Hypersensitivity
Type-I Hypersensitivity (Immediate reaction)
Type-II Hypersensitivity&
Autoimmunity
Type-III Hypersensitivity&
Autoimmunity
Type-IV Hypersensitivity&
Autoimmunity
Classification depends on pathophysiological immunological
mechanisms (Coombs and Gell, 1963)
The immune system has to decide, whether an immune response
against an antigen is initiated or not…
… is the antigen self or foreign? Is it dangerous or
harmless?
Mast-Cell
IgE
IgE-Receptor
What happens during a Type I-reaction?
Mast-Cell
IgE
IgE-Receptor
Mast-Cell
IgE
IgE-Receptor
Allergen
Mast-Cell
IgE
IgE-Receptor
Allergen
Allergy is a disease of the T-
Cells!
Tr1
Tr1Tr1
Th1Th1
Th1Th1
Th2
Th2
Th2
Th2
Tnaiv
Tnaiv
Tnaiv
Cellular defense,
Inflammation
Humoral defense,
Inflammation
Tolerance,
Anti-inflammation
Tc1Tc1
Tc1Tc1
Tnaiv
Cellular defense,
Inflammation
Modified from Jacob, Grage-Griebenow et.al, Allergo J, 2003.
Some day in the lymphnode: T-cell programming
Allergy
no Allergy
no Allergy
Th0
Th2
Th1
IL-4, IL-5
IL-13
IFN-g
IgE
IgG4
IgG1
DTH
In the lymphnode: T-Cell Programming
Epithelial cells
How does an antigen become
an allergen?
Pollen
Milben
(Exkremente)
Tiere
(Haare, Speichel,
Serum)
Pilze
(Sporen)
Insekten
(Gifte)
Nahrungsmittel
Medikamente
(Haptene)
ChemikalienPflanzen
Bakterien
Rizinusbohnen
Latex
Ficus Benjamina
Bäume
Gräser
Kräuter
Alternaria
Cladosporium
Aktinomyceten
Dermatophagoides
pteronyssinus
Dermatophagoides
farinae
BieneWespe
Mücke
Pferd
Hund
Katze
Milch
Ei
Früchte
Getreide
Penizillin
Analgetika
Narkotika
Isozyanate
Formaldehyd
Ethylenoxid
Extrakte
• It has to be a protein or it must be able to covalently bind to a protein
• 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
• It should be stable and resistant to harsh environmental conditions
• Allergens have to carry or come along with adjuvants for Th2-sensitzation!
Important properties for an
allergen
Proteases as allergens
Adjuvances for sensitization I
Example 1: PALMs= Pollen associated Lipid Mediators from
birchpollen
Example 2: House dust mite contain lipopolysaccharides
That are bound to a MD-2 like molecule
Human MD-2Der 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
Acute phase of the allergic immune reaction in the lung
Chronic phase of the allergic immune reaction in the lung
Goblet cell hyperplasia Eosinophilic Granulocytes
Th0
Th2
Th1
INFECTIONS
Pathogenes
Allergy
NO Allergy
IL-4
IFN-g
Hygiene-Hypothesis
Type-I Hypersensitivity (Immediate reaction)
Type-II Hypersensitivity&
Autoimmunity
Type-III Hypersensitivity&
Autoimmunity
Type-IV Hypersensitivity&
Autoimmunity
Type-II Hypersensitivity&
Autoimmunity
Cytolysis
ComplementreactionPhagocytosis
IgG-mediated
Example: Rhesus-
Incompatibility
Erythroblastose fetalis
The first pregnancy of a
Rh-negative woman with a
Rh-positive child does
not bear complications
2nd pregnancy
Red blood cell
From the fetus
antibodies towards
the Rhesus factor from
the mother
Example: Myasthenia Gravis
Antibodies notice the Acetylcholinereceptor, the
antibody-receptor complex gets endocytosed and is
degraded in the lysosome. Additionally, degradation of
acetylcholine is intensified (by an esterase), no
activation of the postsynapsis by a transmitter leads
to lower signaltransduction. RESULT: Paralysis.
Synapse
Autoantigen:
Acetylcholinreceptor,
Type-I Hypersensitivity (Immediate reaction)
Type-II Hypersensitivity&
Autoimmunity
Type-III Hypersensitivity&
Autoimmunity
Type-IV Hypersensitivity&
Autoimmunity
Typ-III Hypersensitivity&
Autoimmunity
Local or systemic
inflammation
Immuncomplexes
Complementreaction
(Auto)antigens
IgG-mediated
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.
