School of Medicine, University of Aberdeen 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

IgE Allergen Mast Cell Histamine release Crosslinking

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 Inflammation Beneficial Removal of insult RESOLUTION Harmful Persistence or constant 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

IgE Allergen Mast Cell Histamine release Crosslinking

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 – FceR1 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

Cytokines Granule proteins IL-3, IL-4, IL-5 MBP, ECP, EPO GM-CSF, IL-6 IL-12, TGF-b Granule proteins MBP, ECP, EPO Epithelial damage/loss Muscarinic M2 dysfunction/ AHR Attract/activate eosinophils Airway remodelling, IgE, Th2 polarisation LTC4, PAF Chemokines Eotaxin, RANTES Mucus hypersecretion Airway narrowing Attract/activate pro-inflammatory cells Attract/activate eosinophils

Mast Cells Mediators: histamine, prostaglandins, PAF, LTC4 & LTD4 Mucosal oedema, vasodilation, mucus secretion, bronchial smooth muscle contraction

Attract and activate neutrophils & Mast Cells Cytokines (e.g. IL-4, IL-5, TNFa, IL-8): LTB4, PAF Attract and activate neutrophils & eosinophils

Connective tissue Mucosal Mast Cell Mast Cell Gut & lung T cell dependent Short lived <40 days 25x105 IgE receptors Lower histamine content Chondroitin sulphate Lower tryptase Ubiquitous Long lived >40 days 3x104 IgE receptors High histamine content Heparin & high 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.