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Distinct immunological pathomechanism
behind hypersensitivity (allergic) reactions
Type-I Hypersensitivity (Immediate reaction)
Type-II Hypersensitivity
Type-III Hypersensitivity
Type-IV Hypersensitivity
Classification depends on pathophysiological immunological
mechanisms (Coombs and Gell, 1963)
Mast-Cell
IgE
IgE-Receptor
Allergen
Histamine: vasodilatation + increased permeability
of the capillaries to serum
Leukotrienes: Chemotactic for leucocytes +
activation of granulocytes
Allergologie
Springer-Verlag
2. Auflage
Allergy is a disease of the T-
Cells!
Modified from Jacob, Grage-Griebenow et.al, Allergo J, 2003.
In the lymphnode: T-cell programming
Th2
Th2
Th2
Th2 T naiv
Humoral defense,
Inflammation
Allergy
Tr1
Tr1 Tr1
T naiv
Tolerance,
Anti-inflammation
no Allergy
Th1 Th1
Th1 Th1
T naiv
Cellular defense,
Inflammation
no Allergy
Th0
Th2
Th1
IL-4, IL-5
IL-13
IFN-g
IgE
IgG4
IgG1
DTH
In the lymphnode: T-Cell Programming
IFN-g blocks
development
of Th2 cells
Pollen
Milben
(Exkremente)
Tiere
(Haare, Speichel,
Serum)
Pilze
(Sporen)
Insekten
(Gifte)
Nahrungsmittel
Medikamente
(Haptene)
Chemikalien Pflanzen
Bakterien
Rizinusbohnen
Latex
Ficus Benjamina
Bäume
Gräser
Kräuter
Alternaria
Cladosporium
Aktinomyceten
Dermatophagoides
pteronyssinus
Dermatophagoides
farinae
Biene Wespe
Mücke
Pferd
Hund
Katze
Milch
Ei
Früchte
Getreide
Penizillin
Analgetika
Narkotika
Isozyanate
Formaldehyd
Ethylenoxid
Allergens
How does an antigen become an allergen?
• It has to be a protein or it must be able to bind to a protein covalently
• Enzymatic functions may facilitate the access of the allergen to distinct tissues
• Weight is between 10 and 40 kDa (good diffusion into tissue)
• It should be water-soluble
• Allergens have to carry or come along with adjuvants for Th2-sensitzation!
Important properties for an
antigen to become an allergen
Proteases as allergens
Der p 1: Dermatophagoides pteronyssinus Peptidase 1
Adjuvances for sensitization I
House dust mite contain lipopolysaccharides that are
bound to a MD-2 like molecule
Human MD-2 Der P2
J. Endotoxin Res. 2005 11: 186
Adjuvances for sensitization II
A low dose of LPS is important to induce the most important parameters
of allergy in a murine model of allergy
J. Exp. Med. 2002, 196(12):1645
High doses of LPS protect from the development of the most
important parameters of allergy in the murine model
Pathogenesis of Allergic Asthma
B-cell
T-cell
Epithelium
Allergen
Th2 APZ
IgE
Mast Cell
IgE
Sensitization
Epithelium
Mediators of inflammation
(Histamin, Leukotriene, etc.)
Mucus-
production
Icreased
permeabilty
>Edema
necrosis
Eos
IL-5
Th2-cells (IL-4, IL-5 and
IL-13)
Allergen
Mast cell
Delayed Reaction
Chronic phase of the allergic immune reaction in the lung
Proteins produced by eosinophilic granulocytes
Epithelium
necrosis
Eosinophil
IL-5
Th2-cell (IL-4)
Allergen
M
M
TNF-a
Th1-cell (IFN-g)
necrosis
Th17-cell
(Th-17)
necrosis
Neutrophil
IL-17
Remodelling
necrosis
TGF-ß
Chronification
Airway pathology in asthma
Hagen-Poiseuille
Law
r
Air flow
normal airway obstructive airway
Smooth muscle
Mucosa
Mucus
Contraction
Edema
Excess Mucus
When the radius of the
airway lumen is reduced
to 50% the
airflow s reduced to 1/16!
Lung function measurement (FEV1) After Allergen-Challenge
Prevalence of Allergic Disease
in Germany
Schlaud M et al. KiGGs-Studie,
Bundesgesundheitsblatt (2007) 50: 701-710
%
Th0
Allergy
Th2 IL-4
Th1
INFECTIONS
Pathogenes
NO Allergy
IFN-g
Hygiene-Hypothesis
Type-I Hypersensitivity (Immediate reaction)
Type-II Hypersensitivity
Type-III Hypersensitivity
Type-IV Hypersensitivity
Type-II Hypersensitivity
Cytolysis
Complementreaction Phagocytosis
Example: Rhesus-
Incompatibility
Red blood cell
From the fetus
antibodies towards
the Rhesus factor from
the mother
Type-I Hypersensitivity (Immediate reaction)
Type-II Hypersensitivity
Type-III Hypersensitivity
Type-IV Hypersensitivity
Typ-III Hypersensitivity
Local or systemic
inflammation
Immuncomplexes
Complementreaction
Antigens
http://www.clevelandclinicmeded.com
Farmers´ lung
Continuous exposure to dust of the farming
environment results in production of IgG towards
undefined antigens. Following a subsequent exposure,
IgG antibodies combine with the inhaled allergen to
form immune complexes in the walls of the alveoli in
the lungs. This causes fluid, protein, and cells to
accumulate in the alveolar wall which slows blood-gas
interchange and compromises the function of the lung.
Immune complex
Antigens from
the farming
environment
Janeway's immunobiology (7th ed.). Garland Science.
Typ-I Hypersensitivity (Immediate reaction)
Typ-II Hypersensitivity
Typ-III Hypersensitivity
Typ-IV Hypersensitivity
Typ-IV Hypersensitivity
Local
Inflammation
APC
IFN-g
cytokines
Th1
Nickel Allergy
Allergic Contact-ekzema: Allergy of
the late type; Hypersensitivity has
been acquired by the contact to the
allergen. Antigens are presented by
Langerhans-cells to T-lymphocytes.
After activation and proliferation of
Nickel specific T-lymphocytes the
sensitization phase is terminated.
After the sensitization phase (at least
5 days) another contact leads to
edema, erosions etc. with a
maximum 24-72h after contact.
Sensitization phase of delayed type Hypersensitivity
Activation and proliferation
of Th1 cells
Nickel binds to human TLR-4 and activates APCs
Effector phase of delayed type Hypersensitivity
