Could Allergies Begin Before Inflammation? New “Layer 1” Hypothesis Points to the Body’s Protective Barriers
A large analysis of biological data from University of Miami Miller School of Medicine researchers and international colleagues suggests that metabolic and mitochondrial dysfunction in epithelial cells may precede overt inflammation in some allergic diseases.
Key Takeaways
- Researcher Dr. Gil Yosipovitch proposes that metabolic and mitochondrial dysfunction in epithelial cells may precede overt inflammation in some allergic diseases.
- The strongest signals in the analysis appeared in eosinophilic esophagitis and atopic dermatitis, while findings differed across tissues and diseases.
- The “Layer 1” model remains a hypothesis. Prospective studies must determine whether the abnormalities are present before allergic disease develops.
A large analysis of patient data supports a new hypothesis that susceptibility to allergic disease may begin with metabolic and bioenergetic dysfunction in the epithelial cells that form the body’s protective barriers. These changes could occur before overt inflammation and symptoms appear.
For decades, scientists have mainly viewed allergic diseases as problems of the immune system. The usual thinking has been that inflammation starts first and then damages the skin, airways or digestive tract. A new hypothesis from an international team of allergy researchers suggests that, in some allergic diseases, an important part of the process may begin even earlier.
In “The Origins of Allergy: An Outside-In, Bioenergetic Hypothesis,” Gil Yosipovitch, M.D., of the University of Miami Miller School of Medicine, and Peter Smith, Ph.D., of Griffith University and Bond University in Australia, propose that susceptibility to allergic disease may begin in epithelial barriers. These are the protective layers of cells that line the skin, airways and digestive tract. Dysfunction within these cells may contribute to the initiation of allergic disease rather than simply result from inflammation.
The researchers call this proposed early stage “Layer 1.” In this state, epithelial cells may have abnormalities in energy metabolism, mitochondrial quality control and the ability to maintain and repair a strong protective barrier. Mitochondria are structures inside cells that help generate energy and coordinate cellular responses to stress. The researchers propose that these abnormalities may precede overt immune activation and create conditions that make allergic inflammation more likely.
This framework may also offer one possible explanation for why allergic diseases have risen sharply in recent decades even though human genetics have changed very little.
A Search for What Comes First
To explore the idea, researchers analyzed a large collection of biological data from people with and without allergic disease. Their analysis included 1,856 gene-expression datasets and a combined analysis of 116 separate studies. Altogether, the studies represented 3,776 patients and 2,164 people without the conditions.
The clearest evidence came from eosinophilic esophagitis, or EoE, an allergic disease that inflames the esophagus. Across 13 separate patient cohorts, researchers consistently found lower activity in genes involved in mitochondrial maintenance and the removal of damaged mitochondria. Three genes, HIF1A, BNIP3 and PINK1, showed lower activity in every cohort studied.
Researchers also found increased activity in pathways involved in cellular danger sensing. These signals were seen in EoE tissue and in skin affected by atopic dermatitis, commonly called eczema.
The results did not show that mitochondrial abnormalities occur in the same way across every allergic disease. Instead, the pattern varied by tissue and disease. The strongest signals appeared in EoE and atopic dermatitis. They were mostly absent in established asthma and less consistent in allergic rhinitis, also known as nasal allergies.
A Possible Common Starting Point
The Layer 1 framework raises the possibility that allergic diseases that look very different may share an early vulnerability in the body’s protective epithelial barriers.
“When we examined large datasets from the skin, esophagus, lung and upper airway, we repeatedly found abnormalities in pathways involved in cellular energy production, mitochondrial function and epithelial integrity,” said Dr. Yosipovitch, professor and Stiefel Chair in Medical Dermatology in the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery and director of the Miami Itch Center.
Conditions such as atopic dermatitis, allergic rhinitis and EoE affect different parts of the body and cause different symptoms. The researchers propose that these and other allergic diseases may share an early vulnerability in epithelial cells, although the strength of the current evidence differs among diseases.
“These diseases look very different clinically, but they may share a common underlying weakness of the epithelial barrier,” Dr. Yosipovitch said. “Our hypothesis is that this vulnerability may come first, while the type of inflammation and the organ involved determine how the disease ultimately appears.”
