Hypersensitivity Reactions (Asthma & Allergy)

Question 1

What are the four types of hypersensitivity?

Answer 1

Type 1: immediate hypersensitivity

Type 2: cytotoxic hypersensitivity

Type 3: serum sickness and Arthus reaction

Type 4: delayed-type hypersensitivity, which includes things like contact dermatitis

Question 2

Describe Type 1 hypersensitivity.

Answer 2

Immediate hypersensitivity results from being exposed to allergens in the environment. This produces an immune response characterised by the production of IgE antibodies. IgE antibodies can attach to immune cells called mast cells.

When exposed to the allergen a second time, the antibodies activate the mast cells to degranulate and release their contents, causing inflammation.

Examples of Type 1 include:

• allergic rhinitis
• asthma
• anaphylaxis (when the reaction is exaggerated)

Question 3

How would you induce an immediate hypersensitivity reaction?

Answer 3

You could induce an immediate hypersensitivity reaction by injecting an allergen into the skin, or just scratching an allergen into the surface of the skin.

If there are mast cells bound with IgE, the mast cells will release inflammatory mediators. This will cause the leeching or surrounding plasma fluid into the area, causing a wheal. Vasodilatation also occurs, resulting in a flare.

Question 4

Describe Type 2 hypersensitivity.

Answer 4

Type II hypersensitivity is caused by an immune response generated against altered components of the human cell. This is because it is seen as new to the immune system, to which an immune response is generated.

For example, we have a blood cell or platelet that is covered in a drug. The immune system will recognise it as a new allergen, and generate an IgG response to that. This activates cells carrying the IgG receptor, such as macrophages. It also causes activation of complement; both of these result in inflammation.

There is also a special type of type II response which is slightly different as it generates antibodies which stimulate receptors or block receptors in the human body.

Examples of Type 2 include:

• some drug allergies (such as penicillin)
• Grave’s disease
• Myasthenia Gravis
• Haemolytic disease of the newborn

Question 5

Describe Grave’s disease.

Answer 5

Normally, the pituitary gland releases a hormone called TSH; it activates on the thyroid to cause the release thyroxin. This exert negative feedback on the pituitary to release less TSH.

In Grave’s disease, the body creates antibodies against the TSH receptor, so they are constantly activating it, leading to the unregulated overproduction and release of thyroxin.

Question 6

Describe Myasthenia Gravis.

Answer 6

At the normal neuromuscular junction, the presynaptic nerve is activated, releasing acetylcholine. These stimulate receptors on the muscle to initiate a response.

However, in myasthenia gravis, the body makes antibodies against the Ach receptors. These antibodies block the Ach receptors, so there is reduced transmission to the muscle.

Question 7

Describe how haemolytic disease of the newborn can manifest in a RhD negative mother and an RhD positive foetus.

Answer 7

During birth, Rh+ foetal erythrocytes lead into the maternal blood after breakage of the embryonic choric, which normally isolates the foetal and maternal blood. Maternal B cells are activated by the Rh antigen and produce large amounts of anti-Rh antibodies.

Rh antibodies titer in the mother’s blood is elevated after first exposure. With a second Rh+ child, Rh antibodies are small enough to cross the embryonic chorion and attack the foetal erythrocytes.

This causes anaemia, and often death, in the child.

Question 8

Describe Type 3 hypersensitivity.

Answer 8

In this reaction, we have the presence of a soluble antigen, to which we generate an IgG response.

Because we already have large amount of antibodies and antigens, we create a lot of immune complexes. These can activate the cells around the capillaries to cause an inflammatory response; the activation of complement causes a further inflammatory response.

Examples of Type 3 include:

• Arthus reaction
• serum sickness
• Farmer’s lung (mould from hay)
• Bagazosis (mould from sugar cane)

The type of histology you get in Type III hypersensitivity depends on the dose of antigen and the route of delivery.

Question 9

Describe Arthus reaction.

Answer 9

Someone who has been vaccinated before has a high level of antibodies.

The reintroduction of the antigen can cause a localised immune response, seen as the Arthus reaction.

An antigen has been locally injected into the skin, which already has the presence of antibodies specific to that antigen. We get formation of immune complexes in the tissues.

These activate mast cells, which also recruit other cells to the site of infection, causing inflammation.

Question 10

Describe serum sickness.

Answer 10

• it’s caused by large intravenous doses of soluble antigens (e.g. drugs)
• IgG antibodies that are produced form small immune complexes with the antigen in excess
• the immune complexes are deposited in tissues e.g. blood vessel walls
• tissue damage is caused by complement activation and the subsequent inflammatory responses

Question 11

Describe farmer’s lung.

Answer 11

The antigen (for e.g. a mould) enters the lungs, and it forms an immune complex within the alveoli. This induces an inflammatory response in the lung. This results in fibrosis, granuloma and inflammation.

