L17 - Allergy

Question 1

Allergy: what is it, what is it caused by, and what types are there?

Answer 1

Immune responses from harmless substances

Mast cells - get activated and then release their chemical mediators

• Type 1 - hypersensitivity (IgE/mast cells)
• Type 2 – IgG mediated
• Type 3 - IgG mediated - soluble antigen
• Type 4 - cell-mediated

Question 2

Type I allergy: what are they caused by, how frequent are they, and how severe are they?

Answer 2

Excessive immune response to harmless antigens (allergens)

Common

Often harmless and just irritating but systemic responses can result in death (anaphylaxis)

Question 3

What are the phases of type 1 immunity?

Answer 3

1 - Sensitisation: Production of Ag specific IgE:

• Exposure to allergen leads to stimulation of Type 2 helper T cells (Th2)
• Th2 cells make Interleukin-4 (IL-4) and help B cells produce antibody -Immunoglobulin E (IgE)
• B cells produce IgE that recognise the allergen
• IgE circulates in the blood and associates with Mast cells in mucosal (e.g. Airways, GI tract) and connective (e.g. Skin) tissues via FcεR (receptor to constant region of IgE)

2 - Re-Exposure and Activation of inflammatory response:
* Allergen binds to IgE on Mast cells (in skin, airways, GI tract)
* Mast cells specialise in releasing mediators of inflammation when the IgE/FcεR on their surface is cross-linked by allergen binding
* Mast cell releases its chemical arsenal (HCLL)

Question 4

Asthma: what type of allergy is it, what part of the body does it affect, what may it be caused by, where is asthma prevalence lower than expected, what symptoms are there, and what is it mediated by?

Answer 4

Type I

Airway hypersensitivity

Link between eosinophils in asthma due to altered exposure of short chain fatty acid derived from microbiome

Very low prevalence of asthma in populations highly exposed to microbial environments (farm children and Amish populations)

Lung epithelium inflammation, smooth muscle contraction, mucus production

IgE - mediated

Question 5

Anaphylaxis: what is it and what is it caused by?

Answer 5

Dilation of blood pressure resulting in a blood pressure drop, unconsciousness, and airway narrowing

Systemic responses to an allergen because of large amounts of histamine

Question 6

Food allergies

Answer 6

Rarer than other type I hypersensitivities

Question 7

Advice on early exposure to peanuts

Answer 7

Eating peanuts in early life may result in reduced likelihood of allergy

Question 8

Hypersensitivities: in what cases can they have clinical implications?

Answer 8

• Allergies to commonly used drugs e.g. penicillin or quinidine
• Allergic responses to e.g. egg proteins in seasonal flu vaccines

Question 9

Type II hypersensitivity: what are they caused by, what are they associated with, and what are the three major syndromes?

Answer 9

Reacting with antigens on cells or tissue

Production of IgG or IgM

• Blood transfusion reactions
• Haemolytic disease of the newborn
• Haemolytic anaemia
• Drug induced hypersensitivity

Question 10

Blood transfusion reactions

Answer 10

Usually IgM mediated

Binds to transfused RBC

IgM good at fixing complement i.e. complement activated

Causes fever, chills, nausea, vomiting

Question 11

Hemolytic disease of the new born: what is it prevented by and what is it caused by?

Answer 11

Preventable by giving mother anti-Rh Ag antibodies before birth - these bind to any free foetal red blood cells and destroy them before they sensitise mother

A rhesus negative mum has a rhesus positive partner and creates antibodies to the rh antigen is the baby is rhesus positive/ first pregnancy will sensitise the mum with second pregnancy potentially having issues where the anti-Rh antibodies attack foetal RBCs and cause anaemia of the new born

Question 12

Type III hypersensitivity: what are they caused by, and what types are there?

Answer 12

Immune complexes of antigen and antibody

• Systemic disease e.g. infection e.g. malaria or in response to serum administration (serum sickness)
• Local disease e.g. repeated inhalation of antigen, Pigeon Fancier’s disease- dried faecal antigens, and Farmer’s lung- mould spores in hay

Question 13

Type III Hypersensitivity - Serum Sickness: how does it wotk?

Answer 13

• Animal serum stimulates antibody response
• 2nd dose of serum
• Antibodies bind to serum proteins
• Form immune complexes
• Complexes deposited in blood vessels e.g. skin, kidney and joints

Question 14

Type IV hypersensitivity: what is it, what is it involved with, and how long does it take to activate?

Answer 14

Delayed Hypersensitivity after reacting to antigens, can be harmless or other types

Does not involve antibody - involves Th, Tc and macrophages

Takes 24-72h

Question 15

Allergy testing: what is an example, how do sensitive people react, and what is the later reaction?

Answer 15

Skin prick test –allergen is introduced to the epidermis by lancet

Sensitive - exhibit a wheal and flare reaction within minutes (lasts for 1h)

Replaced with a late phase reaction (4-6h later)

Question 16

Allergies: are they caused by genetics?

Answer 16

Likelihood of allergy increases with two atopic parents - in identical twins – concordance of atopy is 60%

Many genes involved - MHC genes, non-MHC genes, etc

Therefore genetics is important but environment must also play a role

Question 17

Allergies: are they caused by environment?

Answer 17

Prevalence of allergy/asthma has increased dramatically over the last 50 years - suggesting an environmental contribution

The exposome, cumulative exposure to the environment, may have a large impact

Question 18

The hygiene hypothesis: what is it and what contrary arguments are there for it?

Answer 18

The hygiene hypothesis was developed to explain observations that people in small families in urban dwellings developed more allergies than those with big families or in rural areas

Exposure to microbes in the environment (“being dirty”) might help to prevent hyper-sensitivities?

• South/Latin America has more asthma than Spain/Portugal, despite similar culture and poorer living conditions. (but high pollution)
• Asthma is increasing in African Americans living in poverty

Question 19

Old Friend’s Hypothesis

Answer 19

Reduced microbial diversity in our microbiome due to western diets and urbanisation may result in higher allergy prevalence

Question 20

Microbiome: in what ways may its alteration result in allergies?

Answer 20

Babies given significant antibiotics in early life more likely to develop allergies (altered microbiome)

Question 21

Why bother with certain methods of protection (Th2 / IgE & Mast cells) then?

Answer 21

Th2 immunity is important for resistance to parasitic worm infection - Th2 & IgE-associated responses are effective at eliminating parasites

“Allergic” IgE responses evolved to protect us against parasite infection

Question 22

Current & future therapies of allergy

Answer 22

• Avoidance
• Low dose allergen therapies (de-sensitisation) - intra-muscular injection of low dose allergen, monthly for 2-5 years which raises IgG, rather than IgE
• Antibody therapy - Duplimab to block cytokine (IL4) that promote Th2 cell activation of B cells
• Oral Tolerance - Oral/mucosal exposure to antigens normally leads to T cell Tolerance (regulatory T cells), low doses of ingested antigen is used to re-train the immune system to be tolerant of allergens
• Treat symptoms:
• Anti-histamines: prevent to actions of histamine
• Steroid anti-inflammatory drugs: reduce the inflammation
• Adrenaline / epinephrine (Epi-Pen): cause vasoconstriction

Question 23

How can we improve our immune system / prevent allergy?

Answer 23

Diversify our microbiome

a cohort of approx 1,200 infants research suggested that a dog might be a baby’s best friend when it comes to avoiding allergies

Dogs (and, to a lesser extent, cats) increase the diversity of bacteria and lower the diversity of fungi in the houses where these babies are raised and this may be associated with a reduced chance of allergy….