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Contact dermatitis – removing a leg from a tripod

Contact dermatitis is one of the most frequent occupational skin reactions resulting from exposure to allergens. Chronic allergic reactions to environmental allergens might sometimes become job- or life-threatening. Prof. Dr. Stefan Martin and his group of researchers in the Allergy Research Group of the Department of Dermatology at the Freiburg University Medical Centre are investigating the molecular mechanisms underlying the disease. One of their major objectives is to develop new therapies and in vitro test systems. The researchers have already clarified numerous molecular details associated with the development of contact dermatitis.

Eczemas can result from nickel contact allergies © Prof. M. Goebeler

Chemicals in household detergents, materials used for bra straps, jewellery containing nickel, volatile substances in perfumes or herbal ointments - around four thousand or so compounds are known to cause contact dermatitis. Unpleasant symptoms of contact dermatitis include skin rash, itching and damp skin caused by contact with a foreign substance. Once the disease is chronic, affected individuals must avoid any contact with the offending agents. Some people are often forced to leave their jobs. It is known that people who regularly handle chemicals as part of their job are frequently affected by contact dermatitis. Contact dermatitis is an allergic disease, i.e. an overreaction of an individual's immune system when it comes into contact with an allergen. "Sufferers are often treated with drugs that suppress the immune system," said Prof. Dr. Stefan Martin from the Allergy Research Group at the Freiburg University Medical Centre going on to add "immunosuppressive drugs only alleviate the symptoms. In future, we need real causal treatments that target the causes of the disease."

Nickel ions in the skin tissue

In order to develop causal treatments for the disease, the researchers need to identify the molecular mechanisms underlying contact allergies. Martin and his team have carried out true pioneering work over the last twenty years. They now know that inflammation that occurs upon contact with an allergy-causing agent (so-called contact allergens) is crucial for the development of contact dermatitis. Taking the allergy to nickel as an example, the processes in the skin can be simplified as follows: When a nickel-containing strap of a new watch rubs on a person’s wrist, the affected individual will start to scratch, and the skin becomes moist with sweat, thus making it more permeable. Nickel ions then enter the skin tissue where they are recognised by skin and immune cells at which point they bind to special receptor proteins located in the membrane of these cells. An inflammatory reaction starts when the immune cells secrete mediators upon contact with nickel, which attracts further immune system cells to the site of irritation. So-called dendritic cells are activated as the inflammatory reaction continues to develop.

Dendritic skin cells (greenish yellow) have invaded the T-cell region of the lymph node where they activate T-cells (red) © Prof. Dr. Stefan Martin

It is the dendritic cells that mediate an allergic reaction because they leave the skin and enter the lymph nodes where they activate T-cells by presenting them with nickel ions, prompting a subpopulation of T-cells with nickel receptors to proliferate. This leads to the generation of so-called memory cells, which are the basis of the immunological memory. When instructed by dendritic cells, the T-cells return to the site of skin inflammation with the result that the immune system overreacts when it next comes into contact with nickel. This overreaction is mediated by dormant T-cells at the site of irritation and typical allergic symptoms occur. Martin and his team have not only shown that the activation of dendritic cells during initial inflammation is a prerequisite for a subsequent allergic reaction to occur. They have also been able to show that activated dendritic cells equip T-cells in the lymph nodes with molecular "tags", enabling them to find the site of inflammation in the skin.

Three interrelated signalling pathways

On contact with the skin, the contact allergen oxazolone leads to the release of ATP from skin cells (right), which in turn leads to the activation of the P2X7 receptor and to the induction of inflammation (see text). The photo on the left shows a control experiment involving a detergent without oxazolone. © Prof. Dr. Stefan Martin

The researchers from Freiburg have clarified many of the individual steps involved in the development of contact allergies, including on the molecular level. Their investigations show that the initial step when nickel enters the skin is mediated by receptor proteins of the group of TOLL-like receptors (TLR), which are also involved in bacterial infections. "Nickel binds to TLR4", said Martin. "This triggers a molecular signalling cascade in the cells, resulting in the activation of a number of genes and finally in the release of proinflammatory mediators." Other allergenic substances induce such a signalling cascade indirectly. Such allergenic substances lead to the degradation of parts of the protective carbohydrate layer around the skin and immune cells. Fragments of this layer then activate TLR2 and TLR4. In addition, contact allergens activate the P2X7 ATP-receptor, which leads to the stimulation of a complex of proinflammatory proteins known as inflammasome. This complex then induces the release of mediators that contribute to the development of inflammation.

A third signalling pathway (besides the two that are mediated by TLR proteins or the inflammasome) induces the formation of reactive oxygen species, which also mobilise the immune system. "All known signalling pathways that mediate the development of contact dermatitis are interconnected," said Martin. "It is sufficient to switch off any one of them in order to prevent an inflammatory reaction from occurring. This can be compared to a tripod that topples over, no matter which one of its three legs is taken away." Martin's team has shown in a mouse model that blocking one of the three signalling pathways is enough to prevent an inflammation from occurring after contact with allergens. This discovery could possibly lead to the development of an anti-inflammatory therapy for contact dermatitis. "Our most important objective is to investigate whether this also works in humans," said Martin. "We also have plans to investigate whether this strategy works in contact allergies that have already become chronic."

Does contact dermatitis mock an infection?

Another question the researchers hope to answer is one related to an individual’s predisposition to developing contact allergies. Are some people more likely than others to develop contact dermatitis? Are there factors that promote the development of the disease? “We believe that genetic polymorphisms in the most important signalling pathways are the major causes of an individual’s predisposition to develop contact dermatitis. However, we need to investigate this assumption in greater detail.” Another interesting aspect relates to the fact that the signalling pathways involved in the development of contact allergies are exactly the same as those that are initiated upon bacterial or viral infections. It is as if contact dermatitis is mocking an infection. Can the simultaneous infection with bacteria enhance an allergic reaction or even turn a weak allergen into a strong one? Martin and his team will also focus some of their investigations on these aspects over the next few years.

Martin and his team of researchers are also part of a large EU project, in which they are developing test systems based on human cell cultures that enable scientists to test whether a certain substance induces a contact allergy. This is important for clinical applications, basic research and also the cosmetics industry, the latter because it needs to test any new product for potentially harmful ingredients. Such tests were carried out with experimental animals up until 2009 when an EU directive became effective, banning the sale of animal-tested cosmetics throughout the EU.

Further information:

Prof. Dr. rer. nat. Stefan Martin
Allergy Research Group
Department of Dermatology and Venerology
Freiburg University Medical Centre
Hauptstrasse 7
Freiburg
Tel.: +49-761-270-6738
E-mail: stefan.martin(at)uniklinik-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/contact-dermatitis-removing-a-leg-from-a-tripod