Targeting fibroblasts in RA Flashcards
What are fibroblasts in normal joint?
In healthy joint tissue resident fibroblasts are covered with a layer of macrophages which form a protective barrier around the synovium and they clear the debris from the joint. This stops immune response from developing. During resolution of inflammation, fibroblasts produce a lot of collagen to form a physical barrier to stop additional immune cells from infiltrating.
What are fibroblasts in RA?
The layer of fibroblasts is thicker and macrophages covering fiibroblasts are activated. There are also activated fibroblasts and there is more blood vessels and infiltration of immune cells. In the synovial tissue of RA patients can be found fibroblasts population which is tissue resident as they are not detectable in blood. There is a population of RA patients who have very strong fibroblast phenotype within their synovial tissue. In areas of accumulation of T and B cells fibroblasts produce matrix metalloproteinases breaking down the matrix to create space, supporting the infiltration of T and B cells.
What are different types of fibroblasts?
There are fibroblasts which contribute to resolving inflammation and there are fibroblasts which contribute to inflammation and damage.
Depending on what fibroblasts are more inflammatory and which contribute to resolving inflammtion?
It depends on their location within the tissue.
- Perivascular fibroblasts located around endothelium are more inflammatory and they are possibly producing cytokines driving recruitment and retention of inflammatory cells within the joint.
- Fibroblasts located in the lining layer in health they provide support to macrophages to produce lubricant to the joint. However, in inflammation these fibroblasts change and start producing signals that drive damage to the bone by stimulating osteoclasts to drive the damage to the bone.
What happens if you inject different fibroblasts into the joint of mouse?
If you inject perivascular fibroblasts, the inflammation will be more severe and will persist for longer. However, if you inject fibroblasts from the lining layer they have no impact on inflammation but they drive bone damage (Croft 2019)
What is the relevance of NOTCH3?
NOTCH3 signalling from the endothelium stimulates fibroblasts to become pro-inflammatory. Mice KO of NOTCH3 show decreased inflammation in RA models (Wei 2020)
What do we want when targeting fibroblasts?
We want to target only the fibroblasts contributing to inflammation, not all fibroblasts.
How can we target fibroblasts?
For example we can
- stop differentiation of fibroblasts into inflammatory subtypes
- or we can deplete inflammatory subtypes
Do we have a specific marker for inflammatory fibroblasts?
Yes, fibroblasts activation protein alpha (FAPa) is a protease expressed on the surface of the cell and is important in attacking fibroblasts to the cartilage. High levels of FAPa in the joint in early stages of inflammation lead to RA later on. FAPa is a biomarker for inflammatory fibroblasts and depletion of FAPa positive fibroblasts leads to suppression of the inflammatory arthritis and less damage to the bone (Croft 2019)
Do we have treatment targeting FAPa?
Yes, CAR T cells treatment targeting FAPa:
- when injected into the knee of mouse RA model they suppress inflammation
- intravenous delivery to mouse leads to CAR T cells homing to the joint and reduced inflammation
- they partially deplete FAPa positive fibroblasts and lead to switch off pathogenic fibroblasts into non-pathogenic fibroblasts
- FAPa is expressed highly in inflammation and in cancer but also low expression is in lymph nodes, bone marrow and muscle. CAR T cells only deplete cells with over expression of FAPa.
What happens after treatment with CAR T cells?
- There is a progenitor population emerging which repair the joint
- Population of protecting macrophages on the lining layer is restored
