Immediate Hypersensitivity (Type I)

Transcription

1 Paul J Bryce Senior Director, Type 2 Inflammation & Fibrosis Immunology & Inflammation TA Allergies FOCIS Advanced Course 2018 Immediate Hypersensitivity (Type I) 2 1

2 Learning Objectives Understand what the term Allergy refers to Understand the key mechanisms of allergic immunity Understand current theories behind development of allergy Understand how therapies relate to specific allergic mechanisms and the allergic diseases Infection Allergy Cancer No Immunity Autoimmune Wrong Immunity 2

3 5 Allergic Conjunctivitis Allergic Rhinitis Oral Allergy Syndrome Eosinophilic Esophagitis Allergic Asthma Food Allergy Anaphylaxis Drug Allergy Atopic Dermatitis Urticaria Contact Dermatitis 3

4 Allergy Diagnosis Clinical history of reactions Reproducibility, timing Physical examination Tissue specific Allergy testing Skin Prick Test The wheal-and-flare reaction in the skin. A, In response to antigen-stimulated release of mast cell mediators, local blood vessels first dilate and then become leaky to fluid and macromolecules, which produces redness and local swelling (a wheal). Subsequent dilation of vessels on the edge of the swelling produces the appearance of a red rim (the flare). B, Photograph of a typical wheal-and-flare reaction in the skin in response to injection of an allergen. (Courtesy of Dr. James D. Faix, Department of Pathology, Stanford University School of Medicine, Palo Alto, California.) Allergy Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 20, Copyright 2015 Copyright 2015, 2012, 2007, 2005, 2003, 2000, 1997, 1994, 1991 by Saunders, an imprint of Elsevier Inc. 4

5 Overview 1. Key Phases of Allergy 2. Allergens 3. Allergic Effector Cells 4. Allergic Susceptibility 5. Treatments 9 Intestinal Epithelium Tolerance Microbiota? Sensitization Antigen x Adjuvants Staph toxins (SEB) Macrophage IL-33 TSLP IL-25 Filaggrin Mast Cell IgE FcεRI CX3CR1 + DC CD103 + DC ILC2 Baso IL-4 IL-5 IL-13 Eos Th2 NKT IL-10 RA IDO TGF- β MLN T reg IL-10 Th0 IgA B Cell Th0 IL-4 Th2 IgE IgG B Cell The immunology of food allergy. Johnston et al. J Immunol Mar 15;192(6):

6 Sequence of events in immediate hypersensitivity reactions. Immediate hypersensitivity diseases are initiated by the introduction of an allergen, which stimulates IL-4 producing helper T cell responses and IgE production. IgE sensitizes mast cells by binding to FcεRI, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic reactions of immediate hypersensitivity. Allergy Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 20, Copyright 2015 Copyright 2015, 2012, 2007, 2005, 2003, 2000, 1997, 1994, 1991 by Saunders, an imprint of Elsevier Inc. Food sensitivity is much more prevalent than food allergy 2.5% 1.3% 0.8% 1-5 years National Health and Nutrition Examination Survey participants across 30 sites within continental USA Specific IgE in Serum Food Allergy Prevalence 6

7 Sequence of events in immediate hypersensitivity reactions. Immediate hypersensitivity diseases are initiated by the introduction of an allergen, which stimulates IL-4 producing helper T cell responses and IgE production. IgE sensitizes mast cells by binding to FcεRI, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic reactions of immediate hypersensitivity. Allergy Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 20, Copyright 2015 Copyright 2015, 2012, 2007, 2005, 2003, 2000, 1997, 1994, 1991 by Saunders, an imprint of Elsevier Inc. Summary 1. Key Phases of Allergy Loss of peripheral tolerance Sensitization towards Th2-associated immunity Activation upon re-exposure 14 7

8 2. Allergens Proteins within environmental substances Chemicals that modify endogenous proteins Most proteins are not allergens Peanut contains only 17 defined allergens* *WHO/IUIS Allergen Nomenclature Sub-committee 15 Prevalence Most common food allergens: 30% 25% 20% Peanut 25.2% Milk 21.1% Shellfish 17.2% 15% Tree Nut 13.1% 10% 5% Egg 9.8% Fin Fish 6.2% Wheat 5.0% Soy 4.6% 0% Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, Holl JL. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 2011 Jul; 128(1):e9-e17. 8

9 Common Features of Allergens Low molecular weight (5-70kD) Stable Highly soluble Highly glycosylated Enzymatic activity e.g. cysteine protease 17 Sensitization Elicitation 9

10 Hammad & Lambrecht. Immunity Jul 21;43(1): Innate stimulatory activity of allergens Ara h 2 directly stimulates IL-33 in skin Tordesillas et al. J Clin Invest Nov;124(11): Dust Mite stimulates Dectin-2 Tjota et al. J Allergy Clin Immunol Sep;134(3): e

11 3. Allergic Effector Cells Th2 Cells ILC2 Mast Cells IL-4 IL-5 IL-13 Basophils Eosinophils 21 Major Th2 functions 22 11

