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IgE HypersensitivityKeri Csencsits SmithDepartment of Pathology and Laboratory MedicineUniversity of Texas Health Science Center at Houston Medical SchoolMay 25, 2009

Keri.C.Smith@uth.tmc.edu1HypersensitivityBroad-spectrum inflammatory response that results in significant tissue injury, serious disease, or deathNot necessarily an increased response, rather, an inappropriate response to an antigen.Hypersensitivity reactions are divided into 4 types21913 Nobel PrizePortier and RichetCoined the term anaphylaxis

Portuguese Man OWar

Booster shotX3The 4 Types of Hypersensitivity ResponseType IIgE mediated hypersensitivityAg induces cross-linking of IgE bound to mast cells and basophils release of vasoactive mediatorsSystemic anaphylaxis, hay fever, asthma, hives, food allergies, eczemaType IIIgG or IgM mediated cytotoxic hypersensitivityAb directed against cell surface antigens mediates cell destrcution via C activation or ADCCBlood transfusion reactions, erythroblastosis fetalis, autoimmune hemolytic anemiaType IIIImmune complex mediated hypersensitivityAg-Ab complexes deposited in tissues induce complement activation and ensuing inflammatory response mediated by massive infiltration of neutrophilsArthus reaction, serum sickness, necrotizing vasculitis, glomerulonephrits rheumatoid arthritis, SLEType IVCell mediated hypersensitivitySensitized Th cells release cytokines that activate macrophages or cytotoxic T cells that mediate cellular damageContact dermatitis, tubercular lesions, graft rejection4

5Type 1 response (the beginning)Induced by Allergens(nonparasitic antigens antigens capable of stimulating type I hypersensitivity reactions)Distinguished by the secretion of IgE

Review IgE structure6Overview of IgE-mediated allergic response

7What leads to IgE response?Inhaled small protein allergensLow-doseMucosal route of entry

8Some enzymes are triggers of allergy

Dust mite cysteine protease Der p 1De9Class switching to IgE

Remember, this is Th2 mediated

IL-4 is the hallmark Th2 cytokine

IL-13 associated with allergic response

10Amplification of IgE response

11Mast cells orchestrate allergic reactions

12Gilfillan et al. Nature Reviews Immunology 6, 218-230 (March 2006) | doi:10.1038/nri1782

Signaling through the FceR113

Consequences of mast cell stimulation14Molecules released by mast cells on activation

15Effects of mast cell degranulation

16Dont forget about basophils!

9, 9-13 (January 2009) | doi:10.1038/nri2458 Karasuyama, et al 9, 9-13 (January 2009) | doi:10.1038/nri2458

Basophils initiate chronic allergic inflammation. In antigen-sensitized animals, antigen-specific IgE antibodies are produced and captured by circulating basophils through the high-affinity Fc receptor for IgE (FcRI) (step 1). When the same antigens enter the skin tissue, IgE-bearing basophils are recruited to the skin lesion, possibly by chemokines released by phagocytic cells that have captured antigen (not shown), and are activated when the antigen binds to the IgEFcRI complex (step 2). Activated basophils secrete cytokines and other factors (step 3) that in turn act on tissue-resident cells, such as fibroblasts, and induce them to produce more chemokines (step 4). Inflammatory cells, such as eosinophils and neutrophils, are then recruited to the skin lesion in response to the chemokines that are released by tissue-resident cells (step 5), resulting in chronic allergic inflammation..17The usual sequence of events in an allergic reaction is as follows:The allergen combines with circulating IgE, then IgE allergen complex binds to mast cellsThe allergen binds to IgE fixed to mast cellsThe allergen is processed by APCs and then binds to histamine receptorsThe allergen is processed by APCs and then binds to mast cellsThe allergen combines with IgGB: IgE binds passively to cells expressing high affinity Fc receptors for IgE, then interacts with the allergen when present. The result is mast cell degranulation.18A human volunteer agrees to be passively sensitized for IgE specific for a ragweed antigen. When challenged with the allergen intradermally, he displayed a typical skin reaction due to an immediate hypersensitivity reaction. If the injection with sensitizing IgE was preceded by an injection (at the same site) of Fc fragments of human IgE, followed by intradermal injection with allergen, which of the following outcomes would you predict?No reaction would occur because the Fc fragments would interact with the allergen and prevent it from gaining access to the sensitized mast cells.No reaction would occur because the Fc fragments would interact with the IgE antibodies, making their ag-binding sites unavailable.No reaction would occur because the Fc fragments would interact with the FceR receptors on mast cellsThe reaction would be exacerbated due to increased local concentration of IgE Fc fragmentsThe reaction would be exacerbated due to the activation of complementC: The soluble Fc fragments would saturate the FceRs, and the allergen specific IgE could not bind to the mast cells.19Phases of the allergic reactionImmediateWithin secondsDue to activity of histamines, prostaglandins and the resulting rapid increase in vascular permeability and contraction of smooth muscle

