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Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Lecture 514.094 The Pathophysiology of Allergy
Chapter 2: Type I allergy: Mechanisms in effector phaseand Anaphylaxis
Eva Untersmayr-ElsenhuberDepartment of Pathophysiologyand Allergy ResearchMedical University Vienna
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Topics of lecture• Clincal presentation of allergic reactions
• Key players in allergic inflammation
• Mechanisms of anaphylactic reactions
− IgE− Allergen− Mast cells− Eosinophils, inflammatory cells
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Clinical presentation of allergic reactions
http://www.raksar.com/shop/r/raksar/img-lib/con_20051229134550_i.JPG
Allergy against inhalative proteins
• Respiratory symptoms
• Cutaneous and gastrointestinal symptoms
Wheezing, rhinitisConjunctivitisAsthma
EczemaOral allergy syndrom
Mild à severeIn all age groups
Gibson PG et al. Lancet 2010
Katelaris CH. Curr Opin Allergy Clin Immunol. 2010
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Clinical presentation of allergic reactions
http://sip.uki.at/img/bauchschmerz/Schmerz_Bauchschmerz.jpg
Allergy against food compounds
• Gastrointestinal symptoms
• Respiratory and cutaneoussymptoms
• Generalized anaphylactic symptoms
Abdomial painNausea, vomitingDiarrhea
Rhinitis, conjunctivitisAsthmaEczema, urticaria, angioedema
Sicherer SH, Sampson HA. JACI 2010
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Clinical presentation of allergic reactions
http://www.allergiewelle.de/wp-content/uploads/2009/11/angioodem-fdgarrett.jpg
Allergy against drugs
• Respiratory symptoms
• Cutaneous symptoms
• Generalized anaphylactic symptoms
Wheezing, rhinitisConjunctivitisAsthma
EczemaUrticariaAngioedema
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Time course of allergic reactionsimmediate Late phase
immediate Late phase
Immediate reactionOnset within secondsdue to preformed or rapidly synthesized mediators à vascular permeabilityà contraction of smooth muscle
Late phase reactionInduced synthesis and release of mediators à recruiting of eosinophilsand Th2 lymphocytesà second phase of smooth muscle contraction, sustained edema, airway hyperreactivity
www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=imm&part=A1734
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Time course of allergic reactions
Key players in immediate reactionsIgE bound via FcεRI to mast cells and basophilsà mediator release
immediate Late phase
www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=imm&part=A1734
Laché M et al. Nat Rev Immunol 2006
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Time course of allergic reactions
Key players in late phasereactionNetwork of inflammatory cells:eosinophils (50% of infiltrate), allergen-specific T-cells, mast cells, basophils, Th1 cells
immediate Late phase
www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=imm&part=A1734
Laché M et al. Nat Rev Immunol 2006
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Chronic allergic inflammation
Galli SJ et al. Nature 2008
Due to repetitive or persistantallergen exposureInnate immune cells (eosinophils, basophils, neutrophils and monocyte/macrophages) and adaptive immune cells (Th2-cells, other T-cells, B-cells) take up residence in tissue
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Mean serum concentration:IgE: 0.02-0.5 mg/mlIgG: 8-16 mg/ml
Percentage of total Ig:IgE: 0.002 %IgG: 80 %
Serum half life time: 2 days
Peak IgE levels occure 4-6 weeks after peak of pollenseason
Total IgE >1000ng/mLàmajor diagnostic criteria forallergic bronchopulmonaryaspergillosis
IgE antibodiesIgE IgG
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Diseases with elevated IgE levels
• Atopic diseases• Parasitic infections (eg.
