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.