Y Y

Allergy-Immunology Sub Division

The basic reaction of hypersensitivity
in allergic diseases
Allergic disease problems
Rising Prevalence
Pathogenic factors
Genetic
Environmental
Immunological
Rising Prevalence
0
5
10
15
20
25
30
Asthma Rhinitis Eczema Total
1979
1991
Aberg. Clin Exp Allergy. 1995.95:815. Swedish Children.
ALERGIC REACTION
MECHANISM of ALLERGY
ALLERGIC INFLAMMATION
ALLERGIC MARCH
PREVENTIVE TREATMENT
ALLERGIC DISEASES
IN CHILDREN
ALLERGIC REACTION
GENETIC FACTOR
ENVIRONMENTAL FACTOR
ALLERGIC REACTION
GENETIC FACTORS
Herediter
Race
Genetic
ALLERGIC REACTION
ENVIRONMENTAL FACTORS
Allergens
Infections
Pollution
Physical activity
Etc.
GENETIC FACTOR
Cytokine dysregulation
Allergens
Infections
Pollutant
FAKTOR LINGKUNGAN
AGE
ALLERGIC DISEASES
Gern JE, Lemanske Jr RF. Immunol Allergy North Amer 1999; 19:233-52.
MECHANISM of ALLERGY
SENSITITATION
ENHANCEMENT
TRIGGERING
Fireman P, Slavin RG. Atlas of allergies, 1991.
SENSITTTATION

Fetus, infant, toddler
Cigarette smoke
Foods
Drugs
Environment
Etc.
MECHANISM of ALLERGY
Risk Factors: Early Allergen Eposure
MECHANISM of ALLERGY
SENSITITATION
Risk Factors
Family History - Overall, Disease-specific
Tobacco Smoke - Pregnancy, Environmental
Absent / short breast feeding
Pollution
Diet
MECHANISM of ALLERGY
SENSITITATION
Risk Factors: Family Size
0
5
10
15
20
25
0 1 2 3 4 >5
% ATOPIC
Number of siblings
Matricardi. JACI 1998.101:439.
MECHANISM of ALLERGY
SENSITITATION
Sensitisation in utero...
T cell responses ~ 22 weeks
Cord T cell responses at birth
mite ~ 47 %
egg, milk ~ 75 %
less IFN and more IL-4 & 10
IgE at birth
milk, wheat, egg
? transplacental protein, peptide, cytokines
MECHANISM of ALLERGY
ENHANCEMENT

Cows milk
Eggs
Nuts
Fish
Cigarette smoke
Environment
Etc.
MECHANISM of ALLERGY
IgE Cat Dander
IgE House
Dust Mite
IgE Grass
Pollen
IgE Milk
IgE Egg
Raised Normal




ETAC. Wahn U. Pediatr Allergy Immunol 1998; 18:165-81.
Occurrence of asthma in children receiving placebo
during the 36-month total study period
95% CI for RR Relative risk*
1.4
1.1
1.6
1.5
1.7
*Relative risk of developing asthma
in the presence of raised marker
40.7%
55.0%
48.3%
52.8%
46.3%
79.4%
44.4%
70.6%
43.4%
66.2%
1.1 - 1.7
0.9 - 1.4
1.3 - 1.9
1.2 - 1.9
1.4 - 2.1
TRIGGERING

