Researchers Find Key Driver Behind Bad Allergies

Adam Williams, of UConn Health and Jackson Laboratory, and Stephanie Eisenbarth of Yale University, in Farmington. (Jackson Laboratory Photo)

Adam Williams of UConn Health and Jackson Laboratory, and Stephanie Eisenbarth of Yale University, in Farmington. (Jackson Laboratory Photo)

An unexpected source drives the molecule behind severe allergies, reports a team of researchers in today’s issue of Science. Their findings may point to a new way to prevent or reduce life-threatening allergic reactions.

Antibodies are large proteins that can grab onto and neutralize disease-causing microorganisms. Sometimes antibodies get confused, and grab onto harmless molecules from things like peanuts and tree pollen. An antibody known as IgE is often the culprit in allergic reactions like these. A kind of super-antibody, known as high-affinity IgE, triggers the most severe reactions, up to and including potentially life-threatening anaphylaxis, which may involve sudden drops in blood pressure, trouble breathing and dizziness.

What drives the immune system to make this high-affinity IgE? A research team co-led by Adam Williams of The Jackson Laboratory for Genomic Medicine and UConn Health, and Stephanie C. Eisenbarth of Yale School of Medicine, tracked down an unexpected driver: a subtype of immune cells designated Tfh13.

“If we can identify the cellular players that drive production of high-affinity IgE,” says Williams, “then we can understand what’s initiating the allergy, and then down the line, maybe we can prevent or reverse the generation of this high-affinity IgE,” thereby reducing the severity of allergic reactions.

The researchers first focused on a genetic disorder, called DOCK8 immunodeficiency. Patients with this disease are susceptible to recurrent staphylococcus bacteria and viral infections and, despite their immunodeficiency, typically have high levels of IgE and severe food allergies.

They generated a mouse model of DOCK8 deficiency, deleting the gene in T cells, a category of immune cells that control and shape how the immune system responds to threats. “These mice develop the same high IgE levels as the patients,” Williams says. “And the IgE they make causes anaphylaxis.” In these mice, the researchers discovered a subtype of T cells called follicular helper 13, or Tfh13. They found that these Tfh13 cells signal to the B cells, another category of immune cell, telling them to make high-affinity IgE.

When the researchers deleted the Tfh13 cells in the DOCK8-deficient mice, the symptoms of the disease disappeared. Similarly, when they induced allergic responses in wild-type mice, they again found the telltale Tfh13 cells. Removing these cells or their ability to message B cells prevented high-affinity IgE production and anaphylaxis.

Compared to non-allergic donors, people with food or respiratory allergies had elevated levels of Tfh13 cells in their blood. This new work points the way to more precise allergy testing as well as identifying new approaches for treating allergies.

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