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Fostering new partnerships in the field of allergy and allergic diseases
Maria YazdanbakhshLeiden University Medical Centre
New epidemiological settingsNew models
New insturments
EU International cooperation:
Now within the field of allergy; Food and Aeroallergy, Asthma
In area of infectious diseases from 1990-2008 under STW, INCO-DEV, FP6
Tropical diseases………………(Filinmor, Tranchi, Schistoinir, Coinfect……)
GLOFAL
EUROPREVALL
GABRIEL
Relationship between parasitic infections and allergies
More Th2
More allergies???
Th2
Wide variation in prevalence of asthma, rhinitis, eczema worldwide (ISAAC group Lancet 1998)
UK, Australia
Indonesia, Ethiopia
Questionnaire based data
Allergens
Not allergic
High allergen specific IgE
Positive skin test to allergen
Atopic diseases
Food allergy Asthma Eczema Rhinitis
Early life exposures:
infections,breast feeding,growth rate, family size, pet exposure etc
leading to immune programming with strong regulation
Early Exposures
(permanent effect)Current Exposures
(removable effect)
Allergens
Current exposures:
infections, energy balance, nutritional status, diet etc
leading to down regulation
Cord blood School children
Peanut allergy is estimated to be about 1.3% in Canada and US
Recent data from Hong Kong and mainland China
Reported adverse reactions to peanut Hong Kong 0.7%Mainland China 0.04%
•Different preparation methods
•Introduction of peanut in early life
• immune tolerance
•Genetics
GhanaIgE+ve 17%SPT+ve 2.0%
The development of the immune system
Effects from the environment
Exposure to micro organismsDietNutrition
In addition to genetics…..
Modern urban lifestyle of the high income countries is associated with the current epidemic of atopic disorders
The inclusion of collaborators in areas with differentdegrees of urbanization will be more likely to reveal the gradation of changes such that the detection of risk factors may be easier
These factors will lead to understanding of the underlying pathophysiological mechanisms that influence allergic disease manifestation
Birth
High allergen specific Ig E
Positive skin test to allergen
Atopic diseases
Asthma Eczema Rhinitis
APC Pro-inflammation Anti-inflammation
+/_
SOCS-1SOCS-3
IL-10IL-12IL-23
Different environment: an altered immune program?
TLRs…….Co stimulatory molecules
Th1Th2 Treg
Th2Th2
Th17
Disease
Physiologic stress
diet
Need models………….
Correlates of disease and protection
8.2
24.0
1.8
46.9
E.colimDC
Th1 22.6
10.8
SEA
Th2
iDC
IL-4
NaïveT cell
Helminthextract
IL-4
IFN-
Everts, van der Ham, Smits unpublished data
IFN-
Dust extract
cfos
delta-4
0.1
1
10
100
LPS + SEA LPS + E. coli
Rela
tive
xprre
ssio
n
mRNA expression cfos delta-4
SEA E.Coli
IL-10
Animal modelsTargeted knock ins and outs
allergen challenge
0 14 16 17 197 18
11 12 13 14
challenge
allergensensitisation challenge
InfectionExposure to factors
allergensensitisation
Spleen
B cells
CD4+ T cells
Local tissue reaction
….Need innovative models…..
LUMC Biomolecular Mass Spectrometry Unit
sample preparationand separation
robotics
separation methods(CE, HPLC, UPLC, GC)
mass spectrometry bioinformatics
data storageand processing
ion traps, ESI-(Q-)TOF, MALDI-TOF(/TOF), FTICR
Unique proteomics- and metabolomics-infrastructure in a clinical setting
• Cell biology proteomics • Glycomics and glycoproteomics • Clinical proteomics • FTICR- and high-throughput proteomics (first 15T in Europe)• Advanced separations and clinical MS-metabolomics • Imaging MS • Biomedical NMR spectroscopy
Total value equipment-infrastructure: approx. 20 M euro
LUMC Biomolecular Mass Spectrometry Unit
m/z
689.
3 D
P 4
851.
4 D
P 5
1175
.5 D
P7
1013
.4 D
P 6
559.
454
6.5
1337
.5 D
P8
1499
.7 D
P 9
600 800 1000 1200 1400 1600
m = 162
m/z
689.
3 D
P 4
851.
4 D
P 5
1175
.5 D
P7
1013
.4 D
P 6
559.
454
6.5
1337
.5 D
P8
1499
.7 D
P 9
600 800 1000 1200 1400 1600
m = 162
Fraction C1Hexose polymer
365.
1
375.
0
551.
1
413.
3
272.
9
381.
1
541.
2
331.
034
0.9
517.
0
261.
0
449.
4
507.
1
305.
1
0.00
0.25
0.50
0.75
1.00
1.25
1.50
4x10
Inte
ns. [
a.u.
]
250 300 350 400 450 500 550m/z
365.
1
375.
0
551.
1
413.
3
272.
9
381.
1
541.
2
331.
034
0.9
517.
0
261.
0
449.
4
507.
1
305.
1
0.00
0.25
0.50
0.75
1.00
1.25
1.50
4x10
Inte
ns. [
a.u.
]
250 300 350 400 450 500 550m/z
Fraction C2Hexose DImer
338.
831
6.8
176.
6
413.
1
360.
8 D
P1
153.
613
6.6
500.
9
391.
1
272.
7
449.
2
536.
9
100 150 200 250 300 350 400 450 500 550 m/z
338.
8
413.
1
699.
0 D
P2
1037
.1 D
P3
500.
9
1375
.1 D
P4
272.
7
449.
2
536.
9
1713
.1 D
P5
400 600 800 1000 1200 1400 1600 1800
m/z
m = 338 sodium adducts of ???
338.
831
6.8
176.
6
413.
1
360.
8 D
P1
153.
613
6.6
500.
9
391.
1
272.
7
449.
2
536.
9
100 150 200 250 300 350 400 450 500 550 m/z
338.
8
413.
1
699.
0 D
P2
1037
.1 D
P3
500.
9
1375
.1 D
P4
272.
7
449.
2
536.
9
1713
.1 D
P5
400 600 800 1000 1200 1400 1600 1800
m/z
m = 338 sodium adducts of ???
Fraction C3unknown
Fraction analysisby Mass Spectrometry
Build onto biobanks Serum
DNA
mRNA
Envoronmental samples
Samples for mRNA analysis through EUROPREVAL and GLOFAL
School children (7-10 yrs)
Centre Nr
Zurich 250
Utrecht 257
Lodz 332
Athens 204
|Reykavik 226
Madrid 240
Hong Kong 400
Canton 400
Tomsk rural 250
Tomsk urban 350
Mysore 400
Bangalore 400
Accra 150
q PCR: measure gene expression
mRNA preserved from allergy patients and controls across Europe, Asia and Africa
Similar in vitro IgE titers but different biological activity
0
10
20
30
40
50
60
70
80
90
100
0,1 10 1000 100000
housedust mite extract (ng/ml)
% h
ista
min
e re
leas
eGabonese sera
0
10
20
30
40
50
60
70
80
90
100
0,1 1 10 100 1000
housedust mite extract (ng/ml)
% h
ista
min
e re
leas
e
Dutch sera
Asn Structural alteration of IgE?
The development of the immune system
Effects from the environment
Nutrition(urban vs rural diet)
Infections
Immune system
Using strongTechnologies“….omics”
Once protective factors/pathways are found Exploit
Develop specific anti inflammatory compoundsGo beyond EuropeModels/dissect the immune system (innate and adaptive cross talk….)Build on cohorts and infrastructureIncorporate training…..clinicalIncorporate training…..clinical