Strongyloidiasis, ascariasis, schistosomiasis)
• Nonparasitic infections (eg. EBV, CMV, HIV, M. tuberculosis)
• Inflammatory disease (eg. Kimura disease, Churg-Stauss vasculitis, Kawasaki disease)
• Malignancies (eg. Hodgkin lymphoma, IgE myeloma)
• Cutaneous diseases (eg. Bullouspemphigoid)
• Cystic fibrosis• Nephrotic syndrome• Primary immunodeficiency
diseases (eg. Hyper-IgEsyndrome, Wiskott-Aldrich syndrome, Omenn syndrome, immune dysregulation, X-linkedinheritance, atypical DiGeorgesyndrome
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Ig switch: - transcription through upstream constant switch region- DNA cleavage of ssDNA at transcription site- DNA repair: recombine VDJ domain + new C domain
Immunoglobulin class switch
IgM expressing B-cell IgG1 expressing B-cell
2 signals for IgE switch1) IL4 or IL13 via STAT6:
activates transcriptionat Sε
2) CD40L (T-cells) andCD40 (B-cells):activates DNA switchrecombination
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Sensitisation to allergens
Lymph nodesor mucosa
Galli SJ et al. Nature 2008
Airway Basophils, mastcells, NK T cells,…
Dendritic cell samplingEntrance through disrupted epitheliaProtease activityà cleaving of epithelialtight junctions
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
High affinity IgE receptor FcεRITetrameric FcεRIαβγ2
According to: Kraft S, Kinet JP. Nature Immunol 2007
αγ2 β
mast cells, basophils
αβ γ2
Antigen independent
effects
Increased cell survival
Antigen dependenteffects
Mediator release
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Trimeric FcεRIαγ2
According to: Kraft S, Kinet JP. Nature Immunol 2007
α
γ2
MHC class II
monocytes, macrophages, dendritic cells, Langerhans cells, eosinophils
Mediator release
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
à ligand:receptor = 1:1à high affinity (1010 M-1) due to low dissociation rate, each binding site has lower intrinsic affinity
1 FcεRIα chain with 2 asymmetric IgE interaction sites:
- 4 solvent-exposed tryptophans àlarge hydrophobic surface- C-C’ loop in the receptor D2 domain
bind dimeric, symmetric IgE Fc (Cε3)
FcεRI and IgE interaction
Garman SC et al. Nature 2000Wan T et al. Nature Immunol 2002
Metzger H. Immunol Rev 1992
Gould HJ et al. Nat Immunol Rev 2008
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Glycoprotein, 45 kDa,single chainhomology to C-type(Ca2+-dependent) lectinsà IgE and CD21 bind tolectin domain
lower affinity for IgE (107 M-1)
B-cells, activated T-cells, monocytes, macrophages, eosinophils, Langerhans cells, intestinal epithelial cells, platelets
Low affinity IgE receptor FcεRII/CD23
Mossalayi MD et al. EMBO J 1992
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
CD23 regulates IgE synthesis
Down-regulation of IgE synthesis
Co-crosslinking of mCD23 and mIgE by allergen-IgEcomplexà Inhibition of B-cell proliferation and IgE production
à Induction of B-cell apoptosis à B-cell populationregulation
B-cell surface
Luo HY et al. J Immunol 1991Sherr E et al. J Immunol 1989
Hibbert RG et al. JEM 2005
From Hibbert RG et al. JEM 2005
Up-regulation of IgE synthesisCo-crosslinking ofmIgE and CD21 bytrimeric sCD23
Aubry JP et al. Nature 1992Hibbert RG et al. JEM 2005
IgE binding tomCD23 protectsmCD23 againstproteolysis andprevents formationof sCD23
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Glycoproteinslow dose à activation of IL4-producing CD4-T-cells
low molecular weight (10-70 kDa) à diffusion through epithelia facilitatedsolubility
Stability stable to head, acid, proteasesenzymatically active, protease some are enzyme inhibitors
abundance in food
Characteristics of allergens
Pollen allergens Food allergens
http://www.umass.edu/tei/TEI/images/UMassEnv/pollen.gif
http://blog.friendseat.com/wp-content/uploads/2010/09/Allergy-Foods.jpg
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
high binding affinity and slow dissociation rates of IgE to the allergenIgE: 10-10 bis 10-11 MIgG: 10-7 bis 10-8 M
IgE – allergen interaction
Kim KE et al. Mol Immunol 1996Pierson L et al. J Immunol Meth 1998Jackola DR et al. Mol Immunol 2002Hantusch B et al. Immunol Lett 2005
à IgE affinity to allergen among the highest biologicallyrelevant binding strength
IgE epitopes on allergens are mainly conformational
