An allergic reaction can be anything from a stuffy nose during pollen season to anaphylaxis after eating a peanut butter sandwich. Regardless of what the allergen is, how it gets into the body, or how severely the body reacts, allergic reactions proceed through the same steps. White blood cells produce immunoglobulin E (IgE) antibodies that recognize a particular allergen and precipitate the release of histamines, which make blood vessels more permeable, and initiate inflammation.  

Antihistamines and steroidal nose sprays can offer relief from seasonal allergies, but for people with more severe reactions to food or drugs, the safest option is often to avoid the allergen all together. 

“Yet they still have that IgE in circulation,” said Jamie Orengo, an immunologist at Regeneron Pharmaceuticals. “Something is keeping that IgE around so that the body is primed to have a response.”

It might not seem surprising to anyone familiar with vaccines that the immune system retains a memory of the allergens it has encountered. But the white blood cells that produce IgE are so unique among the immunoglobulin-producing cells and so difficult to study that a complete understanding of the source of allergic memory — not to mention a comprehensive strategy for eliminating it — has historically proved elusive.

Now, that appears to be changing. After immunologists spent decades working out the details of IgE cell development, Orengo and her team have shown that blocking the formation of new IgE cells is only half of the battle; eliminating old IgE cells — once thought to be a biological impossibility — appears to be important as well. Their work and that of others points to a new, two-pronged strategy that uses existing technologies to help patients overcome allergies for good.

Jamming the switch on memory B cells

To create most antibodies, the process is relatively straightforward. A memory B cell encounters a molecule that binds to a B cell receptor (BCR) on its surface. Then the memory B cell differentiates into a plasma cell that produces and releases free-floating immunoglobulin antibodies that bind the same molecule — or antigen — that bound to the BCR before.

But IgE is unique. When Maria Lafaille, an immunologist at Mount Sinai, went looking for IgE memory B cells in 2007, she couldn’t find any (1). 

“That was really the beginning,” said Lafaille. “The differentiation of IgE-producing cells wasn’t in the classical way. It was different.” 

She showed that the expression of IgE biases B cells to become plasma cells and that the pathogenic IgE plasma cells responsible for allergic disease actually come from IgG memory B cells.

“We call that ‘to switch,’” said Lafaille. “It’s a switch from one class of antibodies to another class, keeping the same binding region for antigen.”

The differentiation of IgE-producing cells wasn’t in the classical way. It was different.
- Maria Lafaille, Mount Sinai

Since that initial study’s publication, Lafaille has worked to characterize the IgG memory B cells that become pathogenic IgE plasma cells. In a pair of studies published in 2023 and 2024, she described unique molecular features that bias IgG memory B cells towards the IgE plasma cell fate (2,3). In 2024, a separate research group published similar evidence to support the existence of these unique B cells (4).

While precisely targeting and eliminating pathogenic memory B cells is one way to prevent the formation of IgE-producing plasma cells, preventing the switching process all together is another option. In fact, scientists have known for decades that the signaling molecule interleukin-4 (IL-4) plays an essential role in the switching process (5). That’s why Regeneron developed dupilumab  (Dupixent), an anti-IL-4 receptor alpha (IL-4Rα) antibody. Since the company patented it in 2007, the FDA has approved the drug to treat eczema, asthma, and other allergic diseases, and scientists at Regeneron have continued to experiment with it to understand what makes it so effective. In 2020, the company’s scientists showed that dupilumab blocked not only IL-4 signaling but also IL-13 signaling and that both effects were important for alleviating allergies (6). 

Taken together, the work of Lafaille and her colleagues and dupilumab’s demonstrated effectiveness might seem to suggest that allergies have been largely solved and that now scientists are just ironing out the details. There’s just one little snag: No matter how much dupilumab people take, their bodies always seem to retain some IgE and, consequently, their allergic memory. 

How long do plasma cells live anyway?

When Orengo looked at the data from Regeneron’s clinical trials of dupilumab, she saw that “you dramatically reduced the IgE, but it wasn’t going away,” she said.

According to Andre Limnander, a member of Orengo’s immunology team, that was surprising. Shortly before Limnander joined Orengo at Regeneron in 2014, two research groups used fluorescent tags to track IgE-producing cells in mice (7,8). Type 2 inflammation — the immune response that allergens elicit — also occurs during parasitic infections, and the researchers elected to study mice infected with parasites. Both groups found evidence that most IgE plasma cells are short-lived. 

“There are unique traits of the IgE BCR that constrain the longevity of those cells,” said Limnander. “They’re very prone to die.”

