1HypersensitivityRobert BeattyMCB150Type I IgE MediatedClassic AllergyType II IgG/IgM Mediatedrbc lysisType III IgG MediatedImmune complexDiseaseType IV T cellDelayed Type HypersensitivityGel and Coombs classification of hypersensitivities. TYPE I HypersensitivityClassic allergyMediated by IgE attached to Mast cells.The symptoms resulting from allergic responsesare known as anaphylaxis.• Includes: Hay fever, asthma, eczema, bee stings, foodallergies.AllergensAllergens are nonparasite antigens that canstimulate a type I hypersensitivity response.Allergens bind to IgE and triggerdegranulation of chemical mediators.AllergensIn the US ---36 million people said to have hay fever! Characteristics of allergensSmall 15-40,000 MW proteins.Specific protein components– Often enzymes.Low dose of allergenMucosal exposure.Most allergens promote a Th2 immune.2AllergensDermatophagoides pteronyssinus (common dust mite) Example: Der P1Der P1 is an enzyme allergen from the fecal pellets of the dust mite. Allergen is easily aerosolized and inhaled.Der P1 breaks down components of tight junctionswhich helps it to cross mucosa.Der P1 AllergenAtopyAtopy is the term for the genetic trait to have apredisposition for localized anaphylaxis.Atopic individuals have higher levels of IgE andeosinophils.Genetic Predisposition Type I hypersensitivityCandidate polymorphic genes include:– IL-4 Receptor.– IL-4 cytokine (promoter region).– FcεRI. High affinity IgE receptor.– Class II MHC (present peptides promoting Th2 response).– Inflammation genes.Mechanisms of allergic response SensitizationRepeated exposure to allergens initiatesimmune response that generates IgEisotype.Th2 cells required to provide the IL-4required to get isotype switching to IgE.Mechanisms of allergic response SensitizationTh2/B cell interactionIL-4IL-4RCD40Drive B cell Activation and IgEisotype switch. Busse and Lemanske NEJM Feb 2001. 344:3503Mechanisms of allergic response SensitizationThe IgE can attach to Mast cells by Fcreceptor, which increases the life span of theIgE.Half-life of IgE in serum is days whereasattached to FcεR it is increased to months.Mechanisms of allergic responseFc ε receptors (FcεR) FcεR1high affinity IgE receptor found on– mast cells/basophils/activated eosinophils.Allergen binding to IgE attached to FcεR1triggers release of granules from cell.Mechanisms of allergic responseFcεRIHigh affinityIgE Fc ReceptorHas ITAMmotifsMechanisms of allergic responseEffector Stage of Hypersensitivity Secondary exposure to allergenMast cells are primed with IgE on surface.Allergen binds IgE and cross-links to activatesignal with tyrosine phosphorylation, Ca++influx, degranulation and release of mediators.FcεRI Triggers Release of MediatorsEarly mediators cause immediate symptomse.g. histamine (preformed in granules)leukotriene C4 and prostaglandin D2 are quickly made 2' mediatorsMediators of Type I HypersensitivityImmediate effectsHistamine– Constriction of smooth muscles. Bronchiole constriction = wheezing.Constriction of intestine = cramps-diarrhea.– Vasodilation with increased fluid into tissuescausing increased swelling or fluid in mucosa.– Activates enzymes for tissue breakdown.LeukotrienesProstaglandins4Immediate vs Late Effects (early mediators) Early/LateEffect on lung airflowORWheezing Mediators of Type I HypersensitivityPrimary MediatorsPre-formed mediators in granulesHistamineCytokines TNF-α, IL-1, IL-6.Chemoattractants for Neutrophils andEosinophils.Enzymes– tryptase, chymase, cathepsin.– Changes in connective tissue matrix, tissuebreakdown.Type I HypersensitivitySecondary mediatorsMediators formed after activationLeukotrienesProstaglandinsTh2 cytokines- IL-4, IL-5, IL-13, GM-CSFContinuation of sensitization cycleMast cells control the immediate response.Eosinophils and neutrophils drive late orchronic response.More IgE production further driven byactivated Mast cells, basophils, eosinophils.Continuation of sensitization cycleEosinophilsEosinophils play key role in late phasereaction.Eosinophils make– enzymes,– cytokines (IL-3, IL-5, GM-CSF),– Lipid mediators (LTC4, LTD4, PAF)Eosinophils can provide CD40L and IL-4for B cell activation.Localized anaphylaxisTarget organ responds to direct contact with allergen.Digestive tract contact results in vomiting,cramping, diarrhea.Skin sensitivity usually reddened inflamedarea resulting in itching.Airway sensitivity results in sneezing andrhinitis OR wheezing and asthma.5Systemic anaphylaxisSystemic vasodilation and smooth musclecontraction leading to severe bronchioleconstriction, edema, and shock.Similar to systemic inflammation.Treatment for Type IPharmacotherapyDrugs.– Non-steroidal anti-inflammatories– Antihistamines block histamine receptors.– Steroids– Theophylline OR epinephrine -prolongs orincreases cAMP levels in mast cells whichinhibits degranulation.Treatment for Type IImmunotherapy– Desensitization (hyposensitization) also known as allergy shots.– Repeated injections of allergen to reduce theIgE on Mast cells and produce IgG.Treatment for Type IEffect of allergy shotsAllergen Specific AntibodiesChange in amount ofeach isotype from moreIgE to more IgG.TYPE II HypersensitivityAntibody mediated cytotoxicity Blood Transfusion reactionsInnocuous antigens on red blood cells.EXAMPLE: ABO blood group antigensA and BcarbohydrateantigensAntibody against rbc antigen binds and mediates killing of rbcs via C’or ADCC causes systemic inflammation.ABO Blood GroupsQuex: Why do we have antibodies to these innocuous antigens even before we get blood transfusion?6Drug reactionsDrug binds to rbc surface and antibodyagainst drug binds and causes lysis of rbcs.Immune system sees antibody bound to"foreign antigen" on cell. ADCCTYPE IIAntibody mediated cytotoxicityRh factor incompatibilityIgG abs to Rh an innocuous rbc antigen– Rh+ baby born to Rh- mother first time fine.2nd time can have abs to Rh from 1stpregnancy.– Ab crosses placenta and baby kills its own rbcs.– Treat mother with ab to Rh antigen right afterbirth and mother never makes its own immuneresponse.TYPE II Hemolytic disease of newbornTYPE II Rh factor incompatibilityTYPE IIIAntigen antibody immune complexes.IgG mediatedImmune Complex DiseaseLarge amount of antigen and antibodiesform