IgE to conformational rather than linear epitopescorrelate with tolerance development in milk and egg allergic children
Foote J et al. PNAS USA 1995
Xia L et al. Mol Immunol 2010Padavattan S et al. J Immunol 2009
Pedraza-Escalona M et al. Mol Immunol 2009
Järvinen KM et al. Allergy 2007Vila L et al. Clin Exp Allergy 2001
repeated epitope presentation on allergen surface required for crosslinkingà allergens are multimers Tan YW et al. J Biol Chem 2009
Schöll I et al. J Immunol 2005
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Morphology of mast cell
http://www.bu.edu/histology/i/22602ooa.jpg
Tissue based inflammatory cellsRespond to signals of innate and adaptive immunity with immediate and delayed release ofinflammatory mediators
20 μm diameterOvoid or irregularly elongated cells with ovoid nucleusAbundant metachromatic cytoplasmatic granules (metachromatic stainingdue to sulfated proteoglycans)
cKIT (CD117) and FcεRI positiveOther cell-surface receptors depending on location and activation:FcγRIIa (in resting state) FcγRI (CD64) (in presence of IFN-γ)β2-adrenergic receptor, adenosine receptor A2B, prostaglandin E2 receptor,C3a, C5a-receptor, IL-3R, IL-4R, IL-5R, IL-9R, IL-10R, GM-CSFR, IFN- γR,CCR3, CCR5, CXCR2, CXCR4, nerve growth factor R, TLRs, …
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Mast cell maturation and tissue distribution
Hematop. Stem cell
Mast cellprogenitor
cKIT (CD 117) – SCF Ligand
Arise from CD34+ progenitors
Galli SJ et al. Nature 2008
Mucosalmast cell
Connectivetissuemast cell
Tryptase pos. In respiratoryand GI mucosaàincreasedwithinflammation
Tryptase, mast cell-specific chymase pos. In connective tissue (dermis, submucosa of GI tract, heart, conjunctivae, perivascular)Small bowel of end-stage immunodeficiencies
Phenotype of maturemast cells depends on growth factor milieu
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
• Antigen-crosslinked surface-bound IgE
• Divalent Ab against IgE Fc region
• Anti-idiotypic Ab
• Anti- Fc receptor Ab
• Covalent cross-linked IgE
• Lectins
• Complement (C3a, C5a) throughC3aR, C5aR (CD88)
• Nerve growth factor
• IgG by FcγRI
• TLR ligands (eg. TLR3 dsDNAà IFN-γ production in mast cells)
Mechanisms of mast cell activation
C3aC5a7
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Mast cell mediators
Granule-ass. preformed mediators• Histamine• Neutral proteases (tryptase in MCT,
tryptase, chymase, cathepsin G, carboxypeptidase in MCTC)
• Proteoglycans (heparin, chondroitinsulfates) neg. chargedà complexeswith histamine
• Chemotactic and activating factors(ECF-A, NCF)
Newly formed mediators• Lipoxygenase pathway products:
SRS-A (LTC4, LTD4), leukotrienes(LTB4)
• Cyclo-oxygenase products: prostaglandines and thromboxanes
• PAF
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Effector function of mediatorsChemo-attractants• NCF• ECF-A• LTB4
Activators• Histamine• PAF• Tryptase• Kininogenase
Spasmogens• Histamine• PGD2• LTC4• LTD4
preformed newly formed
Attractants ofNeutrophils, eosinohils, monocytes, basophils
Vasodil., Vascular permeability
Kininsà Vasodil. à edemaProteolyt. enzyme, activates C3Microthrombi
• Bronchial smooth muscle contraction
• Mucosal edema• Mucus secretion
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Clinical aspects of mast cell activation
Allergen dosageand entranceroute are decisivefor clinical reaction
MCTMCTCintravenoushigh dose
subcutaneouslow dose
inhalationlow dose
uptake withfood
Mast cell activation
Anaphylaxis Wheal andflare reaction
Allerg. rhinitisAsthma
Nausea, pain, vomiting diarreha
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Morphology of basophils
http://microanatomy.net/blood/basophil3.jpg
Share many features with mast cells: FcεRIsecretion of Th2 cytokinesmetachromic stainingrelease of hisatmine after activation
But distinct lineage
5-8 μm diameter, segmented condensed nucleus, little proliferative capacityRapid and potent expression of IL-4 and IL-13Express Cytokine receptors (IL-3R, IL-5R, GM-CSF receptor)
Chemokine receptors (CD11c, CD11c, CD35 and CD88)Ig receptors (FcεRI, FcγRIIb)TLR
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
http://focosi.altervista.org/blood-cell-development.jpg
