Athritis

Question 1

How does the sulfasalzine drug treatment work for arthritis?

Answer 1

• It has the ability to scavenge free radicals made by some immune cells
• These would otherwise make toxic enzymes in an inflammatory response

Question 2

What is the ciclosporin drug?

Answer 2

• this works to stop transplant rejections

It binds to a protein called cyclophilin

Question 3

What is the protein cyclophilin and what does it do?

Answer 3

• it is a immunophilin
• it’s found in the cytosol of cells
• it controls transcription
• it binds to calcineurin

Question 4

What happens to calcineurin when cyclophililin binds to it?

Answer 4

Calcineurin is a calcium sensing protein.
It is a An enzyme called a calcium activate phosphatase.

This is how it is involved in the immune response:When immune cells are activated, there is an increase in intracellular calcium

Note cyclophilin binds to calcineurin.

When the drug ciclosporin is given, it can bind to cyclophillin (the protein which has bounds to the calcineurin)

This binding (of the drug to ciclophillin) causes the depolarisation of the transcription factor Nfkappa b
Once this factor is phosphorylated it goes into the nucleus where it controls transcription of many pro inflammatory cytokines.

Question 5

What does the transcription factor Nfkappa b do?

Answer 5

It goes into the nucleus where it controls the transcription of pro inflammatory cytokines
For example:
IL 2 = helps with the activation and proliferation of TH1 cells
TH1 cells then go onto mediate the immune reactions of rhumetoid arthritis
Control of these pro inflammatory cytokines by the transcription factor said helps to dampen down the signalling cascade of the immune system.

Question 6

Examples of new biological drugs?

Answer 6

• MAB: monoclonal antibody - antibody is humanised so it isnt recognise foreign when it enters the body
• adalimumab - neutralises TNF alpha for example
• when the antibody is bound to the target TNF, TNF can’t bind to its receptor and thus the immune response is dampened.

Question 7

How does the Decoy receptor work?

Answer 7

A protein can be made which fits the bidning domain of a TNF alpha cytokine
This cytokine will bind to this decoy receptor
The name of this drug is humira
This is used to treat rheumatoid arthrisis

Question 8

Asthma - 3 features

Answer 8

Its chronic
It causes bronchial hyper reactivity
It causes REVERSIBLE airway obstruction - but with age this becomes permanent

Question 9

Drugs which can treat asthma?

Answer 9

Bronchodilators (salbutomol)

Anti - inflammatory agents (prednisolone (glucocorticoids) & omalizumab)

Question 10

Bronchodilators problems?

Answer 10

Beta 2 adrenoreceptors which are targeted by the drug show polymorphisms.

Question 11

Common source of allergens which causes asthma?

Answer 11

Pollen
Dander from domesticated animals
Mold spores
Faeces of very small animals - dust mites
These can cause anaphylactic shock

Question 12

Examples of materials that can be injected and may cause allergies?
(Not exclusive to asthma)

Answer 12

Injected venoms
Vaccines
Drugs
Therapeutic proteins

Question 13

Ingested materials which may cause allergens?

Answer 13

• food

Question 14

Contacted materials which may cause allergens?

Answer 14

Plant leaves - poison ivy
Industrial products from plants
Synthetic chemicals
Metal

Question 15

How do you diagnose allergies?

Answer 15

• Take a little bit of allergen and inject into a region of the body
• Then observe if there is a response
• the swelling is caused by a large filtration of immune cells to the damaged site.

Question 16

What is the relationship between the IgE antibody and allergies?

Answer 16

• people often develop asthma after viral infections
  At the same time they may inhale an allergen like pollen for instance
  The body the produces an IgE class antibody in reponse to the allergen
  This is bad as it causes an immune response to the pollen the next time the body comes in contact with the pollen, mistaking it as harmful due to the previous viral infection
  This causes inflammation and swelling.

Question 17

Mast cells and an allergic response. What happens?

Note it is the mast cells which are causing the allergic response: Note it is the mast cells which are causing the allergic response:

Answer 17

• mast cells are activated when allergen is recognised by the IgE antibody
• immediately the mast cells degranulate and release granules
• Inside of these granules there is high levels of histamines
• these granules also contain TNF alpha - which cause a pro inflammatory response which is bad

Mast cells also produce prostaglandins
- these are lipid mediators remember and are what cause a proinflammatory response

Question 18

What are the positive roles of mast cells?

Answer 18

They have a homeostatic role in the body and help wound healing

Question 19

Airway allergy classifications:

Answer 19

• if allergies are restricted to the upper airways:
• this is hayfever or allergic rhinitis
• if its in the lower airways - then this is asthma

Question 20

What happens once mast cells (in the lungs remember) are degranulated?

REMEMBER this occurs in the lungs

Answer 20

• you have the whole release of cytokines and pro inflammatory material
• but then this dies down and you enter a late phase

However once in the late phase

• the nfkappa b transcription factor becomes activated
• this causes the synthesis of pro inflammatory cytokines
• this attracts other immune cells to the lungs
• we want to treat this late phase ideally

Question 21

What makes asthma a chronic allergic disease?

Answer 21

• asthma is associated with overactivity of TH2 cells
• These helper cells then interact with B cells which produce antibodies
• These IgE antibodies bind permanently to receptors on the surface of mast cells
• this mast cell receptors remain activated when allergen move towards to them
• the mast cells secrete cytokines
• eosinophils (proinflammatory mediator) also respond to the IgE antibodies

Thus a pro inflammatory repsonse occurs\

Question 22

So what is the late phase of an asthma attack?

Answer 22

• this is when the symptoms of the asthma attack decrease and the get strong again after 30 minutes as the mast cells start recruiting immune cells into the lungs.

Question 23

Treatment to stop the late phase of an asthma attack?

Answer 23

• use glucocorticoids
• this binds to glucocorticoid receptor - a nuclear receptor
• when the receptor becomes bound to the prednisolone it activates transcription of some genes and inhibits the transcritption of others
• these inhibit the cytokines which give rise to the late phase of asthma

Question 24

How many phases are the for an asthma attack?

Answer 24

Two

- early and late

Question 25

What are the effects of mediators on the lungs in the early phase of an asthma attack?

Answer 25

• in early phase you get smooth muscle contraction due to histamines - this causes tightening of the lungs
• you also get fluid build up in the lungs and swelling.
  This is caused by prostaglandins making the membranes more fluid permeable
• mucous is further secreted into the lungs via the histamine
• nerve ending are also stimulated. This contributes to coughing seen with allergic response.

Question 26

What is the issue with poor control of asthma?

Answer 26

• causes cumulative damage overtime
  Tissue itself changes with age
  Epithelial layer which is protective to the lung gets holes in it
  This causes lung capacity to be lost

Various types of immune cells begin to live permanently in the lung tissues which causes them to respond more quickly overtime
- for instance mast cells move from their usual locations
- they take up residence with smooth muscles themeselves
When the mast cells are activated you get a much more dramatic contraction of the lungs in this instance
Cells in the lungs also become much larger causing bronchospams in the lungs to be more dramatic

Question 27

Glucocorticoids?

Answer 27

• usually involved in homeostasis but too much causes cataracts