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Prof. Dr. Rudolf Valenta 1
Pathomechanismen der Allergie
Prof. Dr. Rudolf Valenta
Medizinische Universität Wien
Zentrum für Pathophysiologie, Infektiologie und
Immunologie
Institut für Pathophysiologie und Allergieforschung
Abteilung Immunpathologie
http://www.allergy-research-program.at/cms/
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Clemens von Pirquet
coined the term “Allergy”
Clemens von
Pirquet
Prof. Dr. Rudolf Valenta
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First mention and definition of the term “Allergy”
Münchener Medizinische Wochenschrift 1906
Prof. Dr. Rudolf Valenta
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Clinical manifestations of alle
1. Hay fever:
Allergic rhinitis
Allergic conjunctivitis
2. Cutaneous manifestations:
Atopic dermatitis
Urticaria
3. Gastrointestinal symptoms
4. Asthma
5. Systemic anaphylaxis
Clinical manifestations of allergy
4 Prof. Dr. Rudolf Valenta
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1963 Description of the four types of
hypersensitivity reactions by Coombs & Gell
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Einteilung der allergischen Reaktionen
nach Coombs und Gell (1963)
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The key ingredients for allergic inflammation
defined by the experiment by Prausnitz and
Küstner
• Allergens
• Serum factors specific for allergic individuals (i.e., allergen-
specific IgE antibodies).
A tissue component present in all persons (i.e., mast cells)
Prausnitz C, Küstner H (1921), "Studien über die
Ueberempfindlichkeit", Zentralbl Bakteriol 86: 160–169
Otto Carl W.
Prausnitz Heinz Küstner
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Die allergische Immunantwort
Sensibilisierung – immunologisches Gedächtnis
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Definition: Allergen source, allergen extract,
allergen
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Development of the concept of component-
resolved allergy diagnosis
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Allergen microarrays open the door for testing for
multiple allergens with minute amounts of serum
FASEB J. 2002
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The allergy march in childhood
Atopic dermatitis
can be the first
sign of a lifelong
susceptibility for
allergic diseases
Genetic factors
Food allergies
Allergic
rhinoconjunctivitis
Bronchial asthma 40% of infants
having atopic dermatitis develop
asthma until the age of 4
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European-wide assessment of the molecular evolution of
allergic sensitization in birth cohorts: MeDALL
Prof. Dr. Rudolf Valenta
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The MeDALL allergen chip
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List of allergens contained on the MeDALLallergen-chip
Lupinek C et al, Methods 2014, 43:1202-16
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Higher sensitivity of the MeDALL-chip to detect allergic
sensitization compared to skin testing and CAP testing
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Prevalences of IgE reactivity to PR-10 proteins
at ages 4, 8 and 16
Westman et al; J Allergy Clin Immunol. 2015, 135, 1199-1206
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Allergic patients exhibit a constant IgE reactivity
profile: A 10 years follow up
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Seasonal exposure to pollen allergens strongly boosts
systemic allergen-specific IgE responses
Niederberger V, et al., Int Arch Allergy Immunol. 2006, 142:133-144
Prof. Dr. Rudolf Valenta
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Allergen contact boosts IgE reactivity to a
pre-established allergen profile
Niederberger V, et al., Int Arch Allergy Immunol. 2006, 142:133-144
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Allergen contact via the nasal but not the dermal route
increases allergen-specific IgE levels
Niederberger V, et al., Int Arch Allergy Immunol. 2006, 142:133-144
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Allergen-induced elevations of specific IgE levels lead to
increased release of histamine from basophils
Niederberger V, et al., Int Arch Allergy Immunol. 2006, 142:133-144
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Acute versus chronic allergic inflammation
?
?
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Induction and maintenance of Type I allergy by
allergens
Valenta R. Nat Rev Immunol. 2002, 2:446-53
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Allergens have different allergenic activity
(i.e., different allergenic potency)
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Allergenic activity: Ability to induce mast cell and
basophil degranulation
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Factors determining the allergenic activity
of allergens
J Allergy Clin Immunol 2007;119:384-90.
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Molecular determinants of allergen-
induced effector cell degranulation
Gieras A., et al., J Allergy Clin
Immunol 2007;119:384-90.
