Lecture 12 - Hypersensitivity Flashcards
What is an allergy?
An innapropriate immune response, made by genetically presidisposed hosts, to non-pathogenic antigens
Allergy is a type I hypersensitivity, but is often associated with Type IV late phase reaction (when T cells go back to the initial site to cause a more severe reaction).
Allergies are induced by what?
Allergens
How do things like penicllin, metals and hair dyes cause allergies?
High reactive substances bind to self proteins, modify them and turn them into allergens.
What are the three components that an allergy requries?
- Allergen (antigen)
- Serum factor (IgE)
- Tissue factor (Mast cells)
What did Prausnitz experiment show?
He took Kustner’s serum (guy who was sensitive to fish) and injected it into his own skin.
He then challenged himself with the fish extract, and the result showed that sensitivity could be transferred by serum factor (Prausnitz-Kuster test)
What are some examples of type I hypersensitivity?
Do you get an itch on first exposure to an antigen? e.g. mosquito
No, you need to first generate an immune response.
Describe the immediate and late phase response to a mosquito bite or challenge at the skin
Initially allergen will bind to IgE on mast cell surface to cause degranulation.
Later on the allergen may be taken up by APC’s, and are then transported via the lymphatics to the lymph node to be presented to T cells. T cells travel back to the intial site and release mediators, causing an itch. This is why a mosquito bit is itchy a hpurs after a bite.
What’s present on the surface of a mast cell that allow it to cause the immediate hypersensitivity reaction?
Mast cells have high affinity receptors to IgE on their surface (don’t have high affinity for other ABs). They bind IgE tightly, and when these are crosslinked mast cells are activated and this causes them to release their inflammatory mediators.
Mast cells have pre-formed IgE on their surface in the receptors, and when the allergen, the mast cells release the granules
When the allergen binds to the IgE on the surface of mast cells, how does the immediate reaction occur?
Conversely, how does the late phase reaction occur?
Allergen binds to IgE on surface on mast cell causing cross linking of the receptors, which activates it. It then releases it’s granules (histamine/lipid mediators) and then cause a vascular/ smooth muscle response (immediate reaction).
For late phase reaction the allergen still binds to IgE on surface to cause crosslinking the mast cell is activated and releases cytokines, which cause the T cells to come back to the initial site of allergen contact to cause inflammation in the late phase reaction.
What are some features of inhaled allergens that may promote the priming of Th2 cells which drive IgE responses?
- Allergens are often glycoproteins, making them a good antigenic substnace - as the carb. side chains makes them more immunogenic.
- Allergens are often enzymatically active, since they are often proteases, which means that they can break down mucosa, barriers to get acces to the immune system underlying the barriers in the mucosa, then can enter lymphatics after uptake by APC
- Often have low molecular weight, where the allergen can diffuse out of particle into mucus, and allows it to move through barriers.
- Often has high solubility, where allergen can be readily eluted from particle and can travel in lymphatics
- They are stable particles, so that they can hang around for a period of time and can cause an allergic response even months after being inhaled.
- Needs to contain peptides that bind host MHC II - this is required for T cell priming, which results in the AB class switch to IgE
What are allergens often released from?
Allergens may be released from large particles, then pass through the mucosa to be uptaken by DC, which then migrates to lymph node to caused an allergen immune response.
A low doese over a long period of time may occur via this route to activate Th2 cells to produce IL-4, which cause AB class switching to IgE in B cells
What is the hygeine hypothesis?
It’s based around the idea that first world countries have higher incidence of allergies.
Risk of developing allergy may be linked to how much exposure one has to bacteria and viruses when growing up.
However those with allergies probably have some genetic predisposition to begin with.
What is atopy?
Genetic predisposition to allergy
What kind of genes may cause the predisposition?
- IL-4 - There may be a promoter variant which causes an overproduction of IL-4.
- Gene variant may produce an IL-4 receptor thats more sensitive, causing increased signalling in response to IL-4
- Gene produces structural variants of MHC II - resulting in enhanced presentation of particular allergen derived peptides
How can we use immunotherapy to carry out desensitisation to an allergen?
You put the allergen under the skin (either sc, IM or even intradermal) - since you’re putting it through a different route and with an escalating dose over time you skew the immune response from a Th2 to a Th1 response.
Need to start at low dose and slowly escalate over time (so we don’t cause severe allergic reaction) slowly to skew the respone to a Th1 response which causes IgG production, allowing IgG to be dominant. IgG will bind the antigen and neutralise it, and it won’t bind to mast cells. Therefore IgG interferes with the action of IgE.
So IgG binds the allergen, stops allergen from bind to allergen and anatagonises the allergic response.
Another thing thats happening is that the immune system is being instructed to make different types of cytokines (e.g. IFN-y).
So in the Th1 response that we’ve developed, we produce more IFN-y, this anatagonises the Th2 pathway.
What are some exampes of type II hypersensitivity?
When antibodies are produced against self-antigens on the cell surface e.g. haemolytic anaemia/ some drug reactions.
And in antibody mediated glomerulonephritis.
Describe how type IV hypersensitivity occurs
- DC takes up antigen and migrates to draining lymph node to cause T cell activation in lymph node.
- T cells then migrate to initto cause inflammation
