1. Keri Csencsits Smith Department of Pathology and Laboratory Medicine University of Texas Health Science Center at Houston Medical School May 25, 2009 Keri.C.Smith@uth.tmc.edu

2. Hypersensitivity Broad-spectrum inflammatory response that results in significant tissue injury, serious disease, or death Not necessarily an increased response, rather, an inappropriate response to an antigen. Hypersensitivity reactions are divided into 4 types

3. 1913 Nobel Prize Portier and Richet Coined the term “anaphylaxis” Portuguese Man O’War Booster shot X

4. The 4 Types of Hypersensitivity Response Type IIgE mediated hypersensitivity Ag induces cross-linking of IgE bound to mast cells and basophils – release of vasoactive mediators Systemic anaphylaxis, hay fever, asthma, hives, food allergies, eczema Type IIIgG or IgM mediated cytotoxic hypersensitivity Ab directed against cell surface antigens mediates cell destrcution via C’ activation or ADCC Blood transfusion reactions, erythroblastosis fetalis, autoimmune hemolytic anemia Type IIIImmune complex mediated hypersensitivity Ag-Ab complexes deposited in tissues induce complement activation and ensuing inflammatory response mediated by massive infiltration of neutrophils Arthus reaction, serum sickness, necrotizing vasculitis, glomerulonephrits rheumatoid arthritis, SLE Type IVCell mediated hypersensitivity Sensitized Th cells release cytokines that activate macrophages or cytotoxic T cells that mediate cellular damage Contact dermatitis, tubercular lesions, graft rejection

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

7. Overview of IgE-mediated allergic response

8. What leads to IgE response? Inhaled small protein allergens Low-dose Mucosal route of entry

9. Some enzymes are triggers of allergy Dust mite cysteine protease Der p 1

10. Class switching to IgE Remember, this is Th2 mediated IL-4 is the hallmark Th2 cytokine IL-13 associated with allergic response

11. Amplification of IgE response

12. Mast cells orchestrate allergic reactions

13. Gilfillan et al. Nature Reviews Immunology 6, 218-230 (March 2006) | doi:10.1038/nri1782 Signaling through the Fc  R1

14. Consequences of mast cell stimulation

15. Molecules released by mast cells on activation

16. Effects of mast cell degranulation

17. Don’t forget about basophils! 9, 9-13 (January 2009) | doi:10.1038/nri2458 Karasuyama, et al 9, 9-13 (January 2009) | doi:10.1038/nri2458

18. The usual sequence of events in an allergic reaction is as follows: A.The allergen combines with circulating IgE, then IgE allergen complex binds to mast cells B.The allergen binds to IgE fixed to mast cells C.The allergen is processed by APCs and then binds to histamine receptors D.The allergen is processed by APCs and then binds to mast cells E.The allergen combines with IgG B: 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.

19. A 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? A.No reaction would occur because the Fc fragments would interact with the allergen and prevent it from gaining access to the sensitized mast cells. B.No reaction would occur because the Fc fragments would interact with the IgE antibodies, making their ag-binding sites unavailable. C.No reaction would occur because the Fc fragments would interact with the Fc  R receptors on mast cells D.The reaction would be exacerbated due to increased local concentration of IgE Fc fragments E.The reaction would be exacerbated due to the activation of complement C: The soluble Fc fragments would saturate the Fc  Rs, and the allergen specific IgE could not bind to the mast cells.

20. Phases of the allergic reaction Immediate Within seconds Due to activity of histamines, prostaglandins and the resulting rapid increase in vascular permeability and contraction of smooth muscle Late-phase 8-12 hours later Caused by induced synthesis and release of leukotrienes, chemokines, cytokines from activated mast cells Induces mucosal edema, mucus secretion, leukocyte infiltration, epithelial damage, bronchospasm Responsible for the most serious long -term illness

21. Immediate and late-phase allergic reactions Asthma Wheal-and-flare

22. Response depends on route of entry and location of mast cells

23. Chronic inflammation IL-5 increases production of eosinophils, eotaxin causes them to migrate Characterized by influx of eosinophils and effector T cells (usually Th2 cytokine secreting) Persistence of antigen drives further IgE secretion and eosinophilia Eosinophil biology section - NIAID

24. Inflammatory mediators secreted by eosinophils

25. Consequences of IgE Hypersensitivity Hay fever (Allergic rhinitis) Increase in capillary permeability and localized vasodilation Food allergies Smooth muscle contraction and vasodilation leads to diarrhea and vomiting Wheal and flare (hives) in skin Allergic dematitis Inflammatory cytokines cause influx of cells and development of skin lesions Atopic children often develop prolonged inflammatory response and a persistent skin rash (eczema)

26. Allergic dermatitis

27. Asthma Events are: Reversible airway obstruction Augmented bronchial responsiveness Inflammation Cytokine induced recruitment of inflammatory cells, particularly eosinophils Cells release oxygen radicals, nitric oxide, cytokines Leads to development of mucus, edema, sloughing of epithelium More Consequences of IgE Hypersensitivity

28. Asthma

29. Pathology of allergic asthma Occlusion of airway by mucus plugInflammatory infiltrate of epithelium

30. Really bad consequences of IgE hypersensitivity Systemic anaphylaxis Can lead to anaphylactic shock Widespread increase in vascular permeability leads to catastrophic loss of blood pressure Airways constrict Epiglottis swells Usually in response to quick absorption of allergen from the gut (peanuts, brazil nuts), or direct introduction into bloodstream (i.v. drug administration, insect bite)

31. Kiss of death

33. Factors that contribute to IgE mediated allergy Genetic Atopy: the tendency to mount IgE responses to a wide variety of common environmental allergens As many as 40% in Western populations Environmental Exposure to infectious disease in early childhood Exposure to bacteria in early childhood Pollution Allergen levels Diet

34. Genetic factors

36. “The Hygeine Hypothesis” “Dirty” kids have fewer allergies Growing 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 products Exposure to tuberculosis Endotoxin exposure Role of the innate immune system? PAMPS bind PRR on APC

37. Toll-like receptors Signaling through TLR expressed dendritic cells up-regulates Th1 cytokines and responses

38. Increasing Th1 response prevents IgE hypersensitivity

39. So why do we have IgE responses? Killing of parasitic worms

40. Treatment of IgE Hypersensitivity In use: Desensitization – increasing doses of antigen drive Th1 response Antihistamines – block histamine H1 receptor (on blood vessels and on unmyelinated nerve fibers) Bronchodilators – act on  -adrenergic receptors, relax constricted muscles Topical or systemic corticosteroids - reduce inflammation Epinephrine – stimulates reformation of endothelial tight junctions, promotes, muscle relaxation, stimulates heart Omalizimab (anti-IgE monoclonal antibody)

41. Treatment of IgE hypersensitivity Experimental Vaccination – use peptides derived from common allergens, may induce T cell anergy CpG adjuvants – promote Th1 responses Inhibit IL-4, IL-5, IL-13 Give IFN  or IFN  Block Ig  R1 binding – IgE Fc construct Block recruitment of eosinophils (anti CCR3)