1. School of Medicine, University of Aberdeen
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
Mast Cell
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
Mast Cell
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

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

30. 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

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

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

33. 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

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

35. 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

36. 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

37. 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.

38. 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

39. 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,

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

41. 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”

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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.