Adam Williams of The Jackson Laboratory and Stephanie Eisenbarth of Yale School of Medicine.
Researchers find driver of ‘high-affinity IgE,’ hallmark of the worst allergic reactions.
An antibody, known as IgE, is the culprit in allergic reactions to everything from peanuts to tree pollen. 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? In research published in Science, a research team co-led by 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. The finding may represent an alternative therapeutic target to prevent or reduce severe allergic reactions, including anaphylaxis.
“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 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. “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, using the cytokine IL-13 (a messenger molecule that immune cells use to talk to each other), 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 make IL-13 prevented high-affinity IgE production and anaphylaxis.
When the researchers compared people with food or respiratory allergies to non-allergic donors they found 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 allergy.
Gowthaman et al.: Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science, August 2, 2019