Late-phase8-12 hours laterCaused by induced synthesis and release of leukotrienes, chemokines, cytokines from activated mast cellsInduces mucosal edema, mucus secretion, leukocyte infiltration, epithelial damage, bronchospasmResponsible for the most serious long -term illness

Long term illness = chronic inflammation due to recruitment of Th2 cells20

Immediate and late-phase allergic reactionsAsthmaWheal-and-flareLooking at the fall in the forced expired volume of air in one second. Late phase is associated with the cardinal features of allergic asthma, the airway hyperreactivity to the non-specific bronchocontrictor stimuli (histamine, methacholine)

Wheal and flare: immediate, then more edmatous response after 8 hours. 21Response depends on route of entry and location of mast cells

22Chronic inflammationIL-5 increases production of eosinophils, eotaxin causes them to migrateCharacterized by influx of eosinophils and effector T cells (usually Th2 cytokine secreting)Persistence of antigen drives further IgE secretion and eosinophilia

Eosinophil biology section - NIAIDEos, upon proper activation, express FCeR1, and can be cross-linked by IgE23Inflammatory mediators secreted by eosinophils

T cell lymphomas can sometimes drive hypereosinophilia can damage endocardium24Consequences of IgE HypersensitivityHay fever(Allergic rhinitis)Increase in capillary permeability and localized vasodilation Food allergiesSmooth muscle contraction and vasodilation leads to diarrhea and vomitingWheal and flare (hives) in skinAllergic dematitisInflammatory cytokines cause influx of cells and development of skin lesionsAtopic children often develop prolonged inflammatory response and a persistent skin rash (eczema)

25Allergic dermatitis

26AsthmaEvents are:Reversible airway obstructionAugmented bronchial responsivenessInflammation

Cytokine induced recruitment of inflammatory cells, particularly eosinophilsCells release oxygen radicals, nitric oxide, cytokinesLeads to development of mucus, edema, sloughing of epithelium

More Consequences of IgE Hypersensitivity 27Asthma

28Pathology of allergic asthma

Occlusion of airway by mucus plugInflammatory infiltrate of epithelium29Really bad consequences of IgE hypersensitivity Systemic anaphylaxisCan lead to anaphylactic shockWidespread increase in vascular permeability leads to catastrophic loss of blood pressureAirways constrictEpiglottis swellsUsually in response to quick absorption of allergen from the gut (peanuts, brazil nuts), or direct introduction into bloodstream (i.v. drug administration, insect bite)30Kiss of death

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32Factors that contribute to IgE mediated allergyGeneticAtopy: the tendency to mount IgE responses to a wide variety of common environmental allergensAs many as 40% in Western populationsEnvironmentalExposure to infectious disease in early childhoodExposure to bacteria in early childhoodPollutionAllergen levelsDiet33Genetic factors

34Genetic factors

Just an example35The Hygeine HypothesisDirty kids have fewer allergiesGrowing up on a farm (1999, 2000)Attended day care (2003)Pet ownership (1999)Lower standard of living (East vs. West Germans, 2002)*Role of bacterial productsExposure to tuberculosisEndotoxin exposureRole of the innate immune system?PAMPS bind PRR on APC

Originally proposed in 1989 by Strachan* Is because lower standard of living in inner-city US is associated with higher incidence of asthma cockroach allergen? PAMPS

36Toll-like receptors

Signaling through TLR expressed dendritic cells up-regulates Th1 cytokines and responsesTies in with bacterial infection associated with lower risk of asthma.37Increasing Th1 response prevents IgE hypersensitivity

38So why do we have IgE responses?

Killing of parasitic worms39Treatment of IgE HypersensitivityIn use:Desensitization increasing doses of antigen drive Th1 responseAntihistamines block histamine H1 receptor (on blood vessels and on unmyelinated nerve fibers)Bronchodilators act on b-adrenergic receptors, relax constricted musclesTopical or systemic corticosteroids - reduce inflammationEpinephrine stimulates reformation of endothelial tight junctions, promotes, muscle relaxation, stimulates heartOmalizimab (anti-IgE monoclonal antibody)

40Treatment of IgE hypersensitivityExperimentalVaccination use peptides derived from common allergens, may induce T cell anergyCpG adjuvants promote Th1 responsesInhibit IL-4, IL-5, IL-13Give IFNg or IFNaBlock IgeR1 binding IgE Fc constructBlock recruitment of eosinophils (anti CCR3)

Vaccination may require lots and lots of peptides, due to the MHC class II allele variation in humans

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