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Allergic Contact Dermatitis (ACD); basal and clinical (retesting) dr. T. Rustemeyer ACD - Immune regulation / Tolerance VUmc, Dermatologie ACD - Socioeconomical impact / Occupation-associated skin diseases

Q: How is the skin build?

Cornified, Granular, Spinous, Basal, Basal membrane, Dermis

Q: Filaggrin mutations: a risk factor of fragrance allergy ?

Filaggrin mutation and increased skin irritability are risk factors for polysensitization to fragrances

Q: Name the two types of DCs in the skin

CD1a: Epidermal Langerhans cells CD-SIGN: Dermal dentritic cells

Q: What does a Langerhans cell bind to?

Lipophilic allergens, -> MHC class I Hydrophilic allergens, -> MHC class II So the cel is bonding: -covalent to thiols, amines coordinative metabolisation of pro-haptens: PPD -> Bandrowski's base

25 important questions on Allergic Contact Dermatitis (ACD); basal and clinical (retesting) dr. T. Rustemeyer ACD - Immune regulation / Tolerance VUmc, Dermatologie ACD - Socioeconomical impact / Occupation-associated skin diseases

What does the horny layer of the skin consist of?

corneocytes

Which size does a contact allergen need to have in order to penitrate the skin, and how is it called?

<400-800D, Hapten

How is the skin build?

Cornified,

Granular,

Spinous,

Basal,

Basal membrane,

Dermis

What important protein is present in the skin?

Filagrin

Filaggrin mutations: a risk factor of fragrance allergy ?

Filaggrin mutation and increased skin irritability are risk factors for polysensitization to fragrances

Name the two types of DCs in the skin

CD1a: Epidermal Langerhans cells

CD-SIGN: Dermal dentritic cells

What does a Langerhans cell bind to?

Lipophilic allergens, -> MHC class I

Hydrophilic allergens, -> MHC class II

So the cel is bonding: -covalent to thiols, amines coordinative

metabolisation of pro-haptens: PPD -> Bandrowski's base

What is PPD and where can you find it?

p-Phenylenediamine, in hairdye

How turns PPD into what?

Proposed oxidation of p-Phenylenediamine and self-conjugation; to Brandowski's base

Name an example of a thiolgroup that activates a Langerhans cell

NFkB & ERK1/2

Name an example of a aminogroup that activates a Langerhans cell

MAPK-p38

What does the TLR on DCs do, and what does it consist of?

It provides a dangersignal, and is made of PAMPS (pathogen associated molecular patterns) like LPS, viruses, … contributing to irritancy of allergens

How does the induction of danger signal by allergens such as Nickel work?

1) The Nickel activates ROS. This leads to (1)degradation of hyaluronic acid; and (2) production of IL-6, IFN-alpha/beta, and TNF-alpha. This activates the TLR 2, which produces MAPK, IRF 3-7 and NF-kB

2) The Nickel directly activates the TLR4, which produces CCL2, TNF-alpha, IFN-alpha/beta, IL-6,8,12. This leads to MAPK, IRF 3-7 and NF-kB.

How does the inflammasome gets activated by Irritant potential of contact allergens?

The allergens make contact with the ER, which start producing ATP, making the NLRP3 active. This leads to release of Caspase-1, Pro-IL-1beta and pro-IL-18, which are transfered to IL-1beta and IL-18

Why do mice hardly get sensized to nickel?

Nickel does not activate the murine TLR4. Murine TLR4 has some differences compared to human, in particular missing several histidines not allowing nickel to ind to and stimulate TLR4 directly Hence, mice get hardly sensitized to nickel. Adjuvants (“irritants”) are needed.

What increases sensitizing potential of nickel?

Concomitant irritation

What sensitization potency of nickel in mice?

IL-12

In what plays NF-kB a role, and what does it activate?

Innate immunity: iNOS, COX2, TNA-alpha, IL-1, HSP27, ...

Adaptive immunity: defensins, cytokines, chemokines, adh. molecules

Cell survival: cAP1 / 2, A1, Bcl-XL, cFLIP, …

What can you add to sensitization potency?

Danger signals:

- Release of unspecific danger signals increases sensitization potency

- Well-known clinical observation:

Extra care should be taken in case of irritating contact allergen (concentrations) and skin contacts with haptens at irritated skin / simultaneous with contact irritants

What do dermal DCs activate, and LCs suppress?

Dermal dendritic cells activate CD4 and CD8 T cells

whereas LC suppress T cell activation

Name 5 properties of contact allergens determining their sensitizing power

1) Skin penetration

2) Binding to (cell-surface) proteins

3) Presentation by MHC-I / -II

4) Cell surface receptor modulation

5) Irritant potential (‘Danger signals’)

Name some examples of contact allergens:

Metal salts: small cations, protein-reactive, irritative capacity

Preservatives: small molecules (<300 D), protein-reactive, …

Fragrances: small molecules (volatile), …

Rubber accelerators

Plastic monomers

Medicaments

Name some Examples of non-contact allergens:

Plastic polymers: too large

Alcohols: non protein-reactive

Fatty acids / detergents: non protein-reactive

Why is Identification of contact allergens in dendritic cell based assays important?

Until now, animal tests are used, and will be banned by 2013. Alternatives are needed.

Dendritic cell assays provide promising data for identification of new allergens. Currently, most reliable allergen detection by CXCL-8 (IL-8). In the future, many more markers to come (screening by gene array techniques).

Name the characteristics of Allergic contact dermatitis:

Acquired immune response

Life-long sensitization

Allergen-specific T cell mediated

Delayed type reaction  eczematous reactions

Diagnostic test: patch test

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