Like a government agency devoted to monitoring food quality, our immune systems ceaselessly surveil the body’s internal landscape, on the lookout for noxious agents we may be exposed to.

Now, new research describes an underrecognized function of the immune system as a command-and-control center for food quality, pinpointing potential threats and guiding decision-making about foods to eat or avoid.  

This finding is reported by Esther Borges Florsheim and her colleagues in a new study appearing in the current issue of the journal Nature.

Florsheim, a researcher in the Biodesign Center for Health Through Microbiomes and the School of Life Sciences at Arizona State University, is concerned with the physiological underpinnings of allergic reactions. Although the current study focuses specifically on food allergies, the findings have broad implications for the understanding of allergies and immunity.

Allergies, including food allergies, are common, with the effects ranging from mild to life threatening. Further, the prevalence of many types of allergies has increased under the environmental conditions in modern-day urban societies.

Yet the reasons why the body reacts with an allergic response are still largely perplexing to medical science.

The new research seeks to ferret out some of the causes of food allergies. Results suggest that allergies occur when a part of the immune system that acts as an early warning of toxic substances is altered by persistent or repeated exposure, resulting in disease.

The study reveals that mouse models exposed to allergens display an immune-mediated alteration in their behavior, limiting or eliminating their subsequent allergen exposure. Such immune-mediated behavioral modification in response to food allergens likely occurs in humans as well, rewiring our brains to avoid such harmful substances in the future.

“Like the classic sensory systems, the immune system can also recognize signals from the environment, translate them to neurons, and change behavior,” Florsheim says. “We find that sensing of toxins by antibodies induce defensive behaviors.”

The rise of allergies

Allergies, a group of inflammatory diseases, have seen a notable rise in occurrence over recent decades. The surge in diseases such as atopic dermatitis, food allergies, asthma and drug hypersensitivities seem to coincide with the advancement of industrialization and the growth of urban lifestyles. The exact biological purposes behind these allergic reactions, however, continue to puzzle researchers.

A particular mode of immune response associated with allergies, known as type 2, seems to play a significant role in protecting the body from harmful environments and substances, including toxins such as venoms, fluids from blood-seeking organisms, foreign substances and irritants.

A common characteristic of these allergic reactions is that they intensify defensive neural reflexes such as sneezing, itching and vomiting, which work to expel harmful substances from the body. Although useful in some cases, allergic reactions can become harmful, and even life threatening, when they become chronic or excessive.

Avoidance behavior also appears to be a reaction to allergies, implying that type 2 immunity might reduce exposure to harmful stimuli, serving as an effective defensive strategy to limit further harm. Just how type 2 responses stimulate these behaviors remains to be understood.

Mission control

The problem of food selection might seem trivial to those living in modern societies, given the easy accessibility of food choices in modern supermarkets. In a natural environment, however, the process of identifying edible and nontoxic food items becomes far more complex and essential for survival.

In such circumstances, the immune system plays a pivotal role in assisting in this decision-making process. These functions might profoundly impact other physiological systems, potentially influencing behaviors and central nervous system activities.

Factors such as the overall health of an organism, its hunger state, and its environment all play crucial roles in shaping these decisions. This early warning system is distinct from the role conventionally associated with the immune system — namely, to pinpoint and destroy microbial pathogens including viruses and  bacteria.

The theory put forward in the new study is that immune-mediated food quality control mechanisms might become exacerbated and disrupted in conditions like food allergies. Excessive immune responses can lead to inflammatory conditions detrimental to health, such as sesis, autoimmune diseases and allergies.

Cellular defenses

The allergic response typically triggers a defensive arsenal in the body that includes white blood cells, antibodies and innate immune cells like mast cells, eosinophils and lymphoid cells. The study explores potential sensory pathways linking immunological sensing to behavioral responses.

Through a series of carefully controlled experiments, the researchers show that the immune system's response to allergens helps the host organism avoid further exposure to harmful substances through the generation of IgE antibodies, which appear to play a critical role in triggering avoidant behavior upon allergen sensing.

The study demonstrates that mouse models sensitized to a protein allergen exhibited specific avoidance behavior to that protein, suggesting the immune system plays a key role in allergen detection.

Allergen exposure triggers activation in brain regions linked to aversive responses to unpleasant stimuli, such as the nucleus of tractus solitarius, external lateral parabrachial nucleus, and central amygdala. These areas, the researchers suggest, likely instigate the allergen avoidance behavior.

The study stresses that IgE antibodies and mast cells, vital components of the immune system, are key to inducing allergen avoidance behavior. Further, the IgE-dependent avoidance isn’t limited to allergic sensitization. The research also describes lipid mediators produced by mast cells known as leukotrienes, which play a critical role in provoking avoidance behavior.

By revealing how the immune system detects allergens and elicits avoidance behavior, the study paves the way for developing treatments that leverage these natural defense strategies. Targeting IgE, mast cells, and leukotrienes could help regulate the body's allergic responses and usher in new therapeutic avenues for allergy management. The study also sheds new light on the evolutionary underpinnings of the allergic response.

Top graphic by Shireen Dooling/ASU Biodesign Institute