Transcript No Slide Title

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
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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
Crosslinking
Histamine
release
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
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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
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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
Harmful
Removal of insult
Persistence or
constant exposure
RESOLUTION
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
Crosslinking
Histamine
release
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
Granule proteins
MBP, ECP, EPO
Cytokines
IL-3, IL-4, IL-5
GM-CSF, IL-6
IL-12, TGF-b
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
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
Ubiquitous
T cell dependent
Long lived >40 days
Short lived <40 days
3x104 IgE receptors
25x105 IgE receptors
High histamine content
Lower histamine content
Heparin & high tryptase
Chondroitin sulphate
Lower tryptase
Histamine
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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
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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 antileukotriene 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.