The ramifications of eczema can be more than skin deep. The majority of children who develop the condition, also called atopic dermatitis, succumb to asthma as they get older. HMS researchers have new clues as to why that is. Writing in the Oct. 2 Proceedings of the National Academy of Sciences, Raif Geha, the James L. Gamble professor of pediatrics at Children’s Hospital Boston, and colleagues report that a specialized type of T helper cell, the Th17 cell, not only sensitizes the immune system to antigens introduced through the skin but also helps drive inflammation of the lungs and air passages if they are subsequently exposed to the same antigen.
“This helps explain why the asthma in people with eczema may be different from that in people without the skin condition,” said Geha. The findings may also help researchers develop new strategies to treat asthma.
Identified only in 2005 and named after the interleukin-17 (IL-17) that they produce, Th17 cells are potent stimulators of neutrophils, releasing cytokines that attract the white blood cells. Even though neutrophils and IL-17 are often elevated in the lungs of asthma patients, the role of Th17 cells in airway inflammation has been controversial. What Geha and colleagues have found is that, as is often the case with immune cells, their responses are heavily biased by presentation.
To address the role of Th17 cells in airway inflammation, research fellow in pediatrics Rui He, who is first author on the paper, and colleagues used a mouse model of atopic dermatitis developed by Geha. “This model recapitulates a lot of what happens in human eczema,” said Geha. In these mice, epicutaneous sensitization—induced by simply peeling Scotch tape from the skin—mimics the dermatitis found in human eczema. He and colleagues found that Th17 cells are present at sensitization sites exposed to a foreign antigen—in this case ovalbumin—and that the antigen also induces IL-17 production. Significantly, the response was not limited to the skin. Th17 cells also turned up in the lymph nodes that drain the skin, and serum IL-17 levels rose more than 10-fold, indicating a systemic response. In contrast, mice injected with ovalbumin had normal serum IL-17.
But it was in the airways where the most relevant changes occurred. When the sensitized mice were allowed to inhale ovalbumin, IL-17 mRNA and protein levels increased around fivefold in the lungs. No such increases were seen in mice that were sensitized by intraperitoneal injection. Furthermore, the inhalation challenge caused a sevenfold increase in neutrophil-attracting chemokines and an influx of neutrophils into the lungs. These white cells contributed to airway hyperreactivity (asthma) because blocking their influx with anti–IL-17 blocked airway hyperreactivity.
How does skin exposure sensitize the lungs to antigens? The researchers found that skin dendritic cells respond to antigens by traveling to the lymph nodes and activating IL-17–producing T cells. They also found that activation of these dendritic cells depends on cytokines released in mouse skin in response to injury. This is consistent with the pathophysiology of atopic dermatitis. “In eczema, antigens are typically introduced through a skin that would normally be impermeable but has been injured due to scratching elicited by a genetically inherited dry skin,” said Geha.
The findings suggest that blocking IL-17, or the cytokines that respond to skin injury, might be useful approaches to controlling eczema-related asthma.
