Unleveling the playing field.

The digestive system is unique in its ability to both take up useful nutrients and defend us from harmful substances; FASI scientists have made a novel discovery describing the role of a specific type of immune cell – the γδ T cell – in bridging these two important functions, and how they can drive the adaptation of intestinal tissues in response to diverse environmental factors, including the food we eat.

Findings such as these are central to FASI’s recognition of food allergy as part of the body’s natural food quality control system – the ways in which our immune, nervous, and digestive systems synergize to protect us from exposure to harmful compounds.

This novel concept, championed by FASI’s scientific director Ruslan Medzhitov, is not simply an expanded explanation of the phenomenon of food allergy. It is a paradigm shift in the way we approach the research, providing insights into the workings of this highly sophisticated control system, and leading us towards a more complete understanding of how disruption leads to disease.

This work was recently published in the journals Science and Cell:

γδ T cells regulate the intestinal response to nutrient sensing Sullivan et al. Science, March 19th 2021 PMID: 33737460

Food allergy as a biological food quality control system Florsheim et al. Cell, March 18th 2021 PMID: 33450204

FASI scientists have uncovered the involvement of the nervous system in food allergies. Our gut and lungs are lined with a coating of immune cells that help maintain healthy tissues. But these cells are a double edged sword: stress signals can activate these epithelial cells to produce chemicals to trigger nearby nervous system cells to provoke an allergic response.

This was identified both in the lungs and the gut, demonstrating hyperreactive response in both organs that can lead to asthma attacks and anaphylaxis.

Not only does this work highlight the importance of this once overlooked connection, but sheds light on the specific mechanisms involved in the initiation of allergic sensitization, paving the way towards targeted, more effective therapies for patients.

This work was recently published in the journal Nature:

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation, Wallrapp et al. Nature, September 21st 2017 PMID: 28902842

We have also identified a novel interaction between nerve cells and immune cells that is involved in controlling allergic sensitization. A specific chemical – the neuropeptide CGRP – influences the growth and behavior of specific immune cells involved in sensitization to allergens. This work describes a link between the brain and immune system, and represents a huge leap forward in the field of food allergy science – not simply an additional aspect of food allergy, this is an important checkpoint at which the body decides to either suppress or trigger an allergic reaction.

This work was recently published in the journal Immunity:

Transcriptional Atlas of Intestinal Immune Cells Reveals that Neuropeptide alpha-CGRP Modulates Group 2 Innate Lymphoid Cell Responses, Xu et al. Immunity, October 15th 2019 PMID: 31618654

Calcitonin Gene-Related Peptide Negatively Regulates Alarmin-Driven Type 2 Innate Lymphoid Cell Responses, Wallrapp et al. Immunity, October 15th 2019 PMID: 31604686

We get the job done…one of FASI’s major initial goals was to create a detailed cellular atlas of the gut. Set at our inception in 2016, and completed one year later, this atlas is helping us understand these cells, and what they do. In turn, this will help us understand how the body senses allergens and develops adverse responses. This is a major achievement for FASI and the field of food allergy research.

Drawing on this knowledge, our team has identified the cells and pathways that recognize and respond to different kinds of food allergens. At the same time, single-cell analysis technology has also allowed our researchers to identify classes of immune cells that change the genes they express when they’re exposed to peanuts, allowing us to zero in on cells that will be particularly relevant to study.

This work was recently published in the journal Nature:

A single-cell survey of the small intestinal epithelium, Haber et al. Nature, November 16th 2017 PMID: 29144463

Your gut is constantly renewing and adapting to the complex mix of chemicals in our diets. Through newly developed technologies we have uncovered a brand-new functional axis, whereby immune cells monitor the gut for potential threats, and provide feedback signals that drive stem cells towards appropriate adaptation. Investigation of this axis not only shows us the far-reaching effects of the immune system, but also suggests possible mechanisms that may drive the adverse adaptations seen in food allergy – and this is but one example of the insights gained from this fundamental work.

This work was recently published in the journal Cell:

T helper cell cytokines modulate intestinal stem cell renewal and differentiation, Biton et al. Cell, November 15th 2018 PMID: 30392957

Food represents an incredibly complex mixture of chemicals derived from plants, animals and additives, all of which can be modified further by the microbiome in our gut. These chemicals can be sensed by specialized cells that line the gut wall, several of which have been newly identified by FASI researchers.

FASI scientists have developed novel methods to identify and characterize these sensing mechanisms, which has enabled collaboration with partners in the ingredient, flavor, and food extract industries. We are currently evaluating a vast library of food-derived compounds and their impact on the body, including the neuro-immune axis, the microbiome, and the gut itself. Insights gained from this research will lead us to understand how the body senses different compounds, and why some are able to cause allergy.

FASI scientists have developed new technologies to enable rapid and extensive characterization of cell types in the intestine of both mice and humans, including the rare neuronal cells that are involved in gut-brain communication.

The enteric nervous system (ENS), known as the gut’s brain, is thought to play a critical role in allergen-sensing and communicating this information to the brain.

