Case 7- Allergies

Question 1

How is histamine produced?

Answer 1

When the antigen binds to the mast cell there is degranulation, one of the main mediators released is Histamine. Histamine then causes allergy symptoms

Question 2

Effect of histamine release- general

Answer 2

1) Itchiness (Pruritus)
2) Increased smooth muscle contraction-bronchospasm
3) Increased gastric acid secretion- diarrhoea and vomiting
4) Raised Tryptase

Question 3

Effect of histamine release- blood vessels

Answer 3

Increased blood flow and permeability in the blood vessels. Fluid shifts into the interstitial space causing pulmonary oedema, swollen eyes and lips

Question 4

Effect of histamine release- mucus

Answer 4

In the eyes, nasal passages and airways there is decreased diameter and increased mucus secretion. This causes congestion and blockage of airways (wheezing, coughing and phlegm). There is swelling and mucus secretion in nasal passages.

Question 5

Immune tolerance and allergy

Answer 5

A complex system causing suppresion of cellular or humoral immune responses. Allergy occurs due to a failure of this response.

Question 6

Allergic reaction

Answer 6

A hypersensitivity reaction initiated by immunological mechanism

Question 7

Allergen

Answer 7

An antigen that triggers an allergic reaction

Question 8

Atopy

Answer 8

a tendency to develop an allergic disease

Question 9

Effects of atopy

Answer 9

Atopy is clinically associated with allergic asthma, eczema and allergic rhinitis. It occurs in 20-30% of the population.

Question 10

The atopy/allergic march

Answer 10

Shows the natural progression of allergies:

Eczema -> Food allergy -> Rhinitis -> Asthma

Question 11

Type 1 allergic reaction- IgE mediated hypersensitivity

Answer 11

It’s split into sensitation stage and the Re-exposure stage
• On exposure to the allergen, the APC processes the antigen and presents it to the TH2 cell and bind together. (sensitisation).
• When it binds together the TH2 cell release IL-4 and IL-12, these mediators activate the B cell. (sensitisation).
• The B cell proliferates and differentiates into plasma cells that synthesize and secrete IgE antibodies (sensitisation).
• The IgE binds to the mast cells by the Fc region, sensitizing the mast cells. (sensitisation).
• Upon subsequent exposure to the allergen, mast cells with IgE bind to the antigen undergo degranulation releasing inflammatory molecules resulting in allergy symptoms. (Re-exposure)

Question 12

Examples of type 1 hypersensitivity reactions

Answer 12

Hay fever, Asthma, Hives and Angiodema (swollen lips and eyes) these are localised reactions. Systemic reactions would be anaphylaxis.

Question 13

Urticaria (hives)

Answer 13

You get it with nettle stings and allergic rashes. It is circumscribed, raised erythematous plaques often with central pallor. It is very itchy. Not all urticaria is caused by allergy for example, stress and viral infection. Can be caused by type 1 hypersensitivity reactions

Question 14

Angioedema

Answer 14

Usually associated with urticaria, its swollen lips and eyes. There is the involvement of the deeper dermis and subcutaneous tissue. Not all angioedema is allergy.

Question 15

Anaphylaxis

Answer 15

A severe life threatening, generalised or systemic hypersensitivity reaction. It is characterised by rapidly developing, life threatening air way, breathing and circulatory changes or gastrointestinal changes usually associated with skin and mucosal changes. The trigger may not always be identified.

Question 16

Type 2 Hypersensitivity: Cytotoxic, antibody mediated

Answer 16

Involves antibody (IgG or IgM) mediated destruction of self cells.
• IgG or IgM (antibodies) bind to either an intrinsic or extrinsic tissue. In the intrinsic tissue they will detect the self antigen as a foreign antigen, there will be a failure in immune tolerance. In the extrinsic tissue the foreign antigen will resemble the host cell, it will get absorbed onto cells as part of the infection of a pathogen. 
•  The antibodies bind to the antigens, forming Ag-Ab complexes promoting the classical  pathway of complement activation. This will eliminate cells presenting foreign antigens.
• Mediators of acute inflammation are generated causing cell lysis and death.

