Mystery of allergic memory gets closer to answer: a rare group of B cells

Maria Curotto de Lafaille’s lab was trying to make human plasma cells in a dish. These weren’t just run-of-the-mill cells, though. The team was vying for something specific: plasma cells that churn out immunoglobulin E (IgE), the antibody that drives allergic reactions. 

It was the mid-2010s, and from a research bench at the Immunology Network of A*STAR in Singapore, one of Lafaille’s postdocs, Sriram Narayanan, was plopping donated human B cells into a culture dish with some proteins, hoping the white blood cells would transform over a few days of incubation. 

But so far, the experiment wasn’t going well.

“We were getting very, very few IgE cells,” Lafaille said. 

She and her colleagues had spent years studying how IgE antibodies are produced in people with allergies. But now they wanted to move from small mammals into humans. 

Confronted by all their failed attempts at getting IgE, the researchers had an idea. They tried using B cells from people with allergic asthma and atopic dermatitis — groups known to “make a lot of IgE,” Lafaille told STAT.

When Narayanan put those cells into culture, he got many more IgE cells. And even when all IgE cells were depleted, more would pop up. How were the cells remembering to make more of the antibody without an allergic trigger? 

“There came the idea,” Lafaille said, that “there was already some imprinting in the B cells from allergic people” that made it easier to churn out IgE-producing cells. 

How and why allergies occur

Allergies affect about 100 million people in the United States, or about 31% of the adult population and 27% of children, the CDC estimates. About 6% of adults and children have a food allergy, and some evidence suggests food allergies are becoming more prevalent. Tens of thousands of Americans go to emergency rooms each year due to allergic reactions to food. Many adults and children live with allergies severe enough to induce anaphylaxis, and many more struggle with day-to-day complications of disease like eczema and asthma. 

Inside the body, allergies play out like a complex ballet. Generally, there are two kinds of immune response: type 1, which happens in reaction to pathogens including some viruses, and type 2, which is triggered by parasitic infections and certain allergens. In type 2 inflammation, newborn B cells go from the bone marrow to the lymph nodes, where they get activated. Along with activated T cells, they signal to other white blood cells, such as mast cells and eosinophils, that an allergen has entered the body. 

Some B cells also turn into plasma cells, which serve one purpose: to create antibodies, including the provoker of allergies, IgE. In order to cause an allergic reaction, a certain amount of IgE must tightly latch onto its specific allergen target. Then, mast cells release chemicals like histamine, and cause the inflammation that leads to sneezing, hives, and other symptoms. 

But a part of that dance has puzzled researchers: the biological process that makes the IgE antibodies needed for a pathogenic immune response. 

This week, two studies in Science Translational Medicine — one from Lafaille, another from researchers out of Canada and Denmark — offer a compelling clue. 

Investigating the peanut allergy

In 2016, Lafaille returned to the U.S. and a post at New York University’s medical school, and kept trying to figure out what her postdoc had observed a year prior. With National Institutes of Health funding, her team was able to figure out that IgE-gushing plasma cells can hatch from another kind of B cell, a finding they first reported in Nature Communications in 2017. 

That paper offered an explanation for why IgE cells, which don’t remember particular allergens — meaning, they don’t have receptors on their surface that stick to the dust of a peanut, or the excrement of a dust mite, for example — were reacting to said allergen anyway. 

Her investigation continued at Mount Sinai’s department of pediatrics, where she was hired in 2019. And, with access to thousands of allergic children through the hospital’s Food Allergy Institute, “the work really took off,” she said. Her team identified a novel population of IgG memory B cells that were found more often in people with allergic diseases, and were correlated with high levels of IgE in the blood. 

While other studies had circled the issue, and some manuscripts had come across the cells during genetic sequencing, her group was the first to formally describe this subpopulation, she said.

But Lafaille wanted to know for sure that the IgG1 memory cells she’d found were converting into IgE cells with the same memory. To do so, she had to prove the cells recognized the same allergen. 

With NIH funding, her group decided to study children with a peanut allergy, since they usually have a severe allergy that persists into adulthood — the cells involved clearly have an enduring hatred for peanut allergens. 