Systemic
Lupus erythematodes
Antibodies recognize different autoantigenes from
different cells and build immuncomplexes. DNA,
histones and ribosomes are constantly available in
many cells so that immuncomplexes can constantly be
build. These immuncomplexes can be found in the
joints, in vessels of the kidneys and in other organs.
There, they induce a complement-reaction which
results in an inflammation.
Immuncomplexes
Autoantigenes:
DNA, Histones,
Ribosomes
Building antibodies against DNA
Histone-spec.
B-cell
DNA-spec.
B-cell
Typ-I Hypersensitivity (Immediate reaction)
Typ-II Hypersensitivity&
Autoimmunity
Typ-III Hypersensitivity&
Autoimmunity
Typ-IV Hypersensitivity&
Autoimmunity
Typ-IV Hypersensitivity&
Autoimmunity
Local
Inflammation
APC
IFN-g or IL-5
cytokines
Th1/2
Problems with Nickel?
Allergic Contact-ekzema: Allergy of
the late type; Hypersensitivity has
been acquired by the contact to the
allergen. Antigens, which have been
changed by Langerhans-cells are
presented to T-lymphocytes. These
T-lymphocytes now build cell-clones
with antigenspecific receptors. After
the sensitization phase (at least 5
days) another contact leads to
odema, weeping erosions etc. with a
maximum 24-72h after contact.
(Pschyrembel 258. Auflage)
TLR-4 MD2
Nickel binds to human TLR-4 and activates APCs
Insulindependent Diabetes
mellitus (Type 1)
If 80% of the b-Cells are destroyed, Insuline is in such a low
concentration that blood sugar cannot be metabolized sufficiently
anymore (hyperglycemia). One short-term effect is shock. Long-
term effects are: Damage of different organs ( Eyes, Kidneys,
Heart, Skin etc.)
Br Med Bull December 1, 2008 .
Cellular mechanism of type 1 diabetes
Factors, that favor the development of
autoimmune diseases
Environment(Infections,
Antigenes)
Immun-
regulation(Tolerance)
Genes (HLA)
Auto-
immune-
disease
Possible triggers of autoimmune
diseases
Unsuccessful negative-selection in the Thymus (T-
Cells) or in the Bone-marrow (B-Cells)
Dendritic Cells
Thymocytes
Medulla
Cortex
Mature
Lymphocyte
Low Affinity,
Survive,
Positive Selection
Low Affinity,
Survive,
Positive Selection
No or high Affinity,
Apoptosis,
Negative Selection
High Affinity,
Apoptosis,
Negative Selection
Corticoepithelial
Cells
MHC I & II
MHC I & II
+ Autoantigenes
In the Thymus: Maturation and Selection of Thymocytes, which
later become T-Cells.
Possible triggers of autoimmune
reactions
Disturbance of peripheral tolerance
T-regulatory Cells
Th0 FoxP3IL-10
TGF-b
+
IL-10
Inflammation ↓
T-Zellen ↓
CD25
Davidson, A. (2001)
N Engl J Med.
345:340-350
Defects in the
expression of
cytokines,
which can be
associated with
autoimmunity
T-regulatory cells
Possible triggers of autoimmune
reactions
Antigenes from viruses or from bacteria can act as
mimotopes
Antigenes of viruses or bacteria as mimotopes
Antibodies against OspA
(Borrelia burgdorferi) crossreact
with LFA-1a on activated T-
Cells
The disease Lyme Arthritis occurs months after a
succesfully treated borreliosis. No Borrellia are
detectable anymore, however a local inflammation
develops in different tissues, most often in the
joints (Synovia).
LFA-1a
T-Cell
Outer surface protein A
(OspA)
Antigenes of viruses or bacteria as mimotopes: e.g.
Psoriasis
Peptid from M-Protein of Streptococcus
Peptidoglucan
TLR2-
Receptor
Psoriasis: T-Cells react to Streptococcus-Peptids but they can also
crossreact with a Keratine-peptide
Cytokines
Perforine
Skin
Antigen-Presentation
& Costimulation
Keratine
T-cell
T-cell
Possible triggers of autoimmune
reactions
The role of the MHC/HLA molecules during
Autoimmunreactions
HLA-Genotype and susceptibility for
Autoimmune diseases
Krankheit Rel. Risiko HLA-Allel Lupus
5,8 %
DR3
Diabetes Mellitus
3,4 %
DR3 und DR4
Myasthenia gravis
2,5 %
DR3
Janeway, C.A. (1997) Immunologie. pp. 464
Possible triggers of autoimmune
reactions
The role of T-Cell programming
T-naive
Th17
IL-6, IL-1ß, TGFß, IL23
Th17 Cells
IL-17A, IL-17F
Neutrophilic granulocyte
Immunological processes during Multiple Sclerosis