Basophil development and activation• CD34+ progenitors• Differentiate and mature in bone marrow• Circulate in periphery, <1% peripheral
leukocytes• Differentiation driven by IL3• Express integrins and chemokine
receptorsà able to inflitrateinflammed tissue (skin in AD, airway of respiratory allergies)
Activation via IgE crosslinkingC3a, C5a, TLR2 and TLR4 à IL-4, IL-13 secretionand potentiation of IgE activationIL-33 through ST2 receptor
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Mediators: preformed: Histamine, less heparin, low tryptase levelsnewly synthesized: LTC4, LTD4, LTE4, no PGD2 productioncytokines: IL-4, IL-13, GM-CSF à source of early IL-4 for Th2 cell differentiation and amplification of IgE synthesis
Role in health and disease
Karasuyama H et al. Nat Rev Immunol 2009Min B. Nat Immunol 2008
Sullivan BM et al. Immunity 2009
Sullivan BM et al. Immunity 2009
• Physiological function remains unknown (host defense against parasites?)• Innate immunity (TLR2 expression)• Predominant source of IL-4 in allergen and helminth parasite activated
PBMCs• In late-phase allergic responses, found in increased numbers in lungs of
asthma patients dying of asthma
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Features of mast cells and basophils
OriginMaturationLifespanLocationSizeNucleusGranulesPeptido-glycansTryptasecontent
Mast cells Basophils
Hematopoietic stem cellConnective tissueMonthsTissue6-12 μmOval or roundSmaller and moreHeparin and chondroitinsulfatesHigh
Hematopoietic stem cellBone marrowDaysIntravascular circulation5-8 μmSegmentedLarger and fewerPredom. chondroitinsulfatesLow
Stone KD et al. JACI 2010
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Morphology of eosinphils
http://student.nu.ac.th/wuth_web/eosinophil2.jpeg
Blood and tissue eosinophilia hallmarks for• helminth infection• allergy and asthma, • eosinophilic gastrointestinal disorders• other rare disorders (eg. Hypereosinophilia Churg-
Strauss syndrom)
Bilobed nucleus, highly condensed chromatinStained with acidic dye eosin
2 major types of granules:Specific granules with electron-dense core, contain cationic proteins:
major basic protein MBP, eosinophil peroxidase EPO, eosinohil cationic protein ECP, eosinophil-derivedneurotoxin EDN
Primary ganules similar to those found in other granulocytesenriched in Charcot-Lyden crystal protein
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Cell surface receptors
http://www.scq.ubc.ca/wp-content/uploads/2006/07/cellsurfaceR.gif
• IgG receptor (FcγRII/CD32)• IgA receptor (FcαRI/CD89)• Complement receptors (CR1, CR3,
CD88 for C3a and C5a)• Cytokine receptors (IL-3R, IL-5R;
receptors for GM-CSF, IL-1α, IL-2, IL-4, IFN-γ, TNF-α)
• Chemokine receptors (CCR1, CCR3)• Adhesion molecules (very late antigen4, α2β7, siglec-8)• Leukotrien receptors (CysLT1R, CysLT2R, LTB4 receptor)• PG receptors (PGD2 type 2 receptor)• PAF receptor• TLR7/8• FcεRI expression is minimal, does not activate eosinophils, unclear
functional significance
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Development and activation
http://www.tpub.com/content/medical/14295/img/14295_284_1.jpg
IL-5, IL-3, GM-CSF à eosinophil developmentfrom CD34+ progenitor cells
Release from bone marrow into circulation after IL-5 and CCL11 (eotaxin-1, via CCR3) stimulation
IL-4, IL-13 promote eosinophil trafficking tomucosal tissue by eotaxin (CCL11, CCL26) upregulation
Eosinophil chemotactic factors: PAF, LTD2, C5a, CCL5 (RANTES)
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=imm&part=A1233&rendertype=figure&id=A1239
Effector function of eosinophilsRelease of proinflammatory mediators:Granule-stored cationic proteins, newly synthesizedeicosanoids and cytokines
MBP 50% of granule protein massacitivity against parasites (helminths, schistosomula)in asthma: serum and BALF MBP correlates withbronchial hyperresponsiveness
EDN, ECP RNAse activitytoxicity to parasites and ssRNA viruses
EPO 25% of granule protein masstoxic to microorganisms and host cells
Role of eosinophils in airway remodelling, airway hyperreactivity, and mucusproduction
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
The allergic effector unit
http://personalpages.manchester.ac.uk/staff/j.gough/lectures/TIB/3imm_intro/mast2.jpg
http://pathmicro.med.sc.edu/bowers/neut-em.jpg
