HypersensitivityPowerPoint PresentationTYPE I Hypersensitivity Classic allergyAllergensAllergensCharacteristics of allergensAllergensSlide 8AtopyGenetic Predisposition Type I hypersensitivityMechanisms of allergic response SensitizationMechanisms of allergic response Sensitization Th2/B cell interactionSlide 13Mechanisms of allergic response Fc e receptors (FceR)Mechanisms of allergic response FceRIMechanisms of allergic response Effector Stage of HypersensitivityFceRI Triggers Release of MediatorsMediators of Type I Hypersensitivity Immediate effectsImmediate vs Late EffectsMediators of Type I Hypersensitivity Primary Mediators Pre-formed mediators in granulesType I Hypersensitivity Secondary mediators Mediators formed after activationContinuation of sensitization cycleContinuation of sensitization cycle EosinophilsLocalized anaphylaxis Target organ responds to direct contact with allergen.Systemic anaphylaxisTreatment for Type ISlide 27Treatment for Type I Effect of allergy shots Allergen Specific AntibodiesTYPE II Hypersensitivity Antibody mediated cytotoxicity Blood Transfusion reactionsABO Blood GroupsTYPE II Antibody mediated cytotoxicitySlide 33TYPE III Antigen antibody immune complexes. IgG mediatedTYPE III Immune ComplexesTYPE III Immune Complex Disease "Frustrated Phagocytes"TYPE III Immune Complex DiseaseSlide 38Serum Sickness Systemic immune complex diseaseDelayed type hypersensitivity Th1 cells and macrophagesStages of Type IV DTHStages of Type IV DTH Effector stageSlide 43Type IV DTH Contact dermatitisContact dermatitisDelayed type hypersensitivity (DTH)Granuloma Formation from DTH Mediated by Chronic InflammationDrug reactions can be any Type of HypersensitivityHypersensitivityRobert 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 Hypersensitivity Classic allergyMediated by IgE attached to Mast cells.The symptoms resulting from allergic responses are known as anaphylaxis. •Includes: Hay fever, asthma, eczema, bee stings, food allergies.Allergens Allergens are nonparasite antigens that can stimulate a type I hypersensitivity response.Allergens bind to IgE and trigger degranulation 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.AllergensDermatophagoides 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 junctions which helps it to cross mucosa.Der P1 AllergenAtopyAtopy is the term for the genetic trait to have a predisposition for localized anaphylaxis. Atopic individuals have higher levels of IgE and eosinophils.Genetic Predisposition Type I hypersensitivityCandidate polymorphic genes include: –IL-4 Receptor. –IL-4 cytokine (promoter region). –FcRI. High affinity IgE receptor. –Class II MHC (present peptides promoting Th2 response). –Inflammation genes.Mechanisms of allergic response SensitizationRepeated exposure to allergens initiates immune response that generates IgE isotype. Th2 cells required to provide the IL-4 required to get isotype switching to IgE.Mechanisms of allergic response Sensitization Th2/B cell interactionIL-4IL-4RCD40Drive B cell Activation and IgEisotype switch. Busse and Lemanske NEJM Feb 2001. 344:350Mechanisms of allergic response SensitizationThe IgE can attach to Mast cells by Fc receptor, which increases the life span of the IgE. Half-life of IgE in serum is days whereas attached to FcR it is increased to months.Mechanisms of allergic responseFc  receptors (FcR) FcR1high affinity IgE receptor found on–mast cells/basophils/activated eosinophils. Allergen binding to IgE attached to FcR1 triggers release of granules from cell.Mechanisms of allergic responseFcRIHigh 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 activate signal with tyrosine phosphorylation, Ca++ influx, degranulation and release of mediators.FcRI 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 tissues causing increased swelling or fluid in mucosa. – Activates enzymes for tissue breakdown. Leukotrienes ProstaglandinsImmediate vs Late Effects (early mediators) Early/LateEffect on lung airflowORWheezingMediators of Type I HypersensitivityPrimary MediatorsPre-formed mediators in granulesHistamineCytokines TNF- , IL-1, IL-6. Chemoattractants for Neutrophils and Eosinophils. Enzymes–tryptase, chymase, cathepsin. –Changes in connective tissue matrix, tissue breakdown.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 or chronic response. More IgE production further driven by activated Mast cells, basophils, eosinophils.Continuation of sensitization cycleEosinophilsEosinophils play key role in late phase reaction. Eosinophils make –enzymes, –cytokines (IL-3, IL-5, GM-CSF), –Lipid mediators (LTC4, LTD4, PAF)Eosinophils can provide CD40L and IL-4 for B cell activation.Localized anaphylaxisTarget organ responds to direct contact with allergen.Digestive tract contact results in vomiting, cramping, diarrhea. Skin sensitivity usually reddened inflamed area resulting in itching. Airway sensitivity results in sneezing and rhinitis OR wheezing and asthma.Systemic anaphylaxisSystemic vasodilation and smooth muscle contraction leading to severe