But there was no denying that dupilumab injections failed to completely eliminate IgE in patients with allergic diseases, even in the long-term. Limnander wondered if other groups were missing something by focusing on parasite-induced type 2 inflammation. When he joined the team, Regeneron had developed a house dust mite (HDM) allergy model, where mice with chronic exposure to the allergen had symptoms similar to allergic asthma. “The first thought was, well, why don’t we interrogate the IgE response there? Because this could actually be really relevant,” said Limnander.

In 2020, Limnander and Orengo published a study showing that a population of long-lived IgE plasma cells began to accumulate in the bone marrow of mice after about two months of HDM exposure (9). When Limnander and Orengo subsequently analyzed the IgE plasma cells in a 2024 study, they found that cells collected from the bone marrow tended to express genes that promote survival and inhibit apoptosis at higher levels than cells collected from lymph nodes, where B cells first differentiate into plasma cells (10).

Marcus Robinson, an immunologist at Monash University who was not involved in the work at Regeneron, was intrigued but somewhat skeptical of Limnander and Orengo’s claim about long-lived IgE plasma cells. He acknowledged that the higher expression levels of pro-survival genes the Regeneron scientists found in the bone marrow population could be indicative of increased longevity. But Robinson is a proponent of genetic timestamps to track the fates and lifespans of plasma cells, and he’d like to see that type of evidence to confirm or refute the existence of long-lived IgE plasma cells (11). “We really need the timestamping to put the nail in the coffin on the idea,” said Robinson.

Limnander, on the other hand, felt that their 2024 study had already provided sufficient evidence that the IgE plasma cells they collected had differentiated considerably earlier. Although he and his team exposed the mice in their study to HDM for a total of five months, they began treating the mice with an anti-IL-4Rα antibody after three months to prevent any more class switching. “It would be great to see a timestamped mouse,” Limnander agreed, but he added, “we have approached this from a different angle.”

Additionally, a separate research group put a preprint online in 2024 that independently corroborated some of Limnander and Orengo’s key observations concerning IgE plasma cells (12). And more recently, Lafaille said that she and her colleagues are preparing a publication right now that will support the conclusion that “most IgE plasma cells are very short-lived, but there is a population of IgE plasma cells that can be long-lived.”

Putting it all together

Even as his colleagues in the field and at Regeneron continued to wrestle with the idea of long-lived IgE plasma cells and the biology that makes them tick, Limnander asked the critical question: “How do we get rid of them?” He added, “And it just so happened that we had the perfect tool in house to do that.”

In 2020, Regeneron’s oncology department filed a patent for a bispecific antibody that binds to the B cell maturation antigen (BCMA) on plasma cells and the cluster of differentiation 3 (CD3) complex on T cells. When a patient has multiple myeloma, BCMAxCD3 can draw T cells and cancerous plasma cells together, prompting the former to kill the latter (13). “We just sort of adapted that tool to the setup of our experiment,” said Limnander.

In a 2023 study, Limnander and the immunology team dosed mice that were experiencing chronic HDM exposure with a combination of anti-IL-4Rα and BCMAxCD3 (14). Then, they used an enzyme-linked immunosorbent assay (ELISA) to check how much IgE was circulating in the mice’s blood serum. “The most exciting day that I’ve had in my ten years of Regeneron was the day we got that first combination experiment,” said Limnander. “The ELISA plate was blank.”

The most exciting day that I’ve had in my ten years of Regeneron was the day we got that first combination experiment.
- Andre Limnander, Regeneron Pharmaceuticals

BCMAxCD3 prompted T cells to kill plasma cells indiscriminately, but whereas other types of plasma cells rebounded after treatment, continued administration of anti-IL-4Rα prevented the class switching necessary to make more IgE plasma cells. Limnander and his team saw similar results when they tried the combination therapy on monkeys as well as on human blood and bone marrow samples.

Despite wanting a little more evidence to confirm the existence of long-lived IgE plasma cells, Robinson is inclined to think Limnander and Orengo’s general strategy, if not their exact method, of preventing class switching in IgG memory B cells and eliminating long-lived IgE plasma cells is likely the future of allergy therapy. “Hitting those two repositories, I think, is going to be where the field is aiming,” said Robinson.

While the rest of the field catches up, Limnander wants to make sure that his findings are widely applicable to all the different types of allergies that afflict people. His team focused on treating mice with allergies to dust because those animals reliably developed long-lived IgE plasma cells. “But it is one of our goals, for example to replicate the development of those cells in a food allergy model,” he said.

Meanwhile, Regeneron has launched a Phase 1 clinical trial to test the safety of their combination therapy on people. “It could be a potential approach that we’re currently evaluating in the clinic,” Orengo said.

References

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