Hypersensitivity Reactions (Asthma & Allergy)

Question 1

What is hypersensitivity?

Answer 1

an inappropriate immune response to non-infectious antigens that results in tissue damage and disease

Question 2

What are the four types of hypersensitivity?

Answer 2

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 3

Describe Type 1 hypersensitivity.

Answer 3

immune response characterised by IgE antibodies which bind mast cells

subsequent exposure to an allergen to which these IgE antibodies are specific causes the IgE antibodies to cross-link and activate mast cells causing cell degranulation and release of inflammatory mediators

Question 4

Example of a type I hypersensitivity reaction

Answer 4

Allergic rhinitis
Asthma
Anaphylaxis (when the reaction is exaggerated)
Eczema

Question 5

How would you induce an immediate hypersensitivity reaction?

Answer 5

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 surrounding plasma fluid into the area, causing a wheal. Vasodilatation also occurs, resulting in a flare.

Question 6

Describe Type 2 hypersensitivity.

Answer 6

immune response characterised by IgG antibodies generated against altered components of human cells
-e.g. penicillin drug attaches to red cell surface, immune response recognises this as an allergen and coats red cells with IgG, activating other immune cells such as macrophages and complement

Question 7

Examples of a type II hypersensitivity reaction

Answer 7

• some drug allergies (such as penicillin)

Question 8

Special type II hypersensitivity reaction

Answer 8

Involves IgG antibodies directed at cell-surface receptors, disrupting the normal functions of the receptor by either:

• uncontrollable activation of receptor
• blocking receptor function

Question 9

Examples of special type II hypersensitivity reaction

Answer 9

Myasthenia Gravis

Graves’ Disease (thyrotoxicosis)

Haemolytic Disease of the newborn

Question 10

Describe Grave’s disease.

Answer 10

Type II hypersensitivity reaction:
-autoimmune disease caused by IgG antibodies which stimulate TSH receptors on the thyroid gland, leading to excess levels of thyroxin in the blood with no negative feedback → thyrotoxicosis

Question 11

Describe Myasthenia Gravis.

Answer 11

Type II hypersensitivity reaction:
-autoimmune disease caused by IgG antibodies which bind to and block the nicotinic Ach receptors on the post-synaptic membrane at the neuromuscular junction, blocking nerve transmission and resulting in nerve paralysis

Question 12

What is haemolytic disease of the newborn?

Answer 12

Type II hypersensitivity reaction:

1) RhD-ve mother pregnant with RhD+ve child
2) When the embryonic chorion disrupts at birth, there is leakage of foetal RhD+ve red cells into the maternal circulation, and the maternal B cells produce anti-RhD+ve antibodies
3) If pregnant with ANOTHER RhD+ve child, the antibodies stimulated from the first pregnancy can cross the placenta and attack the red cells bearing the RhD+ve antigen, causing anaemia and often death in the child

Question 13

Describe Type 3 hypersensitivity.

Answer 13

immune response to a soluble antigen (e.g. vaccine) to which you have ALREADY generated an IgG response

on subsequent exposure to same antigen (e.g. boosting dose), large amounts of antigen and antibody (IgG) at the site of injection results in formation of immune complexes which can activate immune cells around the capillaries to cause an inflammatory response, activating complement and recruiting phagocytes to clear the immune complexes

Question 14

Example of type III hypersensitivity reaction

Answer 14

Arthus reaction
Serum sickness
Farmer’s lung

Question 15

Describe Arthus reaction.

Answer 15

A type III hypersensitivity reaction:

• locally injected (intradermal) antigen in immune individual with large amounts of IgG in circulation →local formation of immune complexes causing activation of mast cells
• mast cells release inflammatory mediators and recruit inflammatory cells (complement and phagocytes) causing localised inflammation, increased blood vessel permeability and blood flow (oedema), and also phagocytosis
• platelets also accumulate, leading to the occlusion of the small blood vessels, haemorrhage and the appearance of purpura

Question 16

Describe serum sickness.

