A new study has shed light on why patients with certain rare immune disorders develop severe, food‑triggered allergic reactions while others with similar diagnoses do not. The findings, published in the Journal of Experimental Medicine, could help guide future treatments for life‑threatening food allergies, including peanut allergy.
“We’ve been really interested in understanding why patients who have a loss-of-function mutation in the DOCK8 gene have something called hyper IgE syndrome, where they make a ton of IgE, especially to food antigens. It’s a very rare form of genetic food allergy,” said Stephanie Eisenbarth, MD, PhD, chief of Allergy and Immunology in the Department of Medicine and the Roy and Elaine Patterson Professor of Medicine, who was co-senior author of the study.
“That’s not how most food allergy happens — it’s a complex interaction of multiple risk factors and environmental triggers. Our thinking was that if we understood how the loss of DOCK8 function forced the immune system down this bad pathway, maybe we could understand aspects of how regular forms of food allergy occur,” Eisenbarth said.
In the study, Eisenbarth and her collaborators investigated hyper‑IgE syndrome — a condition marked by extremely high levels of IgE antibodies and recurrent infections — and compared two genetic causes of the disease: loss‑of‑function mutations in the DOCK8 gene and dominant‑negative mutations in STAT3. While both disorders fall under the same diagnosis, only DOCK8 deficiency consistently leads to elevated food‑specific IgE and clinically significant allergic reactions.
The new study identifies a key reason: the two disorders affect a specialized group of immune cells in very different ways.
Previous research in mouse models showed that DOCK8 normally acts as a brake on Tfh13 cells, a subset of helper T-cells known to drive the production of anaphylactic IgE — the antibodies that drive severe allergic reactions. But the biological mechanism behind this has remained unclear, Eisenbarth said.
The new findings reveal that DOCK8 helps activate STAT3, a transcription factor that in turn suppresses GATA3, a driver of Tfh13 cell development. Without DOCK8, STAT3 activity falters, allowing GATA3 and Tfh13 cells to expand.
However, only patients with DOCK8 deficiency, not those with STAT3 mutations, showed elevated levels of Tfh13 cells in their blood.
To probe deeper, the investigators engineered mice lacking either DOCK8 or STAT3 specifically in T-cells. When the animals were orally exposed to peanut alongside an immune-boosting drug, also called an adjuvant, both groups produced high levels of peanut‑specific IgE and Tfh13 cells.
But during adjuvant‑free oral exposure — which more closely mimics how humans encounter food allergens in everyday life — the two models diverged dramatically.
Mice lacking DOCK8 in T-cells developed strong peanut-specific IgE responses and abundant Tfh13 cells, but mice lacking STAT3 did not.
The key difference turned out to be regulatory T-cells (Tregs), which normally work to suppress allergic sensitization. DOCK8‑deficient mice showed reduced levels of Foxp3+ Tregs, while STAT3‑deficient mice retained them. When the investigators intentionally depleted Tregs in the STAT3‑deficient mice, Tfh13 cells emerged even without an adjuvant — mirroring what happens naturally in DOCK8 deficiency.
The findings suggest that two immune-system failures together set the stage for severe food allergies: Loss of DOCK8–STAT3 signaling, which removes restraints on Tfh13 cells; and impaired Treg function, which removes the immune system’s tolerance‑promoting safeguards.
Because DOCK8 deficiency affects both pathways, patients with this mutation are far more likely to develop life-threatening food allergies than those with STAT3 mutations alone.
The study identifies Tfh13 cells as a potentially important biomarker for severe food allergy risk, including in patients with rare immunodeficiencies. It also points toward therapeutic strategies that could someday reduce allergic responses by restoring the DOCK8–STAT3–GATA3 balance or strengthening regulatory T-cells.
The new research could also help clarify why food allergies have dramatically risen in the general population, as it highlights two key immune pathways that maintain tolerance to food antigens, Eisenbarth said.
“In the immune system, there’s always a push and a pull,” Eisenbarth said. “And here we illustrate this one-two punch: if you lose both DOCK8 and STAT3 and Treg function, it generates these aberrant Tfh13’s that drive the wrong antibody response.”
Moving forward, Eisenbarth and her collaborators will continue to study genetic mutations and immune checkpoints that lead to severe allergic reactions.
“Trying to understand the signals that drive T-cells to do this, when DOCK8 is intact, is the next big piece for us,” Eisenbarth said. “We’re still trying to understand all the downstream consequences of when you lose DOCK8 in the T-cells and you have Tfh13 cells, why does that drive this very weird IgE response? That’s another project that’s ongoing in the lab.”
Uthaman Gowthaman, PhD, a former postdoctoral scholar in the Eisenbarth lab who is now an assistant professor at the University of Massachusetts Medical School, was co-senior author of the study.
“This study is a great example of how science is collaborative,” Eisenbarth said. “DOCK8 and STAT3 deficiency are very rare. These patients are not typically seen in most clinics, but they come to the NIH because it’s a hub for treating and studying these diseases. They were incredible collaborators.”
The study was supported by the Smith Family Foundation; the Charles Hood Foundation; the Food Allergy Science Initiative; the National Health and Medical Research Council of Australia (grant ID 2017463) and the Allergy and Immunology Foundation of Australasia; the Intramural Research Program of the National Institutes of Health (NIH); and NIH grants R01 AI187460, R01 AI136942 and R01 AI168016.