Question 17

Examples of a type 2 allergic reaction- transfusion reactions

Answer 17

Transfusion reaction produced by mismatched blood. It will destroy foreign RBC by complement-mediated lysis triggered by IgG. This produces fever and intravascular clots. The free Hgb produced will either pass in the urine- haemoglobinuria or breaks down into bilirubin which can be toxic

Question 18

How long is a type 2 allergic reaction

Answer 18

Hours or days

Question 19

Examples of type 2 allergic reactions- drugs

Answer 19

• Drug induced Thrombocytopenis- drugs (antibiotics) bind to the surface of platelets the IgG binds to the drug and mediates destruction of platelets by phagocytes through binding of Fc receptors on the cell surface

Question 20

Examples of type 2 allergic reactions- diseases

Answer 20

• Autoimmune haemolytic anaemia- the antibodies bind to RBC membrane antigens causing cell lysis and death.
• Graves disease- antibodies produced bind to thyroid hormone receptors.
• Goodpasture’s syndrome- the antibodies produced bind to the kidney/lungs basement membrane receptors

Question 21

Type 3 Hypersensitivity- immune complexes

Answer 21

• IgG/IgM (antibodies) binds to antigens in the circulation producing immune (Antigen-antibody) complexes.
• Insoluble immune complexes form in the blood and are deposited in various tissues, typically the skin, kidney and joints.
• It binds to Fc receptors on leukocytes (i.e. mast cells) leading to an inflammatory response and damage to the cell.

Question 22

Type 3 allergic reaction example- post-streptococcal glomerulonephritis

Answer 22

After a streptococcus infection there are Streptococcal cell wall antigens circulating in the blood. The antibodies in our body bind the antigen forming an immune complex, it gets trapped in the kidneys causing inflammation.

Question 23

Other examples of type 3 allergic reactions

Answer 23

1. Reactive or rheumatoid arthiritis: Bacterial antigens form immune complexes and get stuck in the joints
2. SLE- DNA/nucleoprotein antigens circulate in the blood.
3. Henoch Schonlien purpria- After a viral infection the antigens react with IgA to form an immune complex which gets trapped under the skin forming a vasculitic rash. In children.

Question 24

How long does a type 4 hypersensitivity reaction take

Answer 24

Takes 2-3 days days

Question 25

Type 4 Hypersensitivity reaction: The delayed type

Answer 25

It is not antibody mediated but is a T-cell mediated response. There are two stages, the sensitisation stage and the effector stage. • Antigen is processed by the antigen presenting cell- Macrophages. (sensitisation) • The antigen is then presented to the T helper. (sensitisation) • The T helper cell releases mediators and more T helper cells (sensitisation). • The T helper cell binds to the resting Macrophage which then releases mediators to form the activated Macrophage. The T help cell releases mediators and activates the T-cytotoxic cell • The cytoxic T cell and activated Macrophage causes direct cell damage.

Question 26

Type 4 hypersensitivity reaction- Tuberculin skin test (Mantoux test)

Answer 26

Aids in the diagnosis of TB. There is intradermal administration of the tuberculin to the forearm. A type 4 hypersensitivity reaction occurs and you measure the transverse diameter of the induration (blister). Its read between 48-72 hours.

Question 27

Type 4 hypersensitivity reaction- Contact hypersensitivity / dermatitis (i.e. nickel)

Answer 27

In nickel contact dermatitis the antigens penetrate the skins and are presented by Langerhans cells to the T-cells. This releases inflammatory mediators activating the macrophage and T-cytotoxic cell causing localised dermatitis. It usually develops 24 hours after exposure, peaking at 73 hours.

Question 28

Where is histamine found?

Answer 28

Histamine is found in high concentrations in the lungs, skin and GI tract, Histamine is mostly found in mast cells and basophils. Non-mast histamine is found in cells of the stomach and the histaminergic neurons of the brain.

Question 29

When is histamine released (complement proteins)

Answer 29

Stimuli for release includes complement proteins (C3a and C5a) that interact with specific surface receptors and the combination of antigen and cell-fixed IgE antibodies.

