Resilient, adaptive, maladaptive responses: an emerging paradigm to explain allergy severity

Photo of dandelion with spores

UT Health San Antonio-VA team studies airway lining integrity and inflammation balance in controlled chamber

Allergies, including asthma, impose a significant health burden on society. Allergies are the sixth most common cause of chronic illness and are among the top health conditions in children.

There is a paradox: Airborne allergens are widespread, yet many people do not develop nasal and eye irritation or allergic asthma. Yet, among those who develop these conditions, some go on to develop severe disease.

Photo of Dr. Robert Jacobs
Collaborating allergist Robert Jacobs, MD, shows a jar of ragweed particles.

To understand the basis of this paradox, a team from The University of Texas Health Science Center at San Antonio (also referred to as UT Health San Antonio) and the South Texas Veterans Health Care System (South Texas VA) published a series of reports. The two most recent studies were published in The Journal of Allergy and Clinical Immunology and Allergy in 2021.

To explain the paradox of variable disease severity despite the widespread presence of airborne allergens in the environment, the San Antonio team coined the terms “resilient,” “adaptive” and “maladaptive.” These terms describe the nature of the allergic responses observed after exposure to airborne allergens such as house dust mites or cedar and oak pollens. Resilient responses correlated with mild symptoms, adaptive responses with moderate symptoms, and maladaptive responses with severe symptoms. The researchers found that the three allergic responses relate to the balance or imbalance between two opposing forces: (1) integrity of the lining of the airways that provides a barrier against airborne allergens and (2) levels of inflammation that develop after exposure to these allergens, also called aeroallergens.

Barriers, breaches and inflammation

Epithelial cells are found throughout the body. “In the airways, the integrity of the epithelial cell lining provides a barrier, protecting against the invasion of environmental irritants such as aeroallergens or infections,” said Sunil K. Ahuja, MD, the senior author on these studies and professor of medicine, microbiology, immunology and biochemistry at UT Health San Antonio. Dr. Ahuja is also director of the Center for Personalized Medicine at the South Texas Veterans Health Care System.

“If the airway epithelial barrier is disrupted, aeroallergens such as house dust mites or cedar pollen can breach this barrier, triggering an allergic immune and inflammatory response,” Dr. Ahuja said.

Aeroallergen challenge chamber

Allergy chamber photo
Chamber for testing allergen exposure and responses in a controlled manner.

The team studied the epithelial barrier-inflammation balance in a highly controlled environment — the aeroallergen challenge chamber at the Biogenics Research Chamber facility in San Antonio. The chamber, independent of UT Health San Antonio, is the creation of Robert Jacobs, MD, a prominent San Antonio allergist who served for many years in the U.S. Air Force and was chairman of the allergy department at the former Wilford Hall Medical Center.

“Imagine a large conference room with pipes going through the top, and people sit in there at desks and inhale allergens such as ragweed, cedar or house dust mites that are delivered through holes in the pipes,” Dr. Jacobs said. “They all inhale the same amount of the airborne allergen, and every 30 minutes their symptoms are recorded.”

Scientists draw blood and collect nasal airway samples before, during and at the end of the challenge. Challenges can last three hours and up to four days. Studies in the chamber expose volunteers to one allergen at a time.

The gamut of allergic responses

“By coupling chamber challenges with experiments in the blood and nasal samples collected, we grouped individuals into those that manifest resilient, adaptive or maladaptive allergic responses,” said Alisha Smith, PhD, the co-first author of both studies published in 2021.

The resilient response results in mild allergy symptoms and is characterized by the dual features of an intact epithelial barrier and low inflammation. People with the adaptive response have moderate symptoms because they can adapt to repeated challenges.

“This adaptation, we suggest, is related to the capacity to preserve the integrity of the epithelial barrier despite higher levels of inflammation,” said Dr. Smith, also of UT Health San Antonio and South Texas VA.

Photo of Hot Water Bottle in HandsIn contrast, the hallmark of the maladaptive response correlates with the most severe symptoms and is characterized by an eroded epithelial barrier and high inflammation.

“Grouping individuals into those with resilient, adaptive and maladaptive responses provides a mechanistic framework to understand why levels of disease severity and treatment responses may differ widely,” said Nathan Harper, MS, the lead biostatistician on the study and co-first author, who also is of UT Health San Antonio and South Texas VA. “Theoretically, those with the maladaptive response may correspond to those who have poor treatment responses.”


Repairing