Farmer’s lung can be triggered as a result of dusts, bacteria or fungi. The most common cause is thermophilic actinomycosis.

Another form is a pigeon protein causing inflammation in the lung.

Question 12

Describe Type 4 hypersensitivity.

Answer 12

There are two forms of delayed-type hypersensitivity. The classical form is related to the type of immune cells that are produced (Th1 and Th2: they will illicit a different immune response). Th1 is typically associated with immune responses to things like intracellular bacteria, while Th2 typically responds to things like worm infections (helminths).

In the case of Th1 delayed-type hypersensitivity, Th1 cells are induced to produce IFN-γ and IL-12, which stimulate macrophages to release cytokines and chemokines. These recruit specific types of cells to the sites of inflammation. In this case, we get a granuloma. This takes about 2-3 days to form.

In the case of Th2 delayed-type hypersensitivity, Th2 cells produce cytokines such as IL-4 and Il-5, which are important in Ig production and the recruiting of things like oesinophils to the site of inflammation.

Examples of Th1 delayed-type would be:

• Tuberculin reaction
• Tuberculoid leprosy

Examples of Th2 delayed-type would be:
- Allergic contact dermatitis (e.g. nickel)

Question 13

Describe the Mantoux test.

Answer 13

You would inject tuberculin (for example) subcutaneously, and then wait to see if there is a reaction to it (if someone has been sensitised). A positive result would be ulceration of the skin.

Question 14

Describe tuberculoid leprosy.

Answer 14

In the tuberculoid response of leprosy, you have a strong Th1 immune response in the presence of leprosy bacilli. This results in typical granuloma.

Question 15

Describe contact dermatitis.

Answer 15

Contact dermatitis (an exaggerated allergic reaction) can develop in response to things such as latex and bleach, or metals such as nickel.

Question 16

Define an allergy.

Answer 16

It is defined as a disease following a response by the immune system to an otherwise innocuous antigen.

It is a major health concern around the world.

~40% of the population in Europe have allergies to one or more common environmental allergens.

Question 17

Describe IgE.

Answer 17

It is the first line of defence against worms (helminths).

IgG has one extra domain in the heavy chain.
It binds to molecules that have the high-affinity IgE receptor, such as basophils and mast cells.

It binds FcεR1 receptor on mast cells and pre-arms mast cells to react when in the presence of the antigen.

Question 18

Describe how allergen-specific IgE is produced?

Answer 18

Our first exposure to (for example) pollen causes activation of the immune response.

The APCs pick up the pollen and take them to local lymph nodes.
They may activate Th2 cells, which release IL-4 to induce B-cells that have the same specificity for allergens to produce IgE.

Question 19

What causes allergic sensitisation?

Answer 19

Exposure to Allergen is critical, this includes:

• nature of the allergen
• dosage of the allergen (high vs. low)
• timing
• location of priming

There is also the role of pro-allergic dendritic cells and cytokines, and a genetic predisposition to allergy.

Question 20

What role does filaggrin have in atopic dermatitis?

Answer 20

Filaggrin links skin integrity and allergy.

When it is defective, atopic dermatitis is greater. This is due to the access for allergens.

When filaggrin is defective, the skin is a far less effective barrier to the environment.

Question 21

What makes dendritic cells pro-allergic?

Answer 21

If you have an injured epithelium or epidermis, that may induce cells such as keratinocytes to induce inflammatory markers. These are pro-Th2 and pro-allergic.

There is also a molecule called TSLP that is important in inducing a inflammatory response.

Question 22

Describe the two phases of the allergic response.

Answer 22

There are two phases of the allergic response: the early and the late.
When we’re exposed to an allergen, we get activation of mast cells, release of mediators, and the typical wheal-flare response. This is the early response.

When the allergen levels stay quite high, we can also get a late response. The levels are so high that we get recruitment of other immune cells to the sites of reaction, which causes a later allergic-type response. It is associated with T cells. This is more prolonged: from 6-8 hours after exposure, it can last for up to 24 hours.

Question 23

Describe the entire immune response to allergens.

Answer 23

We have primary exposure to the allergen, so we get sensitisation. There are activation of different cells; dendritic cells present the antigen to the T cells in an environment that is more likely to produce an allergic response or a Th2 response.
Those T cells produce IL-4 and IL-13, which cause B cells to release IgE. The IgE lines the mast cells, ready for that secondary allergen exposure. When that happens, you get activation of mast cells, and release of inflammatory mediators.
This results in an acute allergic reaction, which is characterised by wheezing and sneezing, urticaria, rhinorrhea and conjunctivitis.