Question 30

What does histamine bind to

Answer 30

It binds to H1, H2 or H3 receptors on the target cell

Question 31

Effect of H1 receptor

Answer 31

The H1 receptor causes increased vascular permeability, Vasodilation and contraction of most smooth muscle.

Question 32

Effect of H2 receptor

Answer 32

The H2 receptors cause stimulation of gastric secretion and cardiac stimulation.

Question 33

How can you divide antihistamines

Answer 33

Into first and second generation. H1 antihistamines can either be neural receptor antagonists or inverse agonists

Question 34

Activity of H1 receptor

Answer 34

Since the H1 receptor displays constitutive activity, is able to produce a response in the absence of a bound ligand. Normally, histamine binds to the H1 receptor and heightens the receptors activity

Question 35

How do Histamine neural receptor antagonists work

Answer 35

They bind to the H1 receptor and block Histamine's effect. The majority of anti-histamine

Question 36

How do Histamine inverse agonists work

Answer 36

They bind to the H1 receptor reducing its activity, the opposite effect to histamine

Question 37

When to take antihistamine

Answer 37

Some patients may need to take daily antihistamines if they have significant allergic symptoms regularly (allergy to dust). Antihistamines can also be used on a as needed basis for those who experience occasional symptoms or symptoms triggered by exposure to certain irritants such as animal hair, plants/flowers, medication and food products.

Question 38

H2 receptor antagonist

Answer 38

A second types antihistamine is primarily used for suppressing acid production in the stomach and treated acid related diseases like ulcers. Example=omeprazole

Question 39

Trends in allergies

Answer 39

They are becoming more common, there are also more cases of anaphylaxis

Question 40

Most common allergies

Answer 40

Eczema, asthma, Hay fever (allergic rinitus), food allergy and animal allergy.

Question 41

Acute allergic conditions

Answer 41

Anaphylaxis, food allergies, oral allergy syndrome, latex allergy and drug allergy.

Question 42

Chronic allergic conditions

Answer 42

Rhino-conjunctivitis, Asthma, Eczema, food allergies and allergic enteropathy (Eosinophilic oesophagitis/gastritis, Food protein induced Enterocolitis syndrome and Proctocolitis).

Question 43

Why you may not get symptoms with sensitisation?

Answer 43

Sensitisation (evidence of immunological notification) is different from clinical disease. So whilst you may be IG positive you may not be having not symptoms. They are both allergies. The inflammatory cells cause the allergic symptoms

Question 44

The immediate IgE dependent effects of mast cell mediators

Answer 44

Vasodilation, vessel leakage, increased mucus secretion, smooth muscle contraction and itchiness. Wheel and flair rash- swollen and red. They will get stridor due to swelling of the larynx due to smooth muscle contraction

Question 45

Delayed type, T cell dependent/mixed symptoms

Answer 45

In the skin you’ll have eczema flares and a rash. In the gut you have Mucous/blood stools, diarrhoea, vomiting, failure to thrive, Malabsorption, Dysphagia and abdominal pain.

Question 46

Intolerance

Answer 46

A non-immune mediated reaction which can be enzymatic, pharmacological and indefined

Question 47

Intolerance- Enzyme deficiency

Answer 47

Lactose intolerance- dont have the enzyme lactate so cant digest lactose effectively Favism- A G6PD deficiency, haemolysis after fava bean ingestion, presents with jaundice

Question 48

Intolerance- Pharmacological reactions

Answer 48

When certain substances cause an adverse reaction. This can be triggered by caffeine which gives them a raising pulse, headache and anxiety. You can also get reactions from biogenic amines which are substances in cheese, wine and chocolate= Tyramine, Histamine, Phenylethylamine. Symptoms include flushing, headache, nausea, vomiting and diarrhoea,

Question 49

Intolerance- undefined

Answer 49

Generally adverse reactions to additives and food colouring agents. Include Tartrazine, Monosodium glutamate, Nitrates and nitrites, Sulphites, Benzoic acid and benzoates.