Miriam Merad, MD, PhD

A 17-year quest to understand Langerhans-cell histiocytosis (LCH)—an inflammatory blood disease that mostly affects children and can result in dementia and death—has led researchers at the Icahn School of Medicine at Mount Sinai and their colleagues in Texas to a transformational discovery and a potential new treatment. Their findings were published in May in Nature Medicine.

The team, led by Miriam Merad, MD, PhD, Director of the Precision Immunology Institute at Icahn Mount Sinai, and Carl E. Allen, MD, PhD, Professor of Pediatrics, Hematology-Oncology, at Baylor College of Medicine, found that individuals with LCH have a mutation that puts a subset of white blood cells into a state called senescence. In this state, the cells stop multiplying as they normally would, express a pro-survival gene, and begin producing inflammatory molecules.

Lesions, a hallmark of the disease, form wherever the inflammation occurs, on the skin and in various organs including the brain and central nervous system, manifesting differently in each patient and causing a range of severity. Roughly one in 100,000 children in the United States develops LCH each year, putting it on par with the incidence of pediatric Hodgkin lymphoma, the third most common cancer in children. LCH appears to be most prevalent in the Middle East and countries such as China.

Understanding the role senescence plays in LCH has enabled the researchers to find a potential treatment that “attacks the cause of the problem,” says Dr. Merad. “We have a therapeutic molecule that can get at this pathway and block the ability of these senescent cells to survive.” When the researchers tested the molecule in animal models and on human cells they found the diseased cells were “super-addicted to this survival signal. So now we have a way of blocking the survival signal.”

Plans are underway, she adds, to launch an international, multi-site clinical trial in September, in conjunction with a pharmaceutical sponsor and the National Institutes of Health. Details will be released when the contracts are formalized.

If successful, Dr. Merad says the therapeutic molecule would replace the use of chemotherapy, the current standard of care, which fails to work in the majority of cases. Chemotherapy helps to eliminate some of the inflammation, she says, but it also kills healthy cells and is unable to reach the diseased cells.

Even with the latest breakthrough, LCH remains a baffling disease. It is not inherited, and there appears to be only one mutation. “It’s very unique,” says Dr. Merad. “We don’t know the cause or what makes some kids more at risk.” Upcoming clinical trials should help shed more light on the disease mechanisms.

Drs. Merad and Allen have been collaborating on LCH research since 2004, when they met at a conference in Greece, which was sponsored by the father of a child with a severe case of LCH, who was frustrated by the lack of scientific knowledge. Five years later, Drs. Merad and Allen were the first to describe LCH as a disease of the hematic system—blood vessels that carry blood throughout the body—which originates in the bone marrow. Prior to that, LCH was categorized as a type of skin cancer.

“This disease should be classified as an inflammatory hematological disease,” says Dr. Merad. “There’s no proliferation; the cell never metastasizes. What we’ve discovered in this latest paper is that the mutation puts the cells into a state that is not cancerous, but one in which the cells are fighting not to expand. They start producing a lot of inflammatory molecules because they sense there is danger. This inflammation is the cause of most of the symptoms.”

She says the next piece of the LCH puzzle will be figuring out how to prevent the disease from causing neurodegenerative damage.

The 17-year journey to reach this latest discovery has been a “story of friendship, commitment, and perseverance,” says Dr. Merad. It was her mentor, the late Nobel laureate Ralph M.  Steinman, MD, who first asked her to join him in studying LCH and brought her to the 2004 conference where she met Dr. Allen. She became committed to understanding the baffling disease after being greeted at the door by the organizer’s teenage son, who had LCH, and by his father, who had enlisted some of the world’s leading scientists to find answers.

“What’s beautiful is that this group we formed in 2004 (with Dr. Allen’s lab) is as strong today as it was then,” says Dr. Merad. “We never stopped working on these questions. Science takes perseverance. We start with the question, and we dig and dig until we have something solid and then we put it out there. No matter what it takes we continue to work on it.”

Unlike larger air pollutants, ultrafine particles are able to burrow deeply into the mother’s lungs, cross the placenta, and reach the developing fetus.