Answer 16

Type III hypersensitivity reaction:

• large intravenous dose of soluble antigen (e.g. anti-venom) in individual with large amounts of IgG in circulation
• small immune complexes form with antigen in excess
• immune complexes deposited in tissues (e.g. blood vessel walls)
• tissue damage is caused by complement activation and the subsequent inflammatory responses

Question 17

Describe farmer’s lung.

Answer 17

Type III hypersensitivity reaction:
-mould (antigen) from hay inhaled into lungs, forming immune complexes within the alveoli which stimulates an inflammatory response inside the lung, resulting in fibrosis, granulation and inflammation

Question 18

What does the pathology of a type III hypersensitivity reaction depend on?

Answer 18

DOSE of antigen
ROUTE of delivery

Subcutaneous (e.g. vaccine)
-localised Arthus reaction with a localised area of perivascular oedema and inflammation

Intravenous delivery of antigen (e.g. anti-venom)
-vasculitis, nephritis and arthritis

Inhaled antigen (e.g. Farmer's lung)
-inflammation of alveolar/capillarity interface

Question 19

Describe Type 4 hypersensitivity.

Answer 19

Delayed-type hypersensitivity, depending on Th1 or Th2 cells.

Th1 delayed type hypersensitivity (e.g. intracellular bacteria)

• antigen processed by APCs which stimulate Th1 cells
• Th1 cells produce cytokines such as IFN-𝛾 and IL-12 which stimulate and activate macrophages
• macrophages release further cytokines, chemokines and cytotoxins which recruit phagocytes and plasma

Th2 delayed type hypersensitivity (e.g. worms)

• soluble antigen processed by APCs which stimulate Th2 cells
• Th2 cells produce cytokines such as IL-4, IL-5 and eotaxin which are important in IgE production, eosinophil activation and recruitment to sites of inflammation

Question 20

Example of Th1 delayed type hypersensitivity

Answer 20

Tuberculin reaction (Mantoux Test) to tuberculosis

Tuberculoid Leprosy to leprosy bacilli resulting in typical granuloma response and induration at the site of bacilli

Question 21

Describe the Mantoux test.

Answer 21

intradermal test to determine recent or past exposure to tuberculosis (TB)

• local subscutaneous injection of tuberculin extract
• wait to see if there is a reaction (localised inflammation and ulceration), showing that the person has previously been sensitised to the antigen

Question 22

Example of Th2 delayed type hypersensitivity

Answer 22

Allergic contact dermatitis (e.g. Nickel, poison ivy)

*people who have been previously sensitised to substance in poison ivy called pentadecacatechol develop a strong contact dermatitis type reaction when exposed again

Question 23

Describe tuberculoid leprosy.

Answer 23

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 24

Describe contact dermatitis.

Answer 24

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

Question 25

Define an allergy.

Answer 25

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 26

Describe IgE.

Answer 26

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 27

Describe how allergen-specific IgE is produced?

Answer 27

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 28

What causes allergic sensitisation?

Answer 28

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 29

What role does filaggrin have in atopic dermatitis?

Answer 29

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 30

What makes dendritic cells pro-allergic?

Answer 30

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 31

Describe the two phases of the allergic response.

Answer 31

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 32

Describe the entire immune response to allergens.

Answer 32

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 33

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

Answer 33

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 34

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

Answer 34

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 35

Describe eosinophils.

Answer 35

They are located in the tissues.

They are recruited to the sites of allergic reactions.

They express FcεRI upon activation.

Question 36

Describe the effector functions of eosinophils.

Answer 36

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 37

Describe the late phase of the allergic response.

Answer 37

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 38

Define asthma.

Answer 38

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 39

What are the two types of asthma?

Answer 39

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 40

What are some characteristics of allergic asthma?

Answer 40

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 41

Describe the acute responses of allergic asthma.

Answer 41

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 42

Describe the chronic responses of allergic asthma.

Answer 42

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 43

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

Answer 43

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 44

How would you treat an allergy in the clinic?

Answer 44

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.