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Allergic Disease

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

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  1. Allergic Disease Dr Garry M. Walsh, School of Medicine, University of Aberdeen

  2. Atopy • The predisposition to produce high quantities of Immunoglobulin (Ig)-E • Immediate (Type I hypersensitivity) • Mast cells, basophils, eosinophils, Th2 cells

  3. 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

  4. Allergic Disease • Seen in 30-35% of the population • Perennial & seasonal allergic rhinitis • Allergic (extrinsic asthma) • Atopic and contact dermatitis • Urticaria • Food intolerance

  5. Allergy • Elevated IgE levels seen in allergy and parasitic infection • Binds to mast cells and basophils • Often specific for harmless environmental factors - allergens

  6. IgE Allergen MastCell Histamine release Crosslinking

  7. Allergic rhinitis • Seasonal (pollen, spores) or perennial (house dust mite) • Mucus production (Runny nose, nasal stuffiness • Itching & sneezing • Treat with antihistamines or nasal steroids

  8. Urticaria • Wheal and flare • Itching • Allergen-induced • Idiopathic – pressure, cold etc. • Food – shellfish, strawberries, peanuts • Treat with antihistamines

  9. 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

  10. 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

  11. Allergens • Environmental substances • Usually benign • Sub-group of individuals exhibit a hypersensitivity reaction (type 1)

  12. Allergens Mite faeces (digestive enzymes) Pollen Animal dander (cats) Insect stings Food

  13. Allergy Inflammation Beneficial Removal of insult RESOLUTION Harmful Persistence or constant exposure HYPERSENSITIVITY

  14. Allergy – an inappropriate immune response

  15. Allergy – an inappropriate immune response

  16. Allergy – an inappropriate immune response • Parasite larvae – proteases • House dust mite – faeces (skin) – proteases • Pollen – proteases • Cat saliva - proteases

  17. IgE Allergen MastCell Histamine release Crosslinking

  18. Mast cells and basophils

  19. Mast Cell

  20. Mast cells  Release pre-formed mediators (histamine) and lipids together with several TH2 cytokines

  21. 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)

  22. Skin prick test

  23. Allergic Inflammation • Much more complex than histamine release • Involvement of a whole host of cells, cytokines, chemokines and mediators

  24. 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

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

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

  27. 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

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

  29. 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

  30. 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

  31. 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.

  32. 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

  33. 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,

  34. Allergic Disease • Dramatic increase in allergic disease over the past three decades, why is this? • Genetics • Environmental factors - pollution • Changes in Lifestyle • Occupational

  35. 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”

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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.

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