We also get recruitment of other immune cells such as eosinophils and other mast cells, which mediates the allergic response for a longer period of time.
This results in a chronic allergic reaction, in which the primary cell is the Th2 immune cell which recruits the other cells. This leads to more prolonged wheezing, sustained blockage of the nose, and eczema.

Question 24

List the effector mediators produced by mast cells during the early and late phase, and what they do.

Answer 24

EARLY PHASE:
Histamine:
- increase vascular permeability
- cause smooth muscle contraction

Leukotrienes:

• increase vascular permeability
• cause smooth muscle contraction
• stimulates mucus secretion

Prostaglandins:
- chemoattractants for T cells, eosinophils and basophils

LATE PHASE:
IL-4, IL-13:
- promotes Th2
- promotes IgE

TNF-α:
- promotes tissue inflammation

Question 25

Describe the different effects of mast cell activation on different tissue.

Answer 25

GI TRACT:

• increase fluid secretion
• increased peristalsis

This leads to:
- expulsion of gastrointestinal tract contents (diarrhoea, vomiting)

AIRWAYS:

• decreased diameter
• increased mucus secretion

This leads to:
- congestion and blockage of airways (wheezing, coughing, phlegm)

BLOOD VESSELS:

• increased blood flow
• increased permeability

This leads to:

• increased fluid in tissues causing increased flow of lymph to lymph nodes
• increased cells and protein in tissues
• increased effector response in tissues

Question 26

Describe eosinophils.

Answer 26

They are located in the tissues.

They are recruited to the sites of allergic reactions.

They express FcεRI upon activation.

Question 27

Describe the effector functions of eosinophils.

Answer 27

1. They release highly toxic granule proteins and free radicals upon activation to kill microorganisms/parasites, but cause tissue damage in allergic reactions.
2. They synthesise and release prostaglandins, leukotrienes and cytokines in order to amplify the inflammatory response by activating epithelial cells and recruiting leukocytes.

Question 28

Describe the late phase of the allergic response.

Answer 28

The late phase of the allergic response is T-cell mediated.

It mostly consists of allergen specific Th2 cells.
These cells recruit other cells by cytokine release to potentiate further responses in the tissue, causing a chronic allergic response.

Question 29

Define asthma.

Answer 29

It is a state of reversible bronchial hyper-reactivity resulting from a persistent inflammatory process in response to a number of stimuli in a genetically susceptible individual.

Question 30

What are the two types of asthma?

Answer 30

We have atopic and non-atopic (allergic and non-allergic).

Non-atopic includes:

• occupational
• exercise-induced
• nocturnal asthma
• post-bronchiolitic
• wheeze (commonly seen in children with a viral infection)

Question 31

What are some characteristics of allergic asthma?

Answer 31

CHARACTERISTICS:
- episodes of wheezy breathing
- narrowing of the airways
- rapid changes in airway obstruction
severity varies 
- slight wheeziness to asthma attack
- common allergens causing asthma include: pollen, HDM (house dust mite), plants, some foods

Question 32

Describe the acute responses of allergic asthma.

Answer 32

It occurs within seconds of allergen exposure.

It results in airway obstruction and breathing difficulties, caused by allergen-induced mast cell degranulation in the submucosa of the airways.

Question 33

Describe the chronic responses of allergic asthma.

Answer 33

It is the chronic inflammation of the airways.

It is caused by the activation of eosinophils, neutrophils, Th2 cells and other leukocytes.

The mediators released by these cells cause airway remodelling, permanent narrowing of the airways, and further tissue damage.

You can get subepithelial fibrosis (below the epithelium). This means that the airway becomes permanently constricted, and unable to relax.
Further episodes of allergic reactions will further damage the airways.

Question 34

What is the difference between a normal airway and an obstructed airway?

Answer 34

In an obstructed airway, you get contraction of the smooth muscle, oedema of the submucosa, and you get increased mucus production. All of these factors serve to reduce the calibre of the airways, so you get an obstructed airway. This causes restriction of airflow and wheezing.

Question 35

How would you treat an allergy in the clinic?

Answer 35

Blockage of effector pathways:
- inhibit effects of mediators on specific receptors
- anti-histamine (block the histamine H1 receptor)
- inhibit mast cell degranulation (by stabilising the mast cell wall)
- mast cell stabilizer (e.g. chromoglycate)
inhibit synthesis of specific mediators (important for the recruitment of others cells)
lipoxygenase inhibitors (e.g montelukast)

We can use steroids – they act directly on DNA to increase transcription of anti-inflammatory mediators (e.g. IL-10) and decrease transcription of pro-inflammatory mediators (e.g prednisolone).

We can also bronchodilators – they reverse the acute effect of allergy on the airways (e.g B2 agonist salbutamol) – it is the first line of care.

Finally, you can use immunotherapy – it reverses the sensitisation to allergen by means of tolerising exposure.