In other words, a related epithelial vulnerability could contribute to different allergic diseases depending on the organ affected, environmental exposures and the immune response that follows.
Frequently Asked Questions
What is the “Layer 1” allergy hypothesis?
The hypothesis proposes that abnormalities in energy metabolism, mitochondrial quality control and barrier repair may create an early vulnerability in epithelial cells before overt immune activation and symptoms appear.
Which allergic diseases showed the strongest signals?
The strongest signals appeared in eosinophilic esophagitis and atopic dermatitis. They were mostly absent in established asthma and less consistent in allergic rhinitis.
Does the analysis prove that barrier-cell dysfunction causes allergic disease?
No. The Layer 1 model remains a hypothesis. Researchers need prospective studies to determine whether the abnormalities occur before allergic disease develops or are consequences of disease that has already begun.
Why do Some People Develop Allergies and Others Do Not?
Many people encounter allergens, pollution, viruses and other environmental pressures. Yet only some develop allergic disease. The Layer 1 hypothesis offers one possible explanation.
“One possibility is that the difference is not simply how much allergen or pollution someone encounters, but how well their epithelial cells cope with that stress,” Dr. Yosipovitch said. “A healthy epithelium has the energy and metabolic flexibility to repair itself after environmental injury. In susceptible individuals, we propose that this resilience is reduced. The same environmental exposure may therefore be harmless to one person but contribute to barrier failure and inflammation in another.”
The framework proposes that environmental pressures including dietary factors, air pollution, alterations in the communities of microbes living in the body and antibiotic exposure could influence epithelial bioenergetics and the ability of these cells to recover from stress. These exposures were not established by this analysis as causes of Layer 1 dysfunction and will require direct testing.
Why the Findings Matter
The Layer 1 model is still a hypothesis. If future studies confirm it, the concept could change how allergic diseases are understood, prevented and treated. Most current therapies act after inflammation has developed. Biologic drugs, for example, block immune signals that drive allergic symptoms.
A Layer 1 approach would focus on an earlier stage of disease, strengthening epithelial resilience, supporting cellular bioenergetics and helping the barrier recover from stress.
“Most current treatments target inflammation after it has already developed,” Dr. Yosipovitch said. “A Layer 1 treatment would take a different approach. The goal would be to strengthen the barrier and its ability to recover from stress, potentially preventing the signals that initiate or sustain inflammation. Ultimately, this could complement existing biologic therapies rather than necessarily replace them.”
The researchers also see a possible future in which clinicians could identify biological vulnerabilitybefore symptoms begin.
“I think, if we have a node of cellular distress, then we may be able to reduce environmental pressures and measure the effects at this node to prevent and treat allergies,” said Dr. Smith.“
That is one of the most exciting possibilities, but it remains to be proven,” Dr. Yosipovitch said. “If a reproducible Layer 1 signature can be detected before symptoms develop, it could potentially identify individuals whose epithelial barriers are biologically vulnerable to allergic disease.”
What Comes Next?
Researchers now need to determine whether Layer 1 abnormalities are present before allergic disease develops or are consequences of disease that has already begun.
“The most important next step is to study people before allergic disease develops, particularly infants at increased risk,” Dr. Yosipovitch said. “If the Layer 1 hypothesis is correct, abnormalities in epithelial bioenergetics and mitochondrial stress responses should already be detectable beforeovert inflammation and clinical disease appear.”
Researchers also want to test whether correcting abnormalities in epithelial bioenergetics and mitochondrial function can restore the protective barrier and reduce inflammation. If prospective studies find that epithelial bioenergetics and mitochondrial function are normal before disease begins, that would be strong evidence against the hypothesis.
“The long-term goal would be to move allergy medicine from treating established inflammation toward predicting risk and intervening before disease becomes established,” Dr. Yosipovitch said. “But prospective studies, particularly beginning early in life, will be essential before we know whether that is possible.”
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A Miller School researcher showed a peptide plays a role in chronic itch severity and can help to identify certain types of itch.
Researchers have demonstrated the effectiveness of nemolizumab in a phase 3 clinical trial involving prurigo nodularis patients.
Tags: allergies, Department of Dermatology and Cutaneous Surgery, dermatology, Dr. Gil Yosipovitch, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, immune system, inflammation, Miami Itch Center