Allergic Disease

Dr Garry M. Walsh,

School of Medicine, University of Aberdeen

Atopy

• The predisposition to produce high quantities of Immunoglobulin (Ig)-E

• Immediate (Type I hypersensitivity)

• Mast cells, basophils, eosinophils, Th2 cells

Allergy

• Allergic Disease is mediated by IgE• First described by Prausnitz & Kustner in

1921• Proposed the existence of “atopic reagin” in

serum of allergic subjects• 45 years later Ishizaka described a new

class of immunoglobulin - IgE

Allergic Disease

• Seen in 30-35% of the population

• Perennial & seasonal allergic rhinitis

• Allergic (extrinsic asthma)

• Atopic and contact dermatitis

• Urticaria

• Food intolerance

Allergy

• Elevated IgE levels seen in allergy and parasitic infection

• Binds to mast cells and basophils

• Often specific for harmless environmental factors - allergens

Mast Cell

IgEAllergen

CrosslinkingHistaminerelease

Allergic rhinitis

• Seasonal (pollen, spores) or perennial (house dust mite)

• Mucus production (Runny nose, nasal stuffiness

• Itching & sneezing

• Treat with antihistamines or nasal steroids

Urticaria

• Wheal and flare

• Itching

• Allergen-induced

• Idiopathic – pressure, cold etc.

• Food – shellfish, strawberries, peanuts

• Treat with antihistamines

Atopic dermatitis

• Allergen –induced particularly milk protein from the gut enters blood stream –deposited in skin – mast cell degranulation

• Exfoliating eczema and itching

• Treat with antihistamines

• May progress to asthma

Anaphylaxis

• Very acute and severe reaction to allergen• Peanuts, shellfish, penicillin, insect stings• Allergen moves from gut to blood stream• Massive histamine release from mast cells

and basophils• Vasodilatation leads to dramatic drop in

blood pressure• Often fatal if not treated with adrenaline

Allergens

• Environmental substances

• Usually benign

• Sub-group of individuals exhibit a hypersensitivity reaction (type 1)

Allergens

Mite faeces (digestive enzymes)

Pollen

Animal dander (cats)

Insect stings

Food

Allergy

InflammationBeneficial

Removal of insult

RESOLUTION

Harmful

Persistence orconstant exposure

HYPERSENSITIVITY

Allergy – an inappropriate immune response

Allergy – an inappropriate immune response

Allergy – an inappropriate immune response

• Parasite larvae – proteases

• House dust mite – faeces (skin) – proteases

• Pollen – proteases

• Cat saliva - proteases

Mast Cell

IgEAllergen

CrosslinkingHistaminerelease

Mast cells and basophils

Mast Cell

Mast cells 

Release pre-formed mediators (histamine) and lipids together with several TH2 cytokines

IgE

• Very low serum concentration – 0.00005 mg/ml)• Sensitises mast cells and basophils by binding via Fc

portion to high affinity receptor – FcR1• Serum half life of a few days• Binding protects IgE from destruction by serum

proteases• Sensitisation can last for many months• Detected by skin prick test or radio absorbant test

(RAST)

Skin prick test

Allergic Inflammation

• Much more complex than histamine release

• Involvement of a whole host of cells, cytokines, chemokines and mediators

Granule proteins

MBP, ECP, EPO

CytokinesIL-3, IL-4, IL-5GM-CSF, IL-6IL-12, TGF-

LTC4, PAF ChemokinesEotaxin, RANTES

Epithelial damage/loss Muscarinic M2 dysfunction/ AHR

Attract/activate eosinophilsAirway remodelling, IgE, Th2 polarisation

Attract/activate eosinophilsMucus hypersecretionAirway narrowingAttract/activate pro-inflammatory cells

Mediators: histamine, prostaglandins,

PAF, LTC4 & LTD4

Mast Cells

Mucosal oedema, vasodilation, mucus secretion, bronchial smooth muscle contraction

