Lecture 20. the Allergic Response

Lecture 20: Allergic response- a deleterious Th2 driven response to innocuous agents?

The allergic response involves a response that is deleterious and involves a Th2 type immune response to an otherwise harmless antigen which should be ignored. These harmless antigens are termed “allergens”

Instead of ignoring this harmless antigen we overreact to it- called a hypersensitivity reaction.

Virtually any immune response has a damaging effect e.g. CD8 response is damaging- kills infected cells during viral infection. There should be a balance

autoimmune diseases are caused by hypersensitivity to self antigen

There are 4 types of hypersensitivity reactions. Type 1 will be the focus: an allergic reaction

Type 2: involves antibody mediated responses to cell surface antigens. The cell labelled K is a cell that is mediating antibody-dependence cytotoxicy. There is something on the surface of the target cell: either antibody or a drug that has bound. The

immune response develops to these cell-surface molecules. Antibodies target this bound molecule which leads to destruction of the cell. Type 2: antibody-mediated responses to cell surface antigen

Type 3: We also make responses to soluble antigen. An immune complex forms somewhere in the body e.g. the kidney and then this is targeted by the immune system and causes damage to the tissue. This is antibody-mediated

activity against soluble antigens. The activity of the immune complexes binding to tissues where they shouldn’t is also type 3.

Type 4: different cells involved. T cells that produce cytokines and activate macrophages and cause an over-stimulation of immunological activity. We want activity of these cells but this response can be driven into overdrive where the macrophages produce dangerous levels of inflammatory mediators causing tissue destruction. This can be seen in TB where macrophages cause destruction of lung tissue and coughing up of blood

Type 1 hypersensitivity reactions are the focus of this lecture. They are allergic reactions present in many different forms: hayfever which is inflammation of the nasal passages.

Do not confuse allergies with intolerance. Intolerance is where you cant process something. Allergy is where there is a type 1 hypersensitivity reaction- this is very different

Mast cells are at the heart of allergic reactions. They are found at mucosal surfaces and lining blood vessels.

At mucosal surfaces: lung and GIT

if you think about allergies most of the responses are occurring at these muscosal surfaces

Mast cells are sensitised by their acquisition of free IgE from solution. IgE is taken by the mast cell. An allergen then has to

come along and cross-link the IgE. it is the cross-linking that causes activation and degranulation of the mast cell. There is then a release of mediators of pre-formed inflammatory agents. Then more inflammatory mediators are produced after the activation event. Cross-linking of IgE on the surface of the mast cells is the activator.

There are other triggers that will cause it to degranulate. Nerve stimulation also causes degranulation – mast cells have nerve endings. There are interactions between the nervous system and immune system e.g. hives are caused by nervous stimulation of the immune system during times of stress.

IgE is Y-shaped like the other antibodies.

This has 4 constant region domains. It is different to other antibodies in that it is found in extremely low levels in the blood. However this low concentration is due to the fact that they are very powerful antibodies

Mast cell bound IgE needs to be cross-linked for the mast cell to degranulate.

People are allergic to the molecules associated with the house dust mite.

It is a molecule in their faeces coming from a digestive enzyme.

The level of exposure to this allergen is really low however it can trigger a large response

The allergic response is made up of 2 phases

This is due to house dust mite allergen. The site of allergen there is a red area of swelling- this is the immediate reaction.

respiratory function is similar in the asthmatic patient: graph below.

The decline in the late phase is mirrored in the house mite skin experiment where you can see a broader area of swelling

Binding of IgE triggers the release of granules stored in the mast cell releasing histamine and heparin along with lots of other proteases. These released proteases contribute to the damage to the surrounding tissue. The cell the starts producing the lipid mediators of inflammation then later cytokines and chemokines. These are produced, released or even stored in the cell.

The Fc epsilon receptors on the mast cells capture the IgE. The mast cells are very granulated. On the right a lot of granules have been released. It is a very quick response that happens in almost seconds. the inflammatory mediators are secreted quickly into the tissues

Histamine is one such inflammatory mediator that causes constriction of smooth muscle.

Diahorea in food allergies is due to constriction of GIT.

Blood vessels: cause relaxation and increased blood flow. Increased blood flow leads to redness. There is increased vascular

permeability into tissue: causes swelling. The H1 receptors are involved in the allergic response. H1 receptor antagonists are used for allergy treatment

lipid mediators of inflammation.

They have similar effects to histamine

Many of the cytokines produced by Th2 cells are also produced by mast cells. They also produce the inflammatory cytokines such as TNF alpha. Mast cells store TNF

Mast cells also produce IL-5. This acts on eosinophils and promotes their activation

and formation. If you look at the cells involved in allergy it is mast cells and eosinophils: mast cells recruit eosinophils. They are responsible for most of the tissue damage you

observe.

Eosinophils also produce highly damaging mediators.

Eosinophils fight multi-cellular parasites along with mast cells and IgE. We need powerful mediators of inflammation for these parasites, they are difficult to deal with. if the release of mediators is directed toward the host it can be extremely damaging because it is targeted to eukaryotic organisms.

IL-5 is being produced.

They also produce the lipid mediators.

These slides demonstrate the allergic response to be a positive feedback mechanism that is out of control. These signals amplify as they continue each other.

The cells that produce the IgE are not shown. The most important cell is the T cell that instructs the B cell to make IgE not the mast or

eosinophils.

Swelling of the mucosal tissues restricts the airway.

Ventalin allows the dilation of the airway

stabilising the mast cell so they don’t degranulate too easily

Sodium.. stabilises the mast cell so its not degranulating: we don’t see the early or late phase.

Steroids eliminate only the late phase

Desensitisation is where they are repeatedly exposed to very low doses or the allergen. Normal exposure of the allergen is already very low so this treatment is really low. The levels of allergen are gradually increased.

Repeated exposure does lead to a decline in the IgE and the symptoms. An increase in the IgG is also observed

Should a mother avoid peanuts during pregnancy? –some evidence suggests the mothers exposure can prevent sensitisation. It is very difficult to avoid allergens.

There is certainly a genetic link in this disease but this does not explain why allergic disease is on the increase.

Factor X in concert with having genetics for high IgE response where you go through the allergic breakthrough

How long were the babies fed for blab la

overexposure to allergens causes the allergic breakthrough. This was concluded.

people who are overexposed to animals become allergic to them.

Exposure to pollutants does the same thing

Virokines are chemicals produced by a virus that mimics the bodys cytokines. This drives cytokine production and the immune system is caused to overreact which is problematic for the host by beneficial for the virus.

While children are still unhygienic why is there still allergies

Because we don’t have enough infection we get allergies

in early life our immune system is directed toward the Th2 response.

Is there evidence for the hygiene hypothesis? –yes, there is but it is indirect

large families= more spreading of disease, less allergies.

parasitic infections are rare in developed countries- allergic disease is reversed

People are now looking at persistent infections because these are caused by parasites

Persistent infections may cause activation of Tregs which will decrease inflammation

Hepatitis has been associated with reduced allergies

the community of organisms within us may protect us from allergic disease. we may change their populations by taking antibiotics or by diet

Class switching. What is the relationship between IgG and IgE? once we learn this we can understand allergic disease. We need to better understand the function of antibodies.