Creation of a detailed atlas of the ENS was another of FASI’s bold initial goals, and its completion represents a huge victory in the fight to end food allergy. We now strongly believe that understanding the role of the ENS will lead us to the true culprits of food allergy and develop the diagnostics and treatments that will save lives.

This work was recently published in the journal Cell:

The Human and Mouse Enteric Nervous System at Single-Cell Resolution, Drokhlyansky et al. Cell, September 17th, 2020 PMID: 32888429

We’ve discovered a critical new interaction between two specific molecules found on cell surfaces that regulates immune activation in response to harmful substances. When this interaction is blocked, the immune response escalates and can result in inflammation and tissue damage, indicating that this pathway plays an important role in limiting certain types of harmful immune activation. Identification of these factors gives us new insight into how allergic reactions are triggered and ultimately how we can stop them.

Studies from Ruslan Medzhitov’s group at Yale have identified a novel role for IgE antibodies – classically viewed as a hallmark of the allergic response – in promoting avoidance behavior, in which allergic individuals develop an aversion to foods containing allergens. Exposure to allergen increases activation in specific areas of the brain, and this activation requires the presence of IgE. This sheds new light on how the same mechanisms underlying food allergy also influence human behavior (anxiety, fight or flight), further highlighting the importance of neuroimmune communications in food allergy.

The mechanisms by which our bodies sense allergens, and determine if they are harmful or not, remain poorly understood. One mechanism involves detection of epithelial integrity and activation of signaling pathways resulting in production of ‘warning’ signals that alert the immune system to mount a defense program – representing the first clear characterization of signaling pathways activated by allergens.

We have identified a control mechanism used by Regulatory T cells, a specialized type of cell involved in helping your immune response strike the balance between rapid elimination of threats and damage caused by over-activation. Blocking this process results in enhanced allergic inflammation, suggesting that these cells are able to control this type of immune response. FASI scientists are investigating the potential of targeting this mechanism in order to stop allergic reactions from ever occurring.

FASI scientists at MIT and Massachusetts General Hospital are working with allergic patients to study oral immunotherapy (OIT) as a treatment for food allergy. Through detailed profiling of individuals’ immune responses, we have identified interactions that help explain why OIT can induce temporary tolerance to allergens, but often doesn’t translate to long term efficacy after treatment is stopped. Identifying such immune mechanisms will enable us to understand – and ultimately remove – the limitations to OIT’s success in food allergy, and highlight ways to personalize treatments to each patient.

This work was recently published in the Journal Nature:

TCR sequencing paired with massively-parallel 3’ RNA-seq reveals clonotypic T cell signatures, Tu et al. Nature Immunology, December 2019 PMID: 31745340

And reviewed in Frontiers in Immunology:

IgE and IgG Antibodies as Regulators of Mast Cell and Basophil Functions in Food Allergy, Kanagaratham et al. Frontiers in Immunology, December 11th 2020 PMID: 33362785

FASI physician-scientists treating patients with Eosinophilic Esophagitis (EoE) are developing a single-cell reference atlas for this allergy-related condition, using data from patients with active disease, patients in remission, and healthy individuals.

Investigating the cellular networks involved is helping us to understand how this disease starts, progresses and responds to different treatments. Harnessing FASI’s collaborative approach, we are able to approach these questions from multiple angles and identify diverse systems that both exacerbate and regulate disease, guiding the development of effective therapies.

It is known that severe allergic reactions can happen the very first time a person eats peanuts, and this raises questions as to how the immune system is being primed to react. FASI researchers are investigating how the skin, and specifically how sensory neurons in the skin can act as the primary sensors of food and environmental allergens. Allergens directly activate nerves in the skin leading to the sensation of itch. These nerves also activate immune cells and can drive them to initiate an allergic response in other parts of the body. This research is helping us understand how the itch response is connected to food allergy, potentially providing a link between atopic dermatitis and food allergy, as well as giving insight into atopic dermatitis. Scientists have identified leukotrienes – a key mediator produced during allergies – as a driver of both acute and chronic itch. Blocking this pathway could be an important therapeutic strategy.

This work was recently published in the journals Immunity and PNAS:

Substance P Release by Sensory Neurons Triggers Dendritic Cell Migration and Initiates the Type-2 Immune Response to Allergens, Perner et al. Immunity, November 17th 2020 PMID: 33098765

The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch, Voisin et al. PNAS, March 30th 2021 PMID: 33753496

Surprisingly, food allergy is just as common in dogs as in people – possibly due to similar recent changes in the amount of processed food in both our diets. Collaborating with Darwin’s Ark, a project implementing large-scale genetic studies in pets, FASI scientists at the Broad Institute have paired food allergy surveys with genetic information from over 2,000 dogs to highlight new genes associated with canine food allergies, as well as identifying specific breeds that are more or less prone to developing allergy. Such studies help to guide our research into the human condition and point us in the right direction – we have already identified the gene AK5 in association with food preference behavior in dogs; this gene is also expressed in the human brain.

Find out more at darwinsark.org