Mast Cells

Attract and activate neutrophils &eosinophils

Cytokines (e.g. IL-4, IL-5, TNF, IL-8): LTB4, PAF

Connective tissueMast Cell

MucosalMast Cell

Ubiquitous

Long lived >40 days

3x104 IgE receptors

High histamine content

Heparin & high tryptase

Gut & lung

T cell dependent

Short lived <40 days

25x105 IgE receptors

Lower histamine content

Chondroitin sulphate

Lower tryptase

Histamine

• Skin – wheal, erythema, pruritis• Eye - conjunctivitis, erythema, pruritis• Nose – nasal discharge, sneeze, pruritis• Lung – bronchospasm of smooth muscle

Histamine

• Therapeutic intervention in allergy often focused on blocking the effects of histamine

• Histamine also functions as a neurotransmitter in CNS

• Very important in maintaining a state of arousal or awareness

First Generation Antihistamines

• The first H1 antagonist synthesised by Bovet & Staub at the Institut Pasteur

• Too weak or toxic

• Phenbezamine first effective antihistamine

• Mepyramine maleate, diphenhydramine & tripelennamine developed in 1940’s

• Still in use today

First Generation Antihistamines

• Easily cross the blood–brain barrier.• Sedative and anticholinergic effects (sedating

antihistamines).• Short half-lives.• Limited use in the treatment of allergic

symptoms. • Still widely used, mainly as over-the-counter

products, often in combination with other drugs.

Second Generation Antihistamines

• Highly effective treatments for allergic disease • Do not cross blood-brain barrier• Lack significant CNS & anticholinergic effects• Long half life• Among the most frequently prescribed and

safest drugs - expensive

Other treatments

• Nasal steroids – must be given before season – relieve nasal blockade

• Antihistamines combined with anti-leukotriene drugs

• Avoidance -mattress covers, specialised Hoovers, wood floors,

Allergic Disease

• Dramatic increase in allergic disease over the past three decades, why is this?

• Genetics• Environmental factors - pollution• Changes in Lifestyle• Occupational  

Genetics (1)

• Family history of allergic disease is a strong risk factor for developing asthma

• Danger of developing asthma particularly if one or both parents are atopic

• Children with atopic dermatitis at risk of asthma -– “the allergic march”

Genetics (2)

• No single "allergy or asthma chromosome". Several markers demonstrated in small selected populations - much further work is required

• The genetics of allergy and asthma are polygenic - influence many factors such as IgE secretion, cytokines and inflammatory cell profiles

Environment (1)

• Children & adults 90% spent time indoors• Allergens in dust (dust mite faeces) or pets (particularly

cats) - increased risk of allergic sensitization in proportion to exposure.

• Most children and adolescents with asthma sensitized to indoor allergens - avoidance often leads to improvement in airway disease.

• Modern housing generally poorly ventilated with fitted carpets and central heating - house dust mite infestation

Environment (2)

• Children exposed to tobacco smoke more likely to develop wheezing and impaired lung function

• Outdoor allergens –seasonal variation and weather• Account for 10-20% of allergic disease in Europe -

mainly hay fever. • Increased pollution not responsible for increase in

allergic disease - pollutants worsen respiratory symptoms in asthmatics and reduce lung function

Changes in Lifestyle (1)

• Hygiene hypothesis - Past 30 years - changes in pattern of childhood infection, many no longer experienced

• Exposure to certain infections may protect against the development of allergies.

• Respiratory viruses may be a risk factor for the development of asthma

• Vaccination programmes not thought to have direct effect on the development of allergic disease

Changes in Lifestyle (2)

• Intake of fresh fruit and vegetables has declined leading to lower anti-oxidant levels.

• Certain fatty acids are able to shift the immune system towards allergic susceptibility

• Food preservatives may effect gut flora leading to allergic sensitization rather than development of tolerance

Changes in Lifestyle (3)

• The immune system is severely compromised by poor nutrition

• Paradoxically the vast improvement in nutrition in the last fifty years might have led to the immune systems of some individuals "over reacting" to benign substances i.e. allergens

Conclusion

• Atopy – propensity to produce high levels of IgE from B cells

• Allergens mimic parasites – processed and presented by APC (e.g. dendritic cells)

• Orchestrated by Th2 cells – cytokine release• Effector cells – mast cells, basophils• Mediators – cytokines, histamine,

leukotrienes, PAF etc.