Anaphylaxis Triggered by a Distinctive Immune Cell Subtype Found in Mice; Scientists See Treatment Target

Anaphylaxis, a life-threatening allergic reaction that causes constriction of the airways and a sudden drop in blood pressure, was found in mice to be driven by the immune cell subtype T follicular helper cell 13 (Tfh13), according to a study published last week in the journal Science.

Additional research examining the presence of Tfh13 in humans confirmed a possible treatment target, the authors wrote.

Scientists from the Jackson Laboratory for Genomic Medicine at Yale University analyzed mice bred with the rare genetic immune disease DOCK8 Immunodeficiency Syndrome to find possible immune cell subtypes associated to anaphylaxis. In humans, DOCK8 deficiency results in recurrent viral infections of the skin and respiratory system, as well as severe allergies and asthma. Severe allergic reactions like anaphylaxis are associated with the heightened production of high-affinity IgE antibodies, known as hyper-IgE syndrome (HIES). In the study, DOCK8 deficiency revealed the presence of a novel Tfh cell population associated with a hyper-IgE state:

• Scientists took mice with normal immune systems and sensitized them with respiratory and food allergens to induce severe allergic reactions leading to anaphylaxis
• Scientists then performed single-cell RNA sequencing on 7 distinct clusters of sorted Tfh cells in the mice and found that Tfh13 cells uniquely expressed high levels of Il4, Il13, and GATA3
• A pairwise analysis between the Tfh13 and Tfh2 clusters identified additional genes that discriminate between these 2 populations, demonstrating that Tfh13 cells are transcriptionally distinct subset from Th2 effector and Tfh2 cells

Mice that had allergic reactions were found to have both Tfh13 cells and high-affinity IgE, as opposed to non-allergic mice that lacked the immune cell subtype. Scientists then tested the correlation of Tfh13 to high-affinity IgE by breeding mice to specifically delete Tfh13 cells. The experiment revealed that IgE GC B cell frequencies were significantly reduced in mice that lacked Tfh13. While researchers found that the differing Tfh2 cell may be sufficient to create total IgE and affinity-matured IgG1 responses, the induction of high-affinity, anaphylactic, IgE to allergens critically depends on Tfh13 cells.

To relate the research to humans, scientists compared blood samples from patients with peanut or respiratory allergies to non-allergic volunteers. Tfh13 cells were identified in the cTfh cell compartment of peanut-allergic patients aged 7 to14 years, but not in healthy adolescents.

Airborne allergens were then examined, as non-sensitized individuals were compared to patients sensitive to airborne allergens. The allergen-sensitized individuals had a significantly higher frequency of Tfh13 cells, similar to the level found in mice whose elevated Tfh13 cells and IgE were associated with severe allergic reactions. Scientists conclusively determined that Tfh13 cells are induced in both mice and humans with anti-specific IgE responses to multiple allergens.

“Our study defines the role of Tfh13 cells in eliciting anaphylactic IgE to allergens, identifying specific molecular targets that could be leveraged diagnostically and therapeutically for allergies,” said the authors. Currently, the use of emergency epinephrine is the sole solution when anaphylaxis occurs. Thus, targeting Tfh13 cells through distinct therapies could prove an innovative breakthrough for anaphylaxis prevention and treatment.

Reference

Gowthaman U, Chen JS, Zhang B, et al. Identification of a T follicular helper cell subset that drives anaphylactic IgE. [published online August 1st, 2019]. Science. Doi: 10.1126/science.aaw6433