The Sinai researchers ran a variety of tests on blood samples from 58 pediatrics patients with a peanut allergy and 13 non-allergic controls. All of their analyses pointed to the same group of memory cells as being the source of antibodies to a peanut protein called Ara h 2. In other words, inside of these patients, there was a small sleeper cell of powerful, chameleonic B cells waiting to be awakened by a trace of peanut protein.

About 400 miles away, in Hamilton, Ontario, another team of researchers was arriving at a similar theory based on their own experiments. 

Across the border, a similar finding

Josh Koenig and his collaborators in Denmark collectively formed their hypothesis between 2021 and 2022, he said. An assistant professor at McMaster University’s Schroeder Allergy and Immunology Research Institute, Koenig got funding — and collaborators — from drugmaker ALK-Abelló to try and understand what keeps people allergic. (The study was also funded by two families, the Schroeder Foundation, the nonprofits Food Allergy Canada and the Canadian Asthma Allergy and Immunology Foundation, and a fellowship from the Cancer Research Institute.)

From its pool of clinical trial participants for a sublingual therapy, ALK randomly selected six adults with a birch allergy (allergic rhinitis) and four with a house dust mite allergy. Koenig and his colleagues sequenced some 90,000 cells from those samples, plus blood from 11 people with peanut allergies. There were 15 non-allergic controls for comparison. 

They found a clear link in the sequencing data between the participants’ IgE levels and their memory B cells, which Koenig calls MBC2s in his paper. More than 80% of the connections the researchers could make were to the cell population. “What we’ve done here is identified the real target in allergic diseases,” he said. 

Since the findings were confirmed in their peanut allergy cohort, and Lafaille’s paper — plus some unpublished works he said found these cells at play in other allergies — Koenig thinks memory B cell subpopulation is involved in an array of type 2 allergy responses. 

Strength in numbers

The researchers’ worlds collided somewhat by chance, at a food allergy conference in Oxnard, Calif., in late 2022 (twice delayed due to the pandemic). Lafaille had been invited to speak, and other people in her lab had posters up. “We were just very open with everything that we were doing,” she said. 

While she spoke on the second morning of the meeting, Koenig sat nervously in the audience. He realized they had separately homed in on the very same, previously unknown population of cells. “You always feel a little terrified” of those kinds of coincidences — of getting scooped, he said. But it was also “very reassuring that we’re on the right track.” 

Koenig approached Lafaille after her talk and, a couple of weeks later, asked in an email whether she’d want to submit to the same journal for publication. She said yes. “There’s always strength in getting similar results by different groups, obtained independently,” she told STAT. 

Their papers, published Wednesday in Science Translational Medicine, are an exciting contribution to the field, said Frances Eun-Hyung Lee, director of Emory University’s asthma, allergy, and immunology program, who did not work on the studies.

“To identify a memory population poised to switch to IgE plasma cells is significant and has eluded us for years,” she said in an email. And having two papers by two independent groups offers more evidence that this rare population of cells is making IgE, she said. “It is nice to see them published together.”

A hope for better allergy treatments

While they try to illuminate an important pathway in allergic reactions, the studies could also lead to a better understanding of how to treat certain allergies. 

Lee, from Emory, wondered whether the cells induce a long-lived IgE plasma cell response or a short one. The researchers can add that to their list of questions. They told STAT they’re interested in how these allergic responses might be stopped, or how IgE cells might even be destroyed, and by what means. ALK has been developing tablets for people with five major classes of allergies, including food. 

Lafaille’s paper suggests a JAK inhibitor could work, since JAK molecules are associated with the same immune response that converts IgG1 cells to IgE cells. JAK inhibitors could “basically block this process of class switching by inhibiting the signaling,” she said. 

A fellow Mount Sinai researcher, who has received grant money from Pfizer, is studying the company’s drug abrocitinib, a JAK inhibitor, in people with food allergy. Lafaille said she might be involved in some of the B cell analysis for that study. (She consulted for Genentech on a single occasion, but said it was unrelated to her work on IgE. Two other authors on the paper are now employed by Janssen Pharmaceuticals.) 

Others are also exploring the untapped potential of antibody therapies. Stephen Quake, a Stanford researcher who was not involved in the studies, co-founded IgGenix to develop new allergy therapeutics based on his findings.

“These deep explorations of allergic memory are valuable to understand the origins of IgE and serve as examples of the power of single-cell transcriptomics in allergy,” said Quake, whose group pioneered the approach. 

STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.