Athritis Flashcards
How does the sulfasalzine drug treatment work for arthritis?
- It has the ability to scavenge free radicals made by some immune cells
- These would otherwise make toxic enzymes in an inflammatory response
What is the ciclosporin drug?
- this works to stop transplant rejections
It binds to a protein called cyclophilin
What is the protein cyclophilin and what does it do?
- it is a immunophilin
- it’s found in the cytosol of cells
- it controls transcription
- it binds to calcineurin
What happens to calcineurin when cyclophililin binds to it?
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.
What does the transcription factor Nfkappa b do?
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.
Examples of new biological drugs?
- 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.
How does the Decoy receptor work?
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
Asthma - 3 features
Its chronic
It causes bronchial hyper reactivity
It causes REVERSIBLE airway obstruction - but with age this becomes permanent
Drugs which can treat asthma?
Bronchodilators (salbutomol)
Anti - inflammatory agents (prednisolone (glucocorticoids) & omalizumab)
Bronchodilators problems?
Beta 2 adrenoreceptors which are targeted by the drug show polymorphisms.
Common source of allergens which causes asthma?
Pollen Dander from domesticated animals Mold spores Faeces of very small animals - dust mites These can cause anaphylactic shock
Examples of materials that can be injected and may cause allergies?
(Not exclusive to asthma)
Injected venoms
Vaccines
Drugs
Therapeutic proteins
Ingested materials which may cause allergens?
- food
Contacted materials which may cause allergens?
Plant leaves - poison ivy
Industrial products from plants
Synthetic chemicals
Metal
How do you diagnose allergies?
- 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.
What is the relationship between the IgE antibody and allergies?
- 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.
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:
- 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
What are the positive roles of mast cells?
They have a homeostatic role in the body and help wound healing
Airway allergy classifications:
- if allergies are restricted to the upper airways:
- this is hayfever or allergic rhinitis
- if its in the lower airways - then this is asthma
What happens once mast cells (in the lungs remember) are degranulated?
REMEMBER this occurs in the lungs
- 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
What makes asthma a chronic allergic disease?
- 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\
So what is the late phase of an asthma attack?
- 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.
Treatment to stop the late phase of an asthma attack?
- 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
How many phases are the for an asthma attack?
Two
- early and late
What are the effects of mediators on the lungs in the early phase of an asthma attack?
- 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.
What is the issue with poor control of asthma?
- 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
Glucocorticoids?
- usually involved in homeostasis but too much causes cataracts
