Mast cells, components of the immune system, are responsible for alleriges and asthma, conditions that debilitate millions. Yet relatively few scientists study them.

Hydar Ali of the University of Pennsylvania is a member of the select group of researchers for whom mast cells are a focus. A professor in the Department of Pathology and director of faculty advancement and diversity in Penn’s School of Dental Medicine, Ali has spent his career discerning the cells’ unique qualities and honing in on strategies to modulate their activity to improve health.

“Obviously I’m biased, but I do think that our findings are critically important,” Ali said. “These cells are relatively poorly understood, and yet we’ve been able to identify some of the most sought-after molecular targets to affect diseases like allergies and asthma that have the potential to kill.”

Mast cells are part of the immune system and reside in tissues rather than in the blood stream. They are important for protecting the body from pathogens and contribute to wound healing but are most notorious for their involvement in inflammatory and allergic conditions. They are rich in histamine which is released when mast cells are activated and can lead to the quintessential signs of an allergic reaction: hives, itching and even anaphylaxis.

“No living human has ever been shown to lack mast cells, and mutant mice that lack them are unable to fight microbial infection,” said Ali, “so it’s pretty clear that mast cells are there to protect us from infection. But the other side of the coin is that people who have too many mast cells can develop skin rashes, itch, nausea, vomiting, diarrhea and abdominal pain.”

Because mast cells are present only in low numbers and cannot be extracted from the tissue, they are considered difficult to work with, and thus the pool of researchers who do so is limited.

Despite these hurdles, Ali started working with mast cells while pursuing his doctorate at University College London. His dissertation examined the diversity of mast cell types.

“I looked at mast cells from different tissues and found tremendous heterogeneity,” he said. “So, for example, if you took a mast cell from the gut, that cell is different from one in the skin. There’s also variability when you go to different species, so there are major differences between mouse mast cells, rat mast cells and human mast cells.”

These differences make translational work, moving from animal models to human treatments, a challenge, as Ali and many of his colleauges in the field have discovered.

After earning his Ph.D., Ali moved into a postdoctoral position at the National Institutes of Health, where a handful of labs focused on mast cells. He recalls headline-making news when scientists in a neighboring lab cloned the gene for the IgE receptor. This receptor binds IgE antibodies and triggers a signaling pathway associated with allergic diseases, eczema and other condtions.

“I remember The New York Times said that a therapy for asthma was on the way,” Ali said. “You read so many things like this and they never come, but this was different.”

Indeed, by the 2000s an asthma drug came on the market to target this receptor

​​​​​​​​​​​​​​Ali saw that the field was ripe for discovery. Wanting to continue his rearch in academica, he took a position at Duke University, working with Ralph Snyderman, who was then chancellor of health affairs. Snyderman’s research portfolio primarily examined white blood cells other than mast cells, notably neutrophils and macrophages, but Ali helped discover that mast cells could be used as a model system to study properties of neutrophil receptors in a different context.

In 1998, Ali was ready to run his own lab. He had had the good fortune of being awarded grants, from the NIH, American Lung Association and American Heart Association, all to study G protein coupled receptors, which, like IgE receptors, are present in large numbers on mast cells.

At Duke, he had discovered that one of these G-protein coupled receptors, or GPCRs, was activated by a protein called C3a, part of the complement pathway that can often promote inflammation. High levels of C3a was also known to be associated with an increased risk of asthma in humans.

After coming to Penn, Ali serendipitously discovered the presence of a new GPCR, known as MRGPRX2, which is found only on mast cells and not other immune cells. 

Pursuing this finding led Ali and colleagues to find that small proteins called antimicrobial peptides, which were believed to only kill microbes directly, could activate mast cells through MRGPRX2 to harness the protective function of mast cells to help clear the invading microbes.

Working with Penn Dental’s Henry Daniell, a professor in the Department of Biochemistry, Ali showed that a couple of these antimicrobial peptides, manufactured through Daniell’s patented biopharmaceutical plant-production platform, were able to activate the mast cells through MRGPRX2, showcasing the “positive” role of mast cells in defending the body against pathogens.

“I think this highlights the fact that mast cells are playing a role in host defense,” said Ali.

On the other side of this fine line, mast cells’ involvement in pathogenic conditions such as asthma, Ali’s lab has been at the forefront in discoveries with the potential to translate to human therapies.

Earlier researchers had found that a key receptor involved in chronic asthma and anaphylaxis in mice did not function the same way in humans. Thus much energy that was poured into developing inhibitors of that receptor in mice ended up being fruitless in the pursuit of human therapies.

Yet, Ali and colleagues showed that, in humans, similar effects were elicited by signaling through MRGPRX2. While they had also shown that activating this receptor led to improved antimicrobial effects, in the context of allergic response, blocking this receptor could inhibit the harmful inflammatory effects.

“It’s two sides of the same coin,” Ali said.

With a new set of grants, Ali’s lab is working with the Fox Chase Chemical Diversity Center to screen for small molecules that mimic known antimicrobial peptides in activating mast cells through the MRGPRX2 and operate with a similar dual function, direct killing and activating mast cells to help in fending off the attack. They’re also looking for potential drugs that block this receptor’s activity to reduce the effects of allergic and chronic inflammatory conditions.

In addition, they’re using mouse models that use human version of molecular receptors to continue unraveling the mysteries of mast cells. One project is looking at the association between MRGPRX2 actviation and worsening asthma, while another is looking at the connection between chronic heart and lung diseases and genetic variations in mast cell receptors.

The goal is keeping the work relevant to humans.

“With animal models,” Ali said, “if you think a gene is important, you knock it out, you over express it, you generate a ton of data and can publish it in a very high-impact journal. And when you submit a grant, it looks like you’re a very productive investigator, you have impressive results in mice. But the question is, does it relate to humans?”

In May, Ali will present his recent findings on the mysteries of controlling mast cells through MRGPRX2 in a keynote lecture at the European Mast Cell and Basophil Research Network International Meeting in Prague.