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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
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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 MastCell 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 • Parasite larvae – proteases • House dust mite – faeces (skin) – proteases • Pollen – proteases • Cat saliva - proteases
IgE Allergen MastCell Histamine release Crosslinking
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)
Allergic Inflammation • Much more complex than histamine release • Involvement of a whole host of cells, cytokines, chemokines and mediators
Cytokines IL-3, IL-4, IL-5 GM-CSF, IL-6 IL-12, TGF-b Granule proteins MBP, ECP, EPO Attract/activate eosinophils Airway remodelling, IgE, Th2 polarisation Epithelial damage/loss Muscarinic M2 dysfunction/ AHR Chemokines Eotaxin, RANTES LTC4, PAF 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
Mast Cells Cytokines (e.g. IL-4, IL-5, TNFa, IL-8): LTB4, PAF Attract and activate neutrophils & eosinophils
Connective tissue Mast Cell Mucosal 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.