Soluble mediatorsmodulate the reciprocalinteraction between mastcells and eosinophils
Mast cell Eosinophil
GM-CSF, IL-3, IL-5, TNF-α, Heparin, LTC4, LTD4, LTE4, Chymase, PGD2, LTB4, IL-2, Tryptase, Histamine, PAF
SCF, NGF, MBP, Eotaxin, EDN, LTC4, LTD4, LTE4, ECP, EPO
Minai-Fleminger Y, Levi-Schaffer F. Inflamm Res 2009
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
The allergic effector unit
http://personalpages.manchester.ac.uk/staff/j.gough/lectures/TIB/3imm_intro/mast2.jpg
http://pathmicro.med.sc.edu/bowers/neut-em.jpg
Physical interactions between mast cells and eosinophils
Mast cell Eosinophil
Receptor-ligand couples
TRAIL – TRAIL ligandCD300a – CD300a
CD48 – CD244ICAM-1 – LFA-1
Minai-Fleminger Y, Levi-Schaffer F. Inflamm Res 2009
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Early phase of allergy
Galli SJ et al. Nature 2008
Allergen-specific IgEcross-linkingàFcεRI aggregation àmast cell activation
Mediator release
BronchoconstrictionVasodilatationInceased vascularpermeability, increased mucusproduction
Transition to latephase: leukocyte recruitment
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Late phase of allergy
Galli SJ et al. Nature 2008
Action of innate andadaptive immune cells and secretion ofinflammatorymediators fromtissue-resident cells
Degradation of type III collagen, injury ofepithelial cellsBronchoconstricition
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Chronic allergic inflammation
Galli SJ et al. Nature 2008
Prolonged allergen exposure
• Increased mucusproduction, thickening ofsubepithelial tissue
• Formation of EMTU (epithelial-mesenchymaltropic unit)
• Smooth musclehyperplasia
• Severe narrowingof airway lumen
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Tissue remodelling in asthma
Galli SJ et al. Nature 2008Normal small bronchus Severe asthmaMucus fills airway lumenNumerous goblet cellsThickened lamina reticularisMany eos and MC in submucosaMore bronchial smooth muscle
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Anaphylaxis= Serious allergic reaction with rapid onset, which can cause death
Anaphylaxis is unpredictable, can occur in anyone, anywhere at any timeUnderrecognized by patients and underdiagnosed by MDs
Incidence: doubled from 21/100.000 person/year (1980s) to 50/100.000 person/year (1990s)
with 70/100.000 person/year younger than19 years
Triggers: Food (peanut, treenut, shellfish, fish, milk, eggs)Medication (β-lactam antibiotics)Insect stings/bitesNatural latex rubberIgG-Ag complexesComplement and coagulation system activation
exercise, cold air or water, medication Simons FER. JACI 2009
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
http://www.bio.davidson.edu/courses/immunology/Students/spring2006/Witcher/figure%2012-11.jpg
Mechanisms
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Patient-specific risk factorsSevere concomitant allergic rhinitis and eczemaSevere asthmaChronic obstructive pulmonary diseaseOther respiratory diseasesCardiovascular diseasesMastocytosis and clonal mast cell disordersDiseases impeding prompt recognition (CNS, psychiatric disorders,..)
Increased risk of severe, life-threatening or fatal anaphylaxis
Diagnosis of anaphylactic event: histamine in serum and 24h urinetryptase
Confirmation of anaphylactic trigger: History, skin tests, allergen-specific IgEChallenge tests
Simons FER. JACI 2009
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Therapy of anaphylaxisPreventive measures:• Avoidance of specific triggers• Immunomodulation (oral desensitization, sc. anti-IgE, TCM medication,
immunotherapy with insect venom)
Emergency preparedness:• Self-injectable epinephrine
Leung DYM et al. N Engl J Med 2003Simons FER. JACI 2006
Srivastava KD et al. JACI 2009
Emergency treatment:• Stop allergen exposure• O2 and volume substitution• Epinephrine gavage• Antihistamines• Corticosteroids• β2-Symptatomimetica
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
The correct use can save lives!
Patient training for EpiPen use
Lecture 514.094 of the Medical University Vienna
The Pathophysiology of AllergyChapter 2: Type I allergy: Mechanisms in
the effector phase and AnaphylaxisEva Untersmayr-Elsenhuber
Department of Pathophysiology and Allergy Research
Thank you foryour attention!