The rawness, itching and oozing of eczema, a chronic skin rash, and the coughing, wheezing and breathlessness of asthma have something in common — something besides their unpleasantness, that is. Both are frequent in young children, and often a child will contract both disorders, first eczema, then asthma.
Learning the language of cellular signaling: Mitsuru Morimoto, PhD, Shadmehr Demehri, PhD, and Raphael Kopan, PhD.
It sounds coincidental, but it’s not always. Asthma follows eczema so often that doctors use the faintly martial phrase, atopic march, to describe the progression. About one-fifth of children get eczema, also called atopic dermatitis, and asthma occurs in one-half to two-thirds of those with moderate to severe eczema.
Immunologists, dermatologists and lung specialists have debated and studied atopic march for years without agreeing on a definitive cause for the mysterious phenomenon. But sometimes a new perspective on a stubborn problem reveals an answer; that’s what happened in the laboratory of Raphael Kopan, PhD, professor of developmental biology and of dermatology.
Although the scientists didn’t set out to investigate asthma, they believe they have pinned down the source of atopic march — a compound called TSLP, which the skin secretes when it’s damaged or defective. They have demonstrated that TSLP can travel from the skin to the lungs and instigate asthmatic symptoms in laboratory mice with a skin dis-order.
“We’ve shown that instead of wondering about the role of myriad immune factors — T helper cells, B cells, myeloid cells — we can narrow atopic march down to one molecule,” Kopan says. “Now the question might be, how can doctors prevent eczemic skin from making TSLP? If that can be done, kids who have eczema may no longer have to worry about it leading to asthma.”
Kopan’s laboratory team is usually not this deeply involved with applied medicine. Their research focuses on fundamental questions about cell development: how different cell types found in adult organisms arise from the primitive cells of the early embryonic stage. One way they investigate this is to look at how skin develops.
Using techniques to manipulate gene activity, they recently engineered a breed of mice with thickened and inflamed skin that mimicked human eczema. Unfortunately, the mice died soon after birth. Busy with a variety of other projects, the researchers put aside the question of why the mice were dying.
Then Shadmehr (Shawn) Demehri joined the lab to conduct research toward an MD/PhD degree, which he completed this spring. He was interested in studying the sick mice, and soon his research showed the mice suffered from a leukemia-like condition. Their blood had 40 to 80 times the normal amount of white cells called B cells. Demehri discovered that TSLP induced the excessive B cell production.
TSLP stands for thymic stromal lymphopoietin. It can be thought of as an alarm sig-nal that warns the immune system of a failure of the body’s protective layers, such as skin and the linings of the lung’s airways — the so-called barrier organs. Interestingly, other research had already shown that the lungs of asthmatic people make TSLP.
“When we found that the skin of these mice produced TSLP, we knew we had to investigate whether this might be connected to atopic march,” Kopan says. “But we weren’t even thinking about asthma until Shawn made that discovery,”
Under normal circumstances, TSLP alerts the immune system to breaches in barrier organs so that it will send cells to help heal them; healing turns the alarm off and sets everything back to normal. But the mice’s skin never healed, so the alarm signal kept sound-ing. As a result, the blood of the mice contained 5,000 times the normal amount of TSLP.
That startling fact set off the researchers’ own alarms. What if this substance, when it gets into the blood, puts the airways of the lung on guard? If that happens, it could lead to respiratory problems like asthma.
Other mechanisms to explain atopic march had already been proposed by different researchers. One idea was that genetic mutations that affect both the skin and lung airways might tie eczema to asthma. Others suggested that people introduced allergens into their system when they scratched their rashes. The allergens might train the immune system to respond to inhaled allergens and trigger asthma.
But Kopan and his research team established that, in mice, skin secretion of TSLP alone is sufficient to trigger an asthmatic reaction.
The researchers compared normal mice to mice with patches of good and bad skin that allowed them to survive longer. The normal animals didn’t react to an inhaled allergen, but the mice with skin problems did — badly. They started wheezing, their lungs filled with mucous, and their airways constricted — classic asthma symptoms.
The team wanted to make sure that TSLP made in the mice’s skin can actually get to the lungs. They found that it can. “The skin is the largest endocrine organ in the body,” Kopan says. “It’s very good at secreting products into the blood stream, and it made this molecule available to the whole body through the circulation.”
Further experiments demonstrated that TSLP is required for the asthmatic response and that no other factor from the skin contributes to the problem.
Finding the key to atopic march has unlocked new doors for Kopan and his team. These ba-sic research scientists are now entering into a collaboration on studies involving human patients. They will test the amount of TSLP in the blood of people with eczema and deter-mine whether higher levels lead to more propensity to asthma.
This research could soon uncover ways to prevent excess TSLP production in ec-zemic skin and thereby break the link to asthma. And further down the road, other research might reveal how to inhibit TSLP production in the lungs to stop asthma even in cases that aren’t associated with eczema.
Kopan says this work is a prime example of why medical schools maintain basic research laboratories. “We backed into this discovery because we are allowed to play to a degree, to start with an observation and follow through without necessarily having a medical application in mind.”
Labs like Kopan’s are also adding to the knowledge physicians need to do their jobs. “Look at it this way: doctors are like repairmen for a very complicated machine; even with a lot of experience, something can go wrong that the repairmen don’t understand,” says Kopan. “Then they need to consult the manufacturer’s manual (present in our DNA). You might say we’re translating this manual to improve our understanding of the body’s manufacturing process and its functions as an integrated system.”
This story appeared in the Summer 2009 issue of Outlook magazine.