The basic reaction of hypersensitivity

in allergic diseases

YY

Allergy-Immunology Sub Division

Allergic disease problems
• Rising Prevalence
• Pathogenic factors
– Genetic
– Environmental
– Immunological
 Rising Prevalence
30

25

20

15 1979
1991
10

0
Asthma Rhinitis Eczema Total

Aberg. Clin Exp Allergy. 1995.95:815. Swedish Children.

 ALLERGIC DISEASES
IN CHILDREN

ALERGIC REACTION
MECHANISM of ALLERGY
ALLERGIC INFLAMMATION
ALLERGIC MARCH
PREVENTIVE TREATMENT
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 FAKTOR LINGKUNGAN

AGE • Allergens
• Infections
• Pollutant
• Cytokine dysregulation

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.
MECHANISM of ALLERGY

SENSITTTATION

 Fetus, infant, toddler

 Cigarette smoke

 Foods

 Drugs

 Environment

 Etc.
MECHANISM of ALLERGY

SENSITITATION
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
25

20

15
% ATOPIC
10

0
0 1 2 3 4 >5
Number of siblings
Matricardi. JACI 1998.101:439.
MECHANISM of ALLERGY

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
 Cow’s milk
 Eggs

 Nuts

 Fish

 Cigarette smoke

 Environment

 Etc.
Occurrence of asthma in children receiving placebo
during the 36-month total study period
Raised Normal Relative risk* 95% CI for RR

40.7%
IgE Egg 1.4 1.1 - 1.7
55.0%

48.3%
IgE Milk 1.1 0.9 - 1.4
52.8%

IgE Grass 46.3%

Pollen
1.7 1.4 - 2.1
79.4%

IgE House 44.4%

1.6 1.3 - 1.9
Dust Mite
70.6%

43.4%
IgE Cat Dander 1.5 1.2 - 1.9
66.2%
*Relative risk of developing asthma
in the presence of raised marker

ETAC. Wahn U. Pediatr Allergy Immunol 1998; 18:165-81.

MECHANISM of ALLERGY

TRIGGERING

 Allergens
 Exercise

 Emotional
MECHANISM of ALLERGY

Allergen of allergic diseases

 ALLERGIC INFLAMMATION
Th2
IL-5
Eosinophil
IL-4 IL-3, IL-4

Mast-cell
B-cell

SENSITATION

IgE
Plasma-cell
ALLERGIC INFLAMMATION

Intact antigen

T Cell

Antigen Presenting Cell

ALLERGIC INFLAMMATION

IL-4
IgE
B-cell
T-cell

•Stimulation
•Class Switching
ALLERGIC INFLAMMATION

IMMUNE RESPONS BALANCE

Th2 IL-4
Th1 IFNg
IL-5
IL-2
IL-10
TNF
IL-13

CELLULAR RESPONS HUMORAL RESPONS

ALLERGIC INFLAMMATION

Th1 / Th2 Skewing

Uncommitted T-cell

Th1 Th2

Intracellular Pathogens Extracellular Pathogens

TNF, IFNg, IL-12 IL-4, 5, 10
Promote inflammation & Promote IgE production &
intracellular killing eosinophil recruitment
ALLERGIC INFLAMMATION

Transplacental
allergen transfer

Fetal Immune Weak Th2

Development Priming

Maternal T cells
produce Th2-like
cytokines in response
to trophoblast
tissue
ALLERGIC INFLAMMATION

Reinforcement
Allergen load, diet, smoke, pollution of Th2
Genetic factors response

Weak Th2
priming Infection, breast feeding, family size

Th1 skewed
response
BIRTH
Intervention ?
Tolerance
ALLERGIC INFLAMMATION

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.
Mast cell degranulation

? AUTOIMMUNE

IgE
ALLERGEN
 Mediator release from
degranulated mast cell
IgE

YY
IL-5

EOSIN B cell

IL-4, 6

Histamine,
mediators, cytokines
ALLERGIC INFLAMMATION

Mast cell mediators

• Preformed • Newly
Synthesised Generated
Histamine Leucotrienes
Chemotaxins Prostaglandins
-eosinophils PAF
-neutrophils Cytokines
Proteases -IL4,5,6,8
-tryptase -TNF-a
-chymase
ALLERGIC INFLAMMATION

Early Allergic Response

IL-5
Sneeze
Eosin Itch

Histamine Mucus

PGD2 Smooth
muscle
Tryptase
Congestion
TNF
ICAM-1
ALLERGIC INFLAMMATION

Late Allergic Response

Arachidonic Acid

5-LO Oedema
Mucus
LT-A4
Chemotaxis
LT-C4 Sm muscle stim

LT-B4 LT-D4 BHR

Chemotaxis LT-E4 Eosinophilia
ALLERGIC INFLAMMATION
Late allergic response
Antigen Antigen
Presenting
Cell
T Cell

IL-5
E
E E
T E
B IgE
 ‘ALLERGIC MARCH’

SENSITATION

HYPERSENSITIVE

ALLERGIC DISEASE
‘ALLERGIC MARCH’

ATOPY

GIT ALLERGIC DISEASES

ATOPIC DERMATITIS

ASTHMA

ALLERGIC RHINITIS
‘ALLERGIC MARCH’

ATOPIC DERMATITIS
GEN GRASS POLLEN
HOUSE DUST MITE
CAT DANDERS

BRONCHIAL ASTHMA
ALLERGIC RHINITIS
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 EARLY TREATMENT

ALLERGIC DISEASES
 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