Rheumatoid Arthritis 1b Flashcards
Which inflammatory cell types infiltrate blood vessels and form lymphoid nodules in RA? [1]
CD4+ (mainly TH17 subclass) collect around BV: forming small lymphoid vessels
Pannus is destructive: erosion of articular cartilage and bone - destroys the joint
Describe which cells / cytokines are influential in RA synovium [4]
What do each cause to occur / become?
neutrophils
* first responders
* phagocytosing the bacterial infection or some other infection and are citrullinating the proteins in that bacteria so they end up looking like a self-protein that we also citrullinate due to the arginine metabolism pathway
CD4 TH17 cells
* Produce IL-17
* Produce IL-1; IL-6; TNF-a & RANKL
TNF-A
* make synovial fibroblasts - leading to proliferation of synovial membrane
Macrophages:
* Differentiate into osteoclasts
Describe the role Anti-Citrullinated protein antibodies (ACPA) in RA pathogenesis [5]
Anti-Citrullinated protein antibodies (ACPA) can stimulate osteoclast differentiation from monocytes leading to initial bone loss
Osteoclasts then produce IL-8:
* attracts neutrophils
* sensitises nociceptors
* attracts more osteoclasts
Synovitis at start of clinical disease leads to production of cytokines, which stimulate osteoclast proliferation and differentiation
Inducing expression of RANKL, plus synergize with RANKL to enhance bone erosion by more osteoclast differentiation
What is the process of citrullination? [1]
Which process does citrullination occur in? [1]
Which enzyme causes this process to occur? [1]
changing of arginine to citrulline by deamination
This occurs during apoptosis.
done by the enzyme peptidyl arginine deiminase (PADs)
Describe the action of IL-17 in RA [4]
TH17 cells produce lots of IL-17:
* Induces RANKL on synovial fibroblasts
* Stimulates local inflammation
* Active synovial macrophages to secrete pro-inflammatory cytokines: TNF-a; IL-1 & IL-6 - these are the prime drivers of RA
What is the overall net effect of RA on osteoblasts? [1]
Describe the cytokines that drive this effect of osteoblasts to occur [3]
Osteoblasts are switched off:
- (TNF-a, IL-1 & IL-6 produce RANKL to turn on osteoclasts)
- AND
- Induced expression of DKK-1: induces sclerostin (reduces osteoblastic bone formation)
Describe the role of neutrophils in RA [4]
Neutrophils:
- Mount a respiratory burst producing the superoxide anion radical = greater free radical damage
- Breaks down the hyalorunic acid strands - makes it thinner
- Directly induce RANKL
- Produce BAFF (B-cell activating factor) - drives disease process further
- Undergo NETosis
State two hallmarks of RA [2]
CD4+T-cell infiltration is a hallmark of RA pathogenesis (TH17 cells)
Anti-citrullinated protein/peptide antibodies (ACPAs)
Which of the following depicts RA
A
B
C
D
Which of the following depicts RA
A
B
C
D
Synovial fluid of what colour would suggest a
Colourless to pale yellow and clear
Red, brown
Colourless to Yellow and purulent (lumpy)
White/creamy and cloudy/shiny
Yellow and cloudy
Which subclass of CD4+ cells are prominent in RA? [1]
TH17 subclass
What do the arrows point to in this person with RA? [1]
Pannus (or the effects of)
Explain the characteristics in disease processes / effects in early [2] and late stage RA [1]
Start of clinical disease:
* Synovitis leads to production of cytokines, which stimulate osteoclast proliferation and differentiation
* This Induces expression of RANKL, plus synergize with RANKL to enhance bone erosion by more osteoclast differentiation
Established / uncontrolled RA:
* Large bone erosions filled with inflamed, synovial derived pannus tissue
Explain the characteristics in disease processes / effects in early [2] and late stage RA [1]
Start of clinical disease:
* Synovitis leads to production of cytokines, which stimulate osteoclast proliferation and differentiation
* This Induces expression of RANKL, plus synergize with RANKL to enhance bone erosion by more osteoclast differentiation
Established / uncontrolled RA:
* Large bone erosions filled with inflamed, synovial derived pannus tissue
Explain the characteristics in disease processes / effects in early [2] and late stage RA [1]
Start of clinical disease:
* Synovitis leads to production of cytokines, which stimulate osteoclast proliferation and differentiation
* This Induces expression of RANKL, plus synergize with RANKL to enhance bone erosion by more osteoclast differentiation
Established / uncontrolled RA:
* Large bone erosions filled with inflamed, synovial derived pannus tissue
Describe the first [3] and second [3] step that occurs in PAD-dependent differentiation and maturation of osteoclasts
1st step:
* Gradual increase in cell citrullination occurs as a consequence of increased PAD enzyme activity in a calcium-rich microenvironment.
* ACPAs present in the circulation can reach and bind to maturing osteoclasts in the bone marrow, leading to an increase in OC activity and
* consecutive bone resorption through a IL-8 dependent autocrine loop.
Second step:
* IL-8 will reach the joint and initiate the chemoattraction and migration of inflammatory cells, particularly neutrophils.
* Neutrophil extracellular traps are released by neutrophils in the presence of ACPAs,
* This further contributes to the joint inflammation and local accumulation of other inflammatory cells, such as macrophages, and activation of synovial fibroblasts
