The human factor in allergy research

Enduring or medicating itchy eyes and a runny nose is a seasonal rite of passage for many people. But if that's all you have to worry about when it comes to allergies, you're one of the lucky ones.

“Allergies also include severe reactions to food and insect venom that can lead to anaphylaxis and death,” says the School of Medicine’s Greg Gomez. “There are more than 60 million Americans suffering from allergies and asthma, and in the past 15 to 20 years, the incidence has definitely increased, something close to doubling. You can see the evidence of the increase in food allergies, particularly peanuts, with most schools now including peanut-free zones or tables in cafeterias.”

That’s a big step backward in a developed nation like the U.S., where the march of time is generally expected to yield progress, particularly in medicine. But even if the number of people affected may have increased, scientists' understanding of allergic reactions has seen progress in recent decades — tremendous progress.

Charting the routes

Biomedical scientists have been working to build a road map defining precisely what happens in the body when an allergy-prone individual comes in contact with an allergen. The map has long had well-defined beginning and end points. It starts with an allergen, which might be cat dander, ragweed pollen or insect venom, making contact with human tissue. It ends with a person suffering from one or more of a wide range of potential complaints, such as incessant sneezing, skin rash, watery eyes or wheezing.

Moving from that single point of contact, between an allergen and human tissue, to a wide range of outcomes that, depending on the severity of the reaction, can potentially lead to death, involves an intricate series of cellular and molecular reactions. And thanks to researchers like Gomez, that series of reactions is no longer a black box. Scientists have developed a detailed map showing how the body’s immune system responds to an allergen, demonstrating how hundreds of different biomolecules are created, interact, and can sometimes cause one type of cell, in particular, to get carried away. 

Mast cells: armories in the immune system

That cell is the mast cell, which is an immune cell that permeates just about all of the organs of the body. It’s not a skin cell, but it’s found throughout skin tissue. It’s not a lung cell, but it’s found throughout lung tissue. And so on. A body’s immune system places mast cells, which are a form of white blood cell, in stationary positions in tissues. In other words, they're white blood cells that are permanently positioned outside of the bloodstream, and they're responsible for a number of functions, including fighting off invaders.

Mast cells do that by acting as an armory of sorts. Each mast cell contains a grab bag of inflammation-causing chemicals that can be released if the immune system directs it to do so. One of those chemicals is histamine, which might sound like a dirty word to a hay fever sufferer, given that anti-histamines are a primary source of relief for the condition. But in the immune system, histamine is just one of many essential chemicals that keeps the body running smoothly in the face of constant attacks by pathogens. Histamine and its biochemical cousins in mast cells can cause problems, though, if they’re released in excessive amounts or for too long; that’s the fate of someone with allergies.

Early in his career in science, as a postdoc, Gomez helped contribute to building the map that charts allergic responses on the molecular and cellular level by working exclusively with rodents, which provide a close analog to humans as a model system.

“That's really the only way you can do some of these mechanistic studies, in mouse models,” Gomez says. “But I really wanted to learn the human mast cell system, and so over seven years ago I transitioned, and now in the lab we work exclusively with human mast cells.” 

The human factor: challenges and rewards

Working with human tissue presents challenges, including less regular access to cells, which are typically derived from tummy tucks and biopsies by the NIH-affiliated outfit that supplies him, but Gomez prefers to be closer to the species of real interest. And the shift has paid some dividends.

Gomez’s lab was able to show, for example, that adenosine, a compound produced naturally by most cells and also used to diagnose and treat certain heart conditions, is not doing what it was long thought to be doing to mast cells.

“If you go to your cardiologist to have a stress test, they will ask you if you’re asthmatic,” Gomez says. “That’s because in a stress test they inject you with adenosine, which can induce bronchoconstriction in human asthmatics. And because of that, for a long time people believed, and many still do, that adenosine causes bronchoconstriction because it enhances the release of mediators, like histamine, from mast cells.”

The story is more complicated, though. His team has shown that adenosine predominantly acts to inhibit, rather than enhance, the release of histamine and its biochemically related ilk from human mast cells. They’re following up to try to fully define what’s going on in a crucial cellular interaction that regulates one of the last steps of the human allergic response.

Gomez adds that the insights they are gaining will likely have utility beyond the field of allergy research.

“When I started with mast cells, they were a bit of a novelty,” Gomez says. “But now mast cells have become quite popular, and a lot of people are working with them. I think it’s moving in the right direction in terms of our understanding of how they participate in not only asthma, but also in the pathogenesis of other diseases, including chronic inflammation, diabetes, and also cancer.”

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