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Molecular Basis of Disease > TGFb as a key driver of fibrosis > Flashcards

TGFb as a key driver of fibrosis Flashcards

1
Q

What are the characteristics of systemic sclerosis?

A

Fibrotic changes

Immune changes

Vascular changes

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2
Q

What are the fibrotic changes seen in systemic sclerosis?

A

Hardened skin of poor quality

Leads to skin becoming broken down and ulcerated

Affects function

Scarring and fibrosis also occurs in internal organs

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3
Q

Which internal organs are affected by fibrotic changes seen in systemic sclerosis?

A

Kidney

Heart

Gut

Lungs

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4
Q

Systemic sclerosis has the highest mortality of the rheumatic diseases

TRUE or FALSE

A

TRUE

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5
Q

Which immune cell is observed in systemic sclerosis?

A

Antinuclear antibodies

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6
Q

What vascular changes can be observed in systemic sclerosis?

A

Large vessels can become blocked due to excessive proliferation

Smaller vessels show dilatation abnormalities due to abnormal blood flow

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7
Q

What molecular pathways are involved in scleroderma?

A

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

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8
Q

What molecule is the master driver of fibrosis?

A

TGFb

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9
Q

What type of molecule is TGFb?

A

Pleiotropic

Cytokine

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10
Q

What are markers of TGFb activation?

A

CTGF

aSMA

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11
Q

What is the indirect evidence that TGFb is important in scleroderma?

A

Molecular analysis of lung fibroblast gene expression

Confirms TGFb is activated in SSC

Observed by upregulated markers of TGFb activation

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12
Q

What is the direct evidence that TGFb is involved in lung fibrosis?

A

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

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13
Q

How does TGF b activate fibroblasts through the canonical pathway?

A
  1. TGF b is found in the latent associated peptide bound via covalent bonding
  2. TGF b is cleaved from LAP
  3. Active TGF b exerts its effect by binding to its receptors
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14
Q

How does TGF b exert its effect through the canonical pathway?

A

Canonical TGF b signalling goes through SMAD proteins

Leads to activation of downstream gene targets

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15
Q

What are the downstream gene targets for TGF b?

A

aSMA

CTGF

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16
Q

How do we know that blocking TGF b is therapeutically beneficial in scleroderma patients?

A

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
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17
Q

What are therapeutic ways to target the canonical TGF b pathway?

A

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

18
Q

Why is blocking the canonical pathway not very therapeutic?

A

TGF b signals through other intracellular pathways

Blocking the canonical pathway will shift the signalling through other pathways

Drives the fibrosis even further

19
Q

What is the most efficient therapeutic treatment for treating scleroderma?

A

Blocking the TGF b before it signals through the cell

20
Q

Name a drug used to block TGF b signalling

A

Fresolimumab

21
Q

Clinical evidence that treatment against scleroderma is therapeutic

A

Improvement in gene expression markers in the skin

Improvement in skin fibrosis score

aSMA marker concentration decreases

22
Q

What is used to determine the diagnosis and prognosis of patients with SSc?

A

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

23
Q

What antibodies give poor prognosis?

A

Antibodies causing lung fibrosis

No treatment

24
Q

What antibodies give good prognosis?

A

Antibodies causing kidney damage

Good treatments available

25
Q

Examples of antibodies causing SSc

A

Centromere

Topoisomerase

RNA polymerase

26
Q

What vascular changes are seen in systemic sclerosis?

A

Narrowing of big vessels due to uncontrolled proliferation

27
Q

What does scleroderma mean?

A

Umbrella term

Hardening of the skin

28
Q

What is the prevalence of scleroderma?

A

1 in 10 000 in the UK

29
Q

What is the F:M ratio of Scleroderma?

A

4:1

30
Q

Onset of Scleroderma

A

30-60 years

31
Q

Subtypes of Sclerosis

A

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

32
Q

What can systemic sclerosis be split into?

A

Diffuse cutaneous sclerosis

Limited cutaneous sclerosis

33
Q

What is the relationship between severity of hardening of the skin and internal organ dysfunction?

A

Positive correlation

Not absolute however

34
Q

What are the three distinct subgroups of patients with diffuse SC?

A

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

35
Q

What is a very poor prognostic feature of dcSSc?

A

Failure of the skin score to improve in the first 12 months

36
Q

4 features that overlap to create the characteristic presentation of disease

A

Susceptibility

Initiation

Progression

Amplification

37
Q

How is cancer related to systemic sclerosis?

A

Cancer prevalence is higher in sclerosis population

Removal of cystic pancreatic lesion = improved skin sclerosis

38
Q

What can genetic analysis of systemic sclerosis reveal?

A

SNPs or microsatellites that increases the risk of scleroderma

Identification of gene expression differences between different subtypes of SSc

39
Q

What therapies are given to SSc sufferers?

A

Immunosuppressant drugs

Cyclophosphamide

Autologous hematopoietic stem cell transplantation

40
Q

What, apart from TGFb, is a potential target for SSc therapy/

A

Anti-IL-6

Involved more specifically in the inflammatory response

Modifies the TGFb signature phenotype of scleroderma patients

Normalises gene expression

Molecular Basis of Disease (28 decks)

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