Immunology - Ruhr-Universit..t Bochum · Type-II Hypersensitivity& Autoimmunity Type-III Hypersensitivity& Autoimmunity Type-IV Hypersensitivity& Autoimmunity Classification depends

Immunology

Marcus Peters, [email protected]

Allergy and Autoimmunity

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



Autoimmunity


Autoimmunity


Autoimmunity


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,



Autoimmunity


Autoimmunity


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.


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


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


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


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

Immunology - Ruhr-Universit..t Bochum · Type-II Hypersensitivity& Autoimmunity Type-III Hypersensitivity& Autoimmunity Type-IV Hypersensitivity& Autoimmunity Classification depends

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