoviocytes during inflammation.
Recall the roles of T cells in RA inflammation.
T cells are the predominant lymphocyte in RA synovium
- CD4+ T cells are most prevalent
- TH17 Cells:
- subset of CD4+ T cells that express IL-17
- recruitment and differentiation induced by IL-6
- express RANKL - differentiation factor for osteoclasts - promote bone erosion
- IL-17 induces expression of other pro-inflammatory cytokines and also RANKL in other cell types; promote inflammatory response
- T regulatory cells:
- subset of T cells identified by CD25+, FoxP3+
- Normally act to suppress immune/inflammatory response
- In RA: cells are present but not functional (reduced expression of IL-10, IL-4)
- TH17 Cells:
Recall the roles of B cells in RA inflammation.
Presence of distribution of B cells is variable among RA patients depends on the stage of disease
- Responsible for antibody production in response to T cell activation by antigen-presenting cells
- Local production of auto-antibodies (e.g. rheumatoid factor, anti-citrulline containing peptide (anti-CCP), anti-collagen type II)
- Present antigen to CD4+ T cell and secrete cytokines
- Source of RANKL (recall significance bro)
Recall the interactions between the cells in the RA synovium.
What is TNF?
TNF belongs to a large family of cytokine that share structural features
- Initially, membrane-bound protein which is cleaved by TNF-alpha converting enzyme (TACE) to form a soluble form
- Both forms (membrane-bound and soluble) are active - but has different functions
- 2 receptors:
- TNFR1 (p55) - expressed constitutively
- TNFR2 (p75) - expression induced
Recall the cellular sources of TNF in RA synovium.
- Activated macrophages (predominantly), activated fibroblast-like synoviocytes and other cells types (e.g. T cells)
- Found at elevated levels in synovial fluid, also in periphery (serum)
Recall the roles of TNF in RA.
Recall about the regulation IL-1 activity.
IL-1 activity is tightly regulated by endogenous inhibitors:
- soluble IL-1 receptors act as decoy receptors
- IL-1 receptor antagonist (IL-1Ra) competes with IL-1 for binding to IL-1 receptor
- Involves the balance between cytokine and inhibitor that determines the effect on IL-1 signalling
Recall the regulation of IL-1ß AND IL-18.
Describe IL-6.
- pro-inflammatory cytokine, anti-inflammatory myokine (released by muscle cells)
- involved in fever and acute phase response
- IL-6 binds either a membrane-bound or soluble IL-6R and interacts with homodimer of gp130 to elicit its effects
Recall other cytokines signal via JAK-STAT signalling.
Recall the impact of cytokines released in RA beyond the affected joint.
What are the pros and cons of rodent collagen-induced arthritis (CIA)?
Recall the results after genetic over-expression of human TNF in a mouse.
What is an hTNF.Tg mouse? What are the pros and cons of their usage?
hTNF.Tg mouse: a genetic mouse model resembling RA
