Pathomechanismen der Allergie - Phadia Companies/Germany/Veranstaltungen... · Prof. Dr. Rudolf Valenta 1 Pathomechanismen der Allergie Prof. Dr. Rudolf Valenta Medizinische Universität

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/

Clemens von Pirquet

coined the term “Allergy”

Clemens von

Pirquet


2

First mention and definition of the term “Allergy”

Münchener Medizinische Wochenschrift 1906


3

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

1963 Description of the four types of

hypersensitivity reactions by Coombs & Gell


Einteilung der allergischen Reaktionen

nach Coombs und Gell (1963)


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


Die allergische Immunantwort

Sensibilisierung – immunologisches Gedächtnis


8

Definition: Allergen source, allergen extract,

allergen


9

Development of the concept of component-

resolved allergy diagnosis


10

Allergen microarrays open the door for testing for

multiple allergens with minute amounts of serum

FASEB J. 2002


11

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


12

European-wide assessment of the molecular evolution of

allergic sensitization in birth cohorts: MeDALL


13

The MeDALL allergen chip


14

List of allergens contained on the MeDALLallergen-chip

Lupinek C et al, Methods 2014, 43:1202-16


15

Higher sensitivity of the MeDALL-chip to detect allergic

sensitization compared to skin testing and CAP testing


16


17

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


18

Allergic patients exhibit a constant IgE reactivity

profile: A 10 years follow up


19

Seasonal exposure to pollen allergens strongly boosts

systemic allergen-specific IgE responses

Niederberger V, et al., Int Arch Allergy Immunol. 2006, 142:133-144


20

Allergen contact boosts IgE reactivity to a

pre-established allergen profile



21

Allergen contact via the nasal but not the dermal route

increases allergen-specific IgE levels



22

Allergen-induced elevations of specific IgE levels lead to

increased release of histamine from basophils



23

Acute versus chronic allergic inflammation

?

?


24

Induction and maintenance of Type I allergy by

allergens

Valenta R. Nat Rev Immunol. 2002, 2:446-53


25

Allergens have different allergenic activity

(i.e., different allergenic potency)


26

Allergenic activity: Ability to induce mast cell and

basophil degranulation


27

Factors determining the allergenic activity

of allergens

J Allergy Clin Immunol 2007;119:384-90.


28

Molecular determinants of allergen-

induced effector cell degranulation

Gieras A., et al., J Allergy Clin

Immunol 2007;119:384-90.


29

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


30

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


31

Clustering of IgE epitopes on allergen surfaces:

Profilin-Bet v 2


32

The localization of IgE epitopes on an allergen is

important for its allergenic activity


33

Construction of artificial allergens with defined numbers

and localization of IgE epitopes

Gieras A., et al., J Allergy Clin Immunol


34

Artificial allergens show similar fold and are

monomeric



35

IgE reactivity of artificial allergens corresponds

to the number of epitopes



36

Visualization of complexes consisting of artificial

allergens and IgE antibodies by negative-stain

electron microscopy



37



electron microscopy



38



electron microscopy



39



electron microscopy



40

Visualization of complexes consisting of artificial allergens and IgE

antibodies by negative-stain electron microscopy



41

Visualization of complexes consisting of artificial allergens and IgE

antibodies by negative-stain electron microscopy



42

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



43

In vivo allergenic activity of artificial allergens also indicates the

importance of epitope proximity for allergenic activity



44

The number and

proximity of IgE

epitopes on an

allergen determine its

allergenic activity

Summary


45

Conformational and sequential

IgE epitopes


46

Calcium binding allergens as example:

Seiberler S, et al., EMBO J. 1994, 13:3481-6

Respiratory allergens contain mainly

conformational epitopes


47



Seiberler S, et al., EMBO J. 1994, 13:3481-6


48



Valenta R. & Kraft D., Immunol Rev., 2001, 179:119-27


49

Recombinant fragments of Bet v 1

(aa 1-74; aa 75-160)

Vrtala S, et al., J.Clin.Invest.1997, 99:1673-1681


50

Recombinant Bet v 1 fragments lack

IgE reactivity due to loss of fold


51

Linhart B, et al., Curr Opin Immunol, 2005, 17:646-55

Disruption of conformational IgE epitopes: A strategy

for the development of hypoallergenic vaccines


52

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


53

Experimental model


54

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


55

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



56

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



57


58

?

?

Acute versus chronic allergic inflammation


59

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


60

http://www.allergy-research-program.at/cms/


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Pathomechanismen der Allergie - Phadia Companies/Germany/Veranstaltungen... · Prof. Dr. Rudolf Valenta 1 Pathomechanismen der Allergie Prof. Dr. Rudolf Valenta Medizinische Universität