The link between prenatal exposure to ultrafine particles in air pollution and the development of asthma in preschool-age children has been established for the first time in the United States by a team of scientists led by Rosalind J. Wright, MD, MPH, Dean for Translational Biomedical Research at the Icahn School of Medicine at Mount Sinai, and Co-Director of the Mount Sinai Institute for Exposomic Research.

Ultrafine particles—the tiniest of toxins released into the air from forest fires, tobacco smoke, automobile and manufacturing emissions, and other sources—are believed to be particularly dangerous to human health. Less than 100 nanometers in diameter or 1/1000th of a human hair, they are able to burrow deeply into the lungs, pass into the bloodstream, and penetrate the placental barrier. Until recently, these particles went largely unmeasured. But increased interest from environmental researchers has led to the development of more sophisticated tools that are beginning to capture the pollutants before they disperse, and link them to health databases.

“If you’re thinking about the placenta as being the gateway into the fetus—these particles can more readily get to the other side and have more direct effects upon the developing infant,” says Dr. Wright. “Once the ultrafine particulates are in the bloodstream they can travel anywhere and have broad health impacts.”

Rosalind J. Wright, MD, MPH

In the study led by Dr. Wright and published recently in the American Journal of Respiratory and Critical Care Medicine, 18 percent of the children of mothers who lived in a higher-risk urban population and were exposed to ultrafine particles during pregnancy developed asthma by the age of three, compared with 7 percent of children in the general population. The study included 376 mothers and their children, most of them Black or Latinx, who lived near high-traffic roadways in the Boston metropolitan area. More than half of the mothers reported having a high school education or less.

The researchers found that female children, in particular, were more susceptible to asthma when exposed to these particles during the third trimester of their mother’s pregnancy, whereas male children had an elevated risk when exposed throughout the pregnancy. According to the research team, further investigation will be needed to explain these differences.

“This is the first study in the United States to show this is happening in our cities in the Northeast,” says Dr. Wright. “We now have to look across different cities and settings, such as areas where we’re experiencing wildfires.”

Measuring the harmful effects of ultrafine particles on other parts of the body needs to be done, as well. “Here we’re focused on pregnancy and asthma, but particulate air pollutants can also affect brain development, so, for example, we need to be looking at ultrafine particles exposure in pregnancy in relation to neurodevelopment in kids, too,” she says.

The study—a collaboration between Dr. Wright, the Department of Civil and Environmental Engineering at Tufts University, and researchers at Harvard University—also sheds light on health disparities, since the mothers lived in underprivileged neighborhoods that tend to be closer to congested roadways with higher levels of air pollution.

“Some people don’t have a lot of choices related to affordable housing. There’s also other factors in these communities impacting health. For example, these populations may experience a lot more stress,” says Dr. Wright. “Higher stress interacts with air pollution to magnify the effects of pollutants. Financial strain, more toxic work environments, more adverse life events to deal with. These emotional challenges are pushing and pulling on the same systems in our bodies that are trying to keep us on a healthy trajectory. This includes our immune system, which plays a significant role in asthma risk. There is an optimal balance that we all strive to maintain and when we are stressed and don’t get enough sleep or we’re not eating right, we’re more likely to get sick. Look at how COVID-19 is hitting those same populations harder. They’re already breathing more toxins in the air and experiencing greater stress that throws our immune system out of balance, and this can impact someone’s vulnerability to viral infections.”

The good news, she says, is that there are short-term ways to mitigate the negative effects of stress and pollution, and health care providers have an important role in educating the public, particularly pregnant women.

“We don’t want to just keep telling people these toxins are out there,” Dr. Wright adds. “We want them to know there are things they can do to counter them.”

These include regular exercise and a diet high in antioxidants, such as beans and berries, and certain polyunsaturated fatty acids found in salmon, walnuts, and sunflower seeds.

“At the same time,” she says, “we have to work on longer-term solutions, such as increasing access to healthy, affordable housing, better educational and job opportunities, and nutritious foods.”