TGFb as a key driver of fibrosis Flashcards
What are the characteristics of systemic sclerosis?
Fibrotic changes
Immune changes
Vascular changes
What are the fibrotic changes seen in systemic sclerosis?
Hardened skin of poor quality
Leads to skin becoming broken down and ulcerated
Affects function
Scarring and fibrosis also occurs in internal organs
Which internal organs are affected by fibrotic changes seen in systemic sclerosis?
Kidney
Heart
Gut
Lungs
Systemic sclerosis has the highest mortality of the rheumatic diseases
TRUE or FALSE
TRUE
Which immune cell is observed in systemic sclerosis?
Antinuclear antibodies
What vascular changes can be observed in systemic sclerosis?
Large vessels can become blocked due to excessive proliferation
Smaller vessels show dilatation abnormalities due to abnormal blood flow
What molecular pathways are involved in scleroderma?
Many molecular pathways and their mediators link together in systemic sclerosis
Growth factors and cytokines give us the biggest clue into what drives the disease
What molecule is the master driver of fibrosis?
TGFb
What type of molecule is TGFb?
Pleiotropic
Cytokine
What are markers of TGFb activation?
CTGF
aSMA
What is the indirect evidence that TGFb is important in scleroderma?
Molecular analysis of lung fibroblast gene expression
Confirms TGFb is activated in SSC
Observed by upregulated markers of TGFb activation
What is the direct evidence that TGFb is involved in lung fibrosis?
Investigation of the role of TGFb in SSc pathogenesis in vivo (mouse model)
Transgenic mouse
TGFb only activated fibroblasts
Activation of these fibroblasts lead to features of scleroderma
Proved that fibroblast activation following TGFb signalling was the mechanism behind scleroderma
How does TGF b activate fibroblasts through the canonical pathway?
- TGF b is found in the latent associated peptide bound via covalent bonding
- TGF b is cleaved from LAP
- Active TGF b exerts its effect by binding to its receptors
How does TGF b exert its effect through the canonical pathway?
Canonical TGF b signalling goes through SMAD proteins
Leads to activation of downstream gene targets
What are the downstream gene targets for TGF b?
aSMA
CTGF
How do we know that blocking TGF b is therapeutically beneficial in scleroderma patients?
Blocking TGF b signalling in transgenic mice prevents progression of fibrosis following Tamoxifen - induced damage
Block the TGF b signalling:
- selective expression of DNA recombinase
- modification in the receptor genes for TGFb
What are therapeutic ways to target the canonical TGF b pathway?
Antibody that blocks active TGF b
Overexpression of soluble receptors that mop up TGF b without leading to an intracellular signal
Overexpression of natural inhibitors (Decorin, SMAD7)
Transcription inhibitors
Why is blocking the canonical pathway not very therapeutic?
TGF b signals through other intracellular pathways
Blocking the canonical pathway will shift the signalling through other pathways
Drives the fibrosis even further
What is the most efficient therapeutic treatment for treating scleroderma?
Blocking the TGF b before it signals through the cell
Name a drug used to block TGF b signalling
Fresolimumab
Clinical evidence that treatment against scleroderma is therapeutic
Improvement in gene expression markers in the skin
Improvement in skin fibrosis score
aSMA marker concentration decreases
What is used to determine the diagnosis and prognosis of patients with SSc?
ACR calssification - scores depending on the presentation and severity of symptoms
Look at antibody profile - depending on what the antibodies are against, the disease presents differently
What antibodies give poor prognosis?
Antibodies causing lung fibrosis
No treatment
What antibodies give good prognosis?
Antibodies causing kidney damage
Good treatments available
Examples of antibodies causing SSc
Centromere
Topoisomerase
RNA polymerase
What vascular changes are seen in systemic sclerosis?
Narrowing of big vessels due to uncontrolled proliferation
What does scleroderma mean?
Umbrella term
Hardening of the skin
What is the prevalence of scleroderma?
1 in 10 000 in the UK
What is the F:M ratio of Scleroderma?
4:1
Onset of Scleroderma
30-60 years
Subtypes of Sclerosis
Localised scleroderma - hardening of the skin in localised areas
Isolated Raynaud’s - abnormalities of the circulation
Systemic sclerosis - combination of fibrosis of skin internally and externally as well as vascular damage
What can systemic sclerosis be split into?
Diffuse cutaneous sclerosis
Limited cutaneous sclerosis
What is the relationship between severity of hardening of the skin and internal organ dysfunction?
Positive correlation
Not absolute however
What are the three distinct subgroups of patients with diffuse SC?
Good skin scores with improvement with therapy = best outcome
Bad skin scores with good improvement = good outcome
Bad skin scores and bad improvement = worse survival
What is a very poor prognostic feature of dcSSc?
Failure of the skin score to improve in the first 12 months
4 features that overlap to create the characteristic presentation of disease
Susceptibility
Initiation
Progression
Amplification
How is cancer related to systemic sclerosis?
Cancer prevalence is higher in sclerosis population
Removal of cystic pancreatic lesion = improved skin sclerosis
What can genetic analysis of systemic sclerosis reveal?
SNPs or microsatellites that increases the risk of scleroderma
Identification of gene expression differences between different subtypes of SSc
What therapies are given to SSc sufferers?
Immunosuppressant drugs
Cyclophosphamide
Autologous hematopoietic stem cell transplantation
What, apart from TGFb, is a potential target for SSc therapy/
Anti-IL-6
Involved more specifically in the inflammatory response
Modifies the TGFb signature phenotype of scleroderma patients
Normalises gene expression