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The number of IgE epitopes on a molecule
determines the intensity of effector cell
degranulation
Gieras A. et al., J Allergy Clin Immunol. 2007, 119:384-390
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The level of allergen-specific IgE antibodies
determines the magnitude of effector cell
degranulation
Gieras A. et al., J Allergy Clin Immunol. 2007, 119:384-390
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Clustering of IgE epitopes on allergen surfaces:
Profilin-Bet v 2
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The localization of IgE epitopes on an allergen is
important for its allergenic activity
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Construction of artificial allergens with defined numbers
and localization of IgE epitopes
Gieras A., et al., J Allergy Clin Immunol
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Artificial allergens show similar fold and are
monomeric
Gieras A., et al., J Allergy Clin Immunol
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IgE reactivity of artificial allergens corresponds
to the number of epitopes
Gieras A., et al., J Allergy Clin Immunol
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Visualization of complexes consisting of artificial
allergens and IgE antibodies by negative-stain
electron microscopy
Gieras A., et al., J Allergy Clin Immunol
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Visualization of complexes consisting of artificial
allergens and IgE antibodies by negative-stain
electron microscopy
Gieras A., et al., J Allergy Clin Immunol
Prof. Dr. Rudolf Valenta
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Visualization of complexes consisting of artificial
allergens and IgE antibodies by negative-stain
electron microscopy
Gieras A., et al., J Allergy Clin Immunol
Prof. Dr. Rudolf Valenta
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Visualization of complexes consisting of artificial
allergens and IgE antibodies by negative-stain
electron microscopy
Gieras A., et al., J Allergy Clin Immunol
Prof. Dr. Rudolf Valenta
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Visualization of complexes consisting of artificial allergens and IgE
antibodies by negative-stain electron microscopy
Gieras A., et al., J Allergy Clin Immunol
Prof. Dr. Rudolf Valenta
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Visualization of complexes consisting of artificial allergens and IgE
antibodies by negative-stain electron microscopy
Gieras A., et al., J Allergy Clin Immunol
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In vitro allergenic activity of artificial allergens: Allergens containing
two binding sites closely together are approximately 10-fold more
allergenic than allergens with two binding sites in distant
localization
Gieras A., et al., J Allergy Clin Immunol
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In vivo allergenic activity of artificial allergens also indicates the
importance of epitope proximity for allergenic activity
Gieras A., et al., J Allergy Clin Immunol
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The number and
proximity of IgE
epitopes on an
allergen determine its
allergenic activity
Summary
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Conformational and sequential
IgE epitopes
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Calcium binding allergens as example:
Seiberler S, et al., EMBO J. 1994, 13:3481-6
Respiratory allergens contain mainly
conformational epitopes
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Respiratory allergens contain mainly
conformational epitopes
Seiberler S, et al., EMBO J. 1994, 13:3481-6
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Respiratory allergens contain mainly
conformational epitopes
Valenta R. & Kraft D., Immunol Rev., 2001, 179:119-27
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Recombinant fragments of Bet v 1
(aa 1-74; aa 75-160)
Vrtala S, et al., J.Clin.Invest.1997, 99:1673-1681
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Recombinant Bet v 1 fragments lack
IgE reactivity due to loss of fold
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Linhart B, et al., Curr Opin Immunol, 2005, 17:646-55
Disruption of conformational IgE epitopes: A strategy
for the development of hypoallergenic vaccines
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Activation of allergen-specific T cells and
induction of allergic inflammation can occur in
an IgE-independent manner
Immunoglobulin E-independent major histocompatibility
complex-restricted T cell peptide epitope-induced late
asthmatic reactions.
Haselden B. M. et al., J.Exp.Med. 1999; 189: 1885-94
Allergen-derived T cell peptide-induced late asthmatic
reactions precede the induction of antigen-specific
hyporesponsiveness in atopic allergic asthmatic subjects.
Oldfield W. L. et al., J.Immunol. 2001; 167: 1734-9
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Experimental model
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A-F: birch pollen allergic individuals G: allergic person without birch pollen allergy H-I: non-allergic individuals 0: buffer control
rBet v 1 fragments lack IgE reactivity
Campana R, et al., J Allergy Clin Immunol 2008,121(2): 528-530
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40 µg/ml
20 µg/ml
20 µg/ml
40 µg/ml
20 µg/ml
40 µg/ml
40 µg/ml
20 µg/ml
rBet v 1 →
rBet v 1 →
F1+F2 →
F1+F2 →
A-E: birch pollen allergic patients suffering from AD F: birch pollen allergic patient without AD
Lack of allergenic activity of rBet v 1 fragments
Campana R, et al., J Allergy Clin Immunol 2008,121(2): 528-530
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Non-IgE-reactive rBet v 1 fragment mix induce a positive
eczematous reaction in almost all AD patients
rBet v 1 →
F1+F2 →
F1+F2 →
rBet v 1 →
16
0 μg/application
A-E: birch pollen allergic patients suffering from AD F: birch pollen allergic patient without AD
Campana R, et al., J Allergy Clin Immunol 2008,121(2): 528-530
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?
?
Acute versus chronic allergic inflammation
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Mechanisms of allergic inflammation
Larche M, et al., Nat Rev Immunol 2006, 6:761-71 Valenta R, et al., Adv Immunol 2004, 82:105-53
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http://www.allergy-research-program.at/cms/
Prof. Dr. Rudolf Valenta