Allergens
Exercise
Emotional
MECHANISM of ALLERGY
Allergen of allergic diseases
MECHANISM of ALLERGY
ALLERGIC INFLAMMATION
IgE
Th2
Plasma-cell
B-cell
Eosinophil
Mast-cell
IL-3, IL-4 IL-4
IL-5
SENSITATION
T Cell
Antigen Presenting Cell
Intact antigen
ALLERGIC INFLAMMATION
T-cell
B-cell
Stimulation
Class Switching
IgE
IL-4
ALLERGIC INFLAMMATION
IMMUNE RESPONS BALANCE
Th1 IFNg
IL-2
TNF
Th2 IL-4
IL-5
IL-10
IL-13
CELLULAR RESPONS HUMORAL RESPONS
ALLERGIC INFLAMMATION
Th1 / Th2 Skewing
Th1 Th2
Intracellular Pathogens Extracellular Pathogens
TNF, IFNg, IL-12 IL-4, 5, 10
Promote inflammation & Promote IgE production &
intracellular killing eosinophil recruitment
Uncommitted T-cell
ALLERGIC INFLAMMATION
Fetal Immune
Development
Transplacental
allergen transfer
Maternal T cells
produce Th2-like
cytokines in response
to trophoblast
tissue
Weak Th2
Priming
ALLERGIC INFLAMMATION
Weak Th2
priming
Reinforcement
of Th2
response
Th1 skewed
response
Tolerance
Allergen load, diet, smoke, pollution
Genetic factors
Infection, breast feeding, family size
BIRTH
ALLERGIC INFLAMMATION
Intervention ?
If Mum Allergic too...
IL-4 & 10 are upregulated in atopics
Higher IL-10 in amniotic fluid (gut, lung)
Increased inheritance of atopy for mum > dad
---> importance of intrauterine environment.
ALLERGIC INFLAMMATION
IgE
ALLERGEN
? AUTOIMMUNE
Mast cell degranulation



Histamine,
mediators, cytokines
IL-5
IL-4, 6
Mediator release from
degranulated mast cell
IgE
EOSIN
B cell
Y Y
Newly
Generated
Histamine
Chemotaxins
-eosinophils
-neutrophils
Proteases
-tryptase
-chymase
Leucotrienes
Prostaglandins
PAF
Cytokines
-IL4,5,6,8
-TNF-a
Mast cell mediators
ALLERGIC INFLAMMATION
Preformed
Synthesised



Histamine
PGD2
Tryptase
TNF
IL-5
Eosin
Early Allergic Response
Sneeze
Itch
Mucus
Smooth
muscle
Congestion
ICAM-1
ALLERGIC INFLAMMATION
Arachidonic Acid
LT-A4
LT-B4
LT-C4
LT-D4
LT-E4
Chemotaxis
Oedema
Mucus
Chemotaxis
Sm muscle stim
BHR
Eosinophilia
5-LO
Late Allergic Response
ALLERGIC INFLAMMATION
T Cell
Antigen
Presenting
Cell
Late allergic response
IL-5
T
E
E
E
E
B
IgE
ALLERGIC INFLAMMATION
Antigen
SENSITATION
A
HYPERSENSITIVE
ALLERGIC DISEASE
ALLERGIC MARCH
ATOPY
GIT ALLERGIC DISEASES
ATOPIC DERMATITIS
ALLERGIC RHINITIS
ASTHMA
ALLERGIC MARCH
ATOPIC DERMATITIS
GRASS POLLEN
HOUSE DUST MITE
CAT DANDERS
BRONCHIAL ASTHMA
ALLERGIC RHINITIS
GEN
ALLERGIC MARCH
THE MANAGEMENT of ALLERGIC DISEASES

ALLERGEN AVOIDANCE
ENVIRONMENTAL CONTROL
MEDICAMENTOUS
IMMUNOTHERAPY
Prevention of Allergy
Dietary Manipulation
Breast feeding ?
Treatment
Antihistamines
Block histamine receptor
Stabilise mast cell membrane
Reduce
Mediator release
ICAM-1 expression
Eosinophil recuitment
Corticosteroids
Mucus secretion
Vascular permeability/oedema
Mediator release
Cytokine production
Inflammatory infiltrate/activation
Langerhan cells in epithelium
ATOPY
ALLERGIC DISEASES
EARLY TREATMENT
Immunotherapy
Reduced allergen-specific IgE
Blocking IgG antibodies
Altered Th1 / Th2 response
reduced IL-4/IL-5 secretion
reduced eosinophil recruitment
Immunotherapy: The Future
Allergoids
Allergen peptides
immunogenic
analogues
Allergen-encoded DNA vaccination
Anti-IgE antibodies