12 IL4 / IL13 Receptors and Signaling IL4 IL4 IL13 IL13 or IL-4R IL13R 1 IL-4R γc IL-4R IL13R 1 IL-13R 2 JAK1 JAK3 JAK1 TYK2 JAK1 TYK2 STAT6 Type I Receptor B cells, T cells, Monocytes, Eosinophils, Fibroblasts STAT6 STAT3 STAT6 Type II Receptor Epithelial cells, Smooth muscle cells, Fibroblasts, Monocytes, Activated B cells STAT3 IL13Rc 2 (decoy?) (TGF, fibrosis) Epithelial cells, Smooth muscle cells, Fibroblasts, Activated B cells Allergic Effector Cells Th2 Cells ILC2 Mast Cells Basophils Eosinophils Histopathologic features of bronchial asthma. Atopic bronchial asthma results from repeated immediate hypersensitivity reactions in the lungs with chronic late-phase reactions. A cross-section of a normal bronchus (A) and a cross-section of a bronchus from a patient with asthma (B) are shown. The diseased bronchus has excessive mucus (M) production, many submucosal inflammatory cells (including eosinophils), and smooth muscle (SM) hypertrophy, and many more goblet cells than in the normal bronchus (black arrows in insets). (From Galli SJ, Tsai M, Piliponsky AM: The development of allergic inflammation, Nature 454: , Courtesy of G. J. Berry, Stanford University, California.) Allergy Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 20, Copyright 2015 Copyright 2015, 2012, 2007, 2005, 2003, 2000, 1997, 1994, 1991 by Saunders, an imprint of Elsevier Inc

13 Morphology of mast cells, basophils, and eosinophils. Photomicrographs of Wright-Giemsa stained perivascular dermal mast cells ( A, arrows ), peripheral blood basophil (B), and peripheral blood eosinophil (C) are presented. Note the characteristic blue-staining cytoplasmic granules of the basophil and red staining of the cytoplasmic granules in the eosinophil. ( A, Courtesy of Dr. George Murphy. B and C Courtesy of Dr. Jonathan Hecht, Department of Pathology, Brigham and Women s Hospital, Boston, Massachusetts.) Allergy Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 20, Copyright 2015 Copyright 2015, 2012, 2007, 2005, 2003, 2000, 1997, 1994, 1991 by Saunders, an imprint of Elsevier Inc

14 27 Mast Cells IL-2 IL-4 IL-5 IL-6 IL-9 IL-10 IL-13 IL-17 IL-25 IL-33 TSLP VEGF TNF GMCSF TGFβ CCL1 CCL2 CCL3 CXCL6 Cold Heat Injury Pressure Substance P VIP CGRP Somatostatin Histamine C3a C3b C5a CD4 TCR CD8 TCR CD80 CD86 CD40 PD-L TLR1 TLR2 TLR3 TLR4 TLR6 TLR7 TLR9 Histamine PAF Proteases Tryptase (MCt) Chymase (MCtc) Heparin Prostaglandin Leukotrienes 14

15 Binding of IgE to its high affinity receptor 1x10-10 M Kd Polypeptide chain structure of the high-affinity IgE Fc receptor (FcεRI). IgE (not drawn to scale) binds to the Ig-like domains of the α chain. The β chain and the γ chains mediate signal transduction. The ITAMs in the cytoplasmic region of the β and γ chains are similar to those found in the T cell receptor complex (see Fig. 7-5 ). Lyn and Syk are tyrosine kinases that bind to the β and γ chains and participate in signaling events. A model structure of FcεRI is shown in Chapter 12. Allergy Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 20, Copyright 2015 Copyright 2015, 2012, 2007, 2005, 2003, 2000, 1997, 1994, 1991 by Saunders, an imprint of Elsevier Inc. Biochemical events of mast cell activation. Cross-linking of bound IgE by antigen activates protein tyrosine kinases (Syk and Lyn), which in turn cause activation of a MAP kinase cascade and phospholipase Cγ (PLCγ). PLCγ catalyzes the release of IP3 and DAG from membrane PIP2. IP3 causes release of intracellular calcium from the endoplasmic reticulum. Calcium and DAG activate PKC, which phosphorylates substrates such as myosin light chain protein and thereby leads to the degradation and release of preformed mediators. Calcium and MAP kinases combine to activate the enzyme cytosolic phospholipase A2 (PLA2 ), which initiates the synthesis of lipid mediators, including prostaglandin D2 (PGD2 ) and leukotriene C4 (LTC4 ). Allergy Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 20, Copyright 2015 Copyright 2015, 2012, 2007, 2005, 2003, 2000, 1997, 1994, 1991 by Saunders, an imprint of Elsevier Inc. 15

16 15 min after injection 6 h after injection Biologic effects of mediators of immediate hypersensitivity. Mast cells and basophil mediators include biogenic amines and enzymes stored preformed in granules as well as cytokines and lipid mediators, which are largely newly synthesized on cell activation. The biogenic amines and lipid mediators induce vascular leakage, bronchoconstriction, and intestinal hypermotility, all components of the immediate response. Cytokines and lipid mediators contribute to inflammation, which is part of the late-phase reaction. Enzymes probably contribute to tissue damage. Activated eosinophils release preformed cationic proteins as well as enzymes that are toxic to parasites and host cells. Some eosinophil granule enzymes probably contribute to tissue damage in chronic allergic diseases. Allergy Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 20, Copyright 2015 Copyright 2015, 2012, 2007, 2005, 2003, 2000, 1997, 1994, 1991 by Saunders, an imprint of Elsevier Inc. 16

17 4. Allergic Susceptibility Increased risk for allergy if mother is allergic GWAS associated SNPs* *Asthma-dominant 33 Filaggrin CD14/MHC II IL-33 IL-4 STAT6 PHF11 Tissue Responses FceRI Sequence of events in immediate hypersensitivity reactions. Immediate hypersensitivity diseases are initiated by the introduction of an allergen, which stimulates IL-4 producing helper T cell responses and IgE production. IgE sensitizes mast cells by binding to FcεRI, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic reactions of immediate hypersensitivity. Allergy Abbas, Abul K., MBBS, Cellular and Molecular Immunology, Chapter 20, Copyright 2015 Copyright 2015, 2012, 2007, 2005, 2003, 2000, 1997, 1994, 1991 by Saunders, an imprint of Elsevier Inc. 17

18 Environmental Influences The Hygiene Hypothesis Exposure to good infection prevents allergy Early life infections, particularly respiratory viruses, are major predisposing factor for developing asthma 35 Staphylococcus aureus Gram positive bacteria Discovered in Aberdeen in 1880 Catalase producing Coagulase producing Evolving resistance to antibiotics 18

19 Staphyloccocus aureus & allergy S. aureus plays an important role in many atopic conditions Atopic dermatitis Disease severity is correlated to S. aureus burden and exposure to SEB >90% AD patients are colonized with SA >50% AD patients have specific IgE against SA-toxins SEB released CD25+ Tregs from their anergic phenotype Murine models: SEB as adjuvant in atopic derm model, chronic exposure to SEB led to expansion of SEB reactive Tregs, but they were nonfunctional CRS, pediatric wheezing, asthma also exhibit associations Dinges et al, Clin Micro Rev 2000 Semic-Jusufagi et al, JACI 2007 Machura et al, Ped All Immun 2008 Heaton et al, Allergy 2003 Okano et al, AM J Rhino 2001 Hollams et al, Eur Resp J 2010 Environmental Factors in Food Allergy Bryce, P. Trends Immunol Oct;37(10):

20 Fig 1. Dual-allergen-exposure hypothesis for pathogenesis of food allergy. Tolerance occurs as a result of oral exposure to food, and allergic sensitization results from cutaneous exposure. GI, Gastrointestinal. Gideon Lack Epidemiologic risks for food allergy Journal of Allergy and, Volume 121, Issue 6, 2008, SPT- children 270 Avoid 272 Consume 40 20

21 4. Therapeutic Strategies Medication and Immunotherapy* Medications: Antihistamines, corticosteroids, LTRAs, life-sparing Immunotherapy: Sub-cutaneous, sub-lingual, oral Biologics *American College of Allergy, Asthma & Immunology 41 Oral Immunotherapy 21

22 Antihistamines Corticosteroids Immunotherapy Rhinitis Asthma Aeroallergy LTRAs Rhinitis & Asthma Epinephrine Food Allergy 43 IgE IL-4 IL-13 IL-5 IL-33 TSLP Monoclonal antibodies: the new magic bullets for allergy. Landolina N, Levi-Schaffer F. Br J Pharmacol Dec

23 Prevention of tolerance loss Control of reactivity Restoration of tolerance Active induction of oral tolerance Lifestyle influences Inhibition of key mediators Disease-specific biology Induction of IgG4 Induction of Tregs 45 Intestinal Epithelium Tolerance Microbiota? Sensitization Antigen x Adjuvants Staph toxins (SEB) Macrophage IL-33 TSLP IL-25 Filaggrin Mast Cell IgE FcεRI CX3CR1 + DC CD103 + DC ILC2 Baso IL-4 IL-5 IL-13 Eos Th2 NKT IL-10 RA IDO TGF- β MLN T reg IL-10 Th0 IgA B Cell Th0 IL-4 Th2 IgE IgG B Cell The immunology of food allergy. Johnston et al. J Immunol Mar 15;192(6):

24 Why? Anti-heminthic Anti-venom 47 24

25 49 Biochem Biophys Res Commun Aug 22;451(2): doi: /j.bbrc Epub 2014 Aug 2. Ancient origin of mast cells. Wong GW1, Zhuo L2, Kimata K2, Lam BK3, Satoh N4, Stevens RL

26 51 26