BioEd Online

A specific immune-system mechanism underlies the skin rashes caused by contact with nickel, one of the world's most common allergens.

German researchers have found that in humans, the metal directly activates a member of the family of receptors that act as gatekeepers of innate immunity, the body's first line of defence against pathogens. Activating this receptor, called Toll-like receptor 4 (TLR4), generates a 'danger signal' that promotes inflammation — causing itching, tenderness, swelling and rashes on the skin — and recruits other immune cells such as T cells to the area.

No one has ever proposed that a single receptor could mediate the initial inflammatory response that leads to an allergic reaction to nickel, explains Matthias Goebeler, a dermatologist at the University of Giessen in Germany, who led the study. What's more, he says, "this is the first time that an inorganic agent has been found to activate this pathway" of the innate immune system.

Nickel is thought to be one of the most prevalent contact allergens. Researchers estimate that about 5–10% of the population in the industrialized world is allergic to nickel on contact, and that figure reaches 10–20% in young women, who are more likely to be exposed to the metal in jewellery — particularly earrings and other piercings — that contain the metal.

But just how nickel causes an allergic response has until now been a mystery. Another perplexing issue was that mice, unlike humans, are not sensitive to nickel, and no one could explain why.

Taking its toll

Researchers have generally held that skin allergies emerge 48–72 hours after exposure to an allergen, but previous work by Goebeler and his colleagues found that after exposure to nickel, the endothelial cells that line the blood vessels produced immune-response-mediating molecules called cytokines within 24 hours — well before T cells arrived¹. This study, and follow-up work, suggested that nickel itself was acting as the signal for T cell recruitment. In the present study, published online in Nature Immunology today², Goebeler's team set out to determine exactly how cells detected and responded to the metal.

The team tested several human TLR molecules, finding that the cascade of inflammatory signalling set off by nickel is dependent on TLR4. Mouse TLR4 signalling was not triggered by nickel, however, so the researchers compared mouse and human versions of the TLR4 protein. They identified two regions in the human protein that contain an amino acid called histidine — not present at those positions in mouse TLR4 — to which nickel might bind and so trigger the signalling cascade. When the researchers expressed these human TLR4 variants in mice, the animals experienced an allergic response to nickel.

"Until now, we could not work in animal models on this, because it didn't work," says Jean-Francois Nicolas, an immunologist at the University of Lyon in France. "Now we understand why it didn't work."

The study not only solves the long-standing mystery of how nickel causes an allergic reaction, but also "opens up another avenue of thought" about how Toll-like receptors work, says Anthony Gaspari, a dermatologist at the University of Maryland in Baltimore.

Allergens are extremely diverse, so the mechanism that triggers nickel sensitivity would not necessarily occur in response to a different allergen, says Goebeler. But the principles may be similar. "It opens up the concept that there's an alternate pathway for activating Toll-like receptors," Gaspari says. "For nickel it's histidine, but maybe for other allergens it would be other amino acids."

The work suggests it may be possible to treat nickel allergy with a topical blocker of TLR4, Gaspari says.

Goebeler's group is now examining whether individuals who aren't sensitive to nickel carry different genetic variants of the TLR4 gene. If so, further studies may allow them to predict an individuals' allergic response to nickel.