Allergic DiseaseDr Garry M. Walsh,School of Medicine, University of Aberdeen

AtopyThe predisposition to produce high quantities of Immunoglobulin (Ig)-E

Immediate (Type I hypersensitivity)

Mast cells, basophils, eosinophils, Th2 cells

AllergyAllergic Disease is mediated by IgEFirst described by Prausnitz & Kustner in 1921Proposed the existence of atopic reagin in serum of allergic subjects45 years later Ishizaka described a new class of immunoglobulin - IgE

Allergic DiseaseSeen in 30-35% of the populationPerennial & seasonal allergic rhinitisAllergic (extrinsic asthma)Atopic and contact dermatitisUrticariaFood intolerance

AllergyElevated IgE levels seen in allergy and parasitic infectionBinds to mast cells and basophilsOften specific for harmless environmental factors - allergens

Mast CellIgEAllergenCrosslinkingHistaminerelease

Allergic rhinitisSeasonal (pollen, spores) or perennial (house dust mite)Mucus production (Runny nose, nasal stuffinessItching & sneezingTreat with antihistamines or nasal steroids

UrticariaWheal and flareItchingAllergen-inducedIdiopathic pressure, cold etc.Food shellfish, strawberries, peanutsTreat with antihistamines

Atopic dermatitisAllergen induced particularly milk protein from the gut enters blood stream deposited in skin mast cell degranulationExfoliating eczema and itchingTreat with antihistaminesMay progress to asthma

AnaphylaxisVery acute and severe reaction to allergenPeanuts, shellfish, penicillin, insect stingsAllergen moves from gut to blood streamMassive histamine release from mast cells and basophilsVasodilatation leads to dramatic drop in blood pressureOften fatal if not treated with adrenaline

AllergensEnvironmental substances

Usually benign

Sub-group of individuals exhibit a hypersensitivity reaction (type 1)

AllergensMite faeces (digestive enzymes)PollenAnimal dander (cats)Insect stingsFood

Allergy

InflammationBeneficial

Removal of insult

RESOLUTIONHarmful

Persistence orconstant exposure

HYPERSENSITIVITY

Allergy an inappropriate immune response

Allergy an inappropriate immune response

Allergy an inappropriate immune responseParasite larvae proteases

House dust mite faeces (skin) proteases

Pollen proteases

Cat saliva - proteases

Mast CellIgEAllergenCrosslinkingHistaminerelease

Mast cells and basophils

Mast Cell

Mast cellsRelease 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 FceR1Serum half life of a few daysBinding protects IgE from destruction by serum proteasesSensitisation can last for many monthsDetected by skin prick test or radio absorbant test (RAST)

Skin prick test

Allergic InflammationMuch more complex than histamine release

Involvement of a whole host of cells, cytokines, chemokines and mediators

Granule proteinsMBP, ECP, EPOCytokinesIL-3, IL-4, IL-5GM-CSF, IL-6IL-12, TGF-b

LTC4, PAFChemokinesEotaxin, RANTESEpithelial damage/loss Muscarinic M2 dysfunction/ AHRAttract/activate eosinophilsAirway remodelling, IgE, Th2 polarisationAttract/activate eosinophilsMucus hypersecretionAirway narrowingAttract/activate pro-inflammatory cells

Mediators: histamine, prostaglandins, PAF, LTC4 & LTD4

Mast CellsMucosal oedema, vasodilation, mucus secretion, bronchial smooth muscle contraction

Mast CellsAttract and activate neutrophils &eosinophilsCytokines (e.g. IL-4, IL-5, TNFa, IL-8): LTB4, PAF

Connective tissueMast Cell

MucosalMast CellUbiquitousLong lived >40 days3x104 IgE receptorsHigh histamine contentHeparin & high tryptaseGut & lungT cell dependentShort lived

HistamineSkin wheal, erythema, pruritisEye - conjunctivitis, erythema, pruritisNose nasal discharge, sneeze, pruritisLung bronchospasm of smooth muscle

HistamineTherapeutic intervention in allergy often focused on blocking the effects of histamineHistamine also functions as a neurotransmitter in CNS Very important in maintaining a state of arousal or awareness

First Generation AntihistaminesThe first H1 antagonist synthesised by Bovet & Staub at the Institut PasteurToo weak or toxicPhenbezamine first effective antihistamineMepyramine maleate, diphenhydramine & tripelennamine developed in 1940sStill in use today

First Generation AntihistaminesEasily cross the bloodbrain 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 AntihistaminesHighly effective treatments for allergic disease Do not cross blood-brain barrierLack significant CNS & anticholinergic effectsLong half lifeAmong the most frequently prescribed and safest drugs - expensive

Other treatmentsNasal steroids must be given before season relieve nasal blockadeAntihistamines combined with anti-leukotriene drugsAvoidance -mattress covers, specialised Hoovers, wood floors,

Allergic DiseaseDramatic increase in allergic disease over the past three decades, why is this?GeneticsEnvironmental factors - pollutionChanges in LifestyleOccupational

Genetics (1)Family history of allergic disease is a strong risk factor for developing asthmaDanger of developing asthma particularly if one or both parents are atopicChildren 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 requiredThe 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 indoorsAllergens 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 functionOutdoor allergens seasonal variation and weatherAccount 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 experiencedExposure to certain infections may protect against the development of allergies. Respiratory viruses may be a risk factor for the development of asthmaVaccination 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 susceptibilityFood 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

ConclusionAtopy propensity to produce high levels of IgE from B cellsAllergens mimic parasites processed and presented by APC (e.g. dendritic cells)Orchestrated by Th2 cells cytokine releaseEffector cells mast cells, basophilsMediators cytokines, histamine, leukotrienes, PAF etc.