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Study Links Overactive Immune Cells in Children to Allergy Progression

human natural killer cell dyed salmon color
Colorized scanning electron micrograph of a natural killer cell from a human donor. | NIAID

A new longitudinal study published in Science Immunology identifies a type of hyperactive natural killer cell in eczema and connects the presence of these cells to allergic sensitivity over time and disease. The research complicates a long-held theory that suggested limited natural killer cell activity makes allergies and asthma worse.

"Our findings reshape the simple dogma of poor natural killer cell activity promoting eczema by demonstrating an unexpected wrinkle. An overactive population of natural killer cells in children with eczema may in fact worsen skin damage and provoke allergic sensitivity or development of asthma," said Gurjit Khurana Hershey, corresponding author of the paper and director of the division of asthma research at Cincinnati Children's Hospital Medical Center.

Results showed that infants and toddlers who had more of these cells — distinguishable by their low expression of a certain receptor protein — appeared more likely to gain heightened allergen sensitivities as they entered childhood.

"Whether these unusually active natural killer cells cause these disease outcomes or are a marker of another disease-shaping process remains to be determined," Khurana Hershey added.

Out With The Old Paradigm

Children with chronic eczema, which is often clinically diagnosed as atopic dermatitis, experience skin inflammation characterized by redness, dryness and itchiness. They also tend to acquire more severe allergies and sometimes asthma later in life.

"The current paradigm suggests that eczema is a result of certain immune cells promoting inflammation and damaging the skin, while other beneficial immune cells that might suppress this skin damage are dysfunctional," explained David Ochayon, first author of the paper and research scientist in the division of asthma research at Cincinnati Children's.

Scientists thought that eczema arose, in part, because impaired natural killer cells could not induce cell death, or apoptosis, in inflammatory immune cells. The problematic cells were then free to overreact to normal skin bacteria without consequences. However, Ochayon and his colleagues' analyses challenge this theory.

"These new data alternatively reveal the emergence of a subset of distinctive natural killer cells with increased activity in some children with eczema that portends worsening or progression of disease. This aberrant natural killer population may be a useful therapeutic target for new therapies to block the progression of eczema to other allergic disease," said Stephen Waggoner, corresponding author of the paper and immunologist at Cincinnati Children's Center for Autoimmune Genomics and Etiology (CAGE).

Pathological Driver or Passenger

While broadly examining natural killer cell samples from children involved in an ongoing early life long-term study called Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) that started in 2016, Waggoner, Ochayon and Hershey observed something surprising. Patients with worse eczema also had higher numbers of natural killer cells that exhibited atypically low expression of the NKG2D receptor, which instigates innate antiviral behavior during infections before adaptive immunity kicks in.

Their unique NKG2D receptor signature made the cells easier to track over time in participants. As they observed, the scientists noted that the cells did underperform in some capacities. However, they overperformed in their production of an inflammatory molecule called TNF-α, which has previously been connected to eczema.

"These findings point[ed] to hyperactivity of a unique subset of natural killer cells as a driver of disease progression in children with eczema," said Ochayon.

"Our new data complicates the simple model and reveals that we need to consider the number, type, and activity of natural killer cells as we design new therapies to modulate these cells to treat eczema or prevent allergic disease," said Waggoner.

He and his co-authors observed that, over the first three years of their lives, patients with higher levels of the unique cells were more likely have severe eczema, which puts them at increased risk for asthma development.

"Since the data do not reveal whether these aberrant natural killer cells develop as a result of severe skin damage and allergic disease, or whether the nature of these cells causes these outcomes, there will be a need for additional mechanistic studies," Khurana Hershey cautioned. MPAACH schedules annual follow-up visits with patients as a resource for solving this immunological chicken-or-egg question.

While the results are promising, their ability to influence clinical approaches remains unclear. Natural killer cells have so many other functions, including fighting tumor cells. Targeting the low NKG2D-expressing natural killer cell group could easily come with unforeseen and harmful consequences.

"Until the entirety of the functional and pathogenic activities of these cells are understood, it would be premature to speculate on how best to modify their activity and what the consequences of those interventions could be in health," Waggoner added.

Learning more about these natural killer cells is a top priority for the team. They want to uncover what exactly is causing the overactive cells to emerge, how the cells respond to surrounding signaling, and whether the cells are drivers or symptoms during eczema progression. Additionally, they plan to look more closely at how these natural killer cells relate to worsened eczema, allergies, and asthma development in children.

"As our understanding of the roles and mechanisms evolves, our long-term goal will be to translate these findings into new prognostic tools to predict disease worsening and into therapies to block development of asthma and allergic disease," said Ochayon.

Author

Abigail Eisenstadt

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