Allergy - Ruhr-Universität Bochum · Nickel Allergy Allergic Contact-ekzema: Allergy of the late...

Immunology – XI

05.Juli 2017, Ruhr-Universität Bochum

Marcus Peters, marcus.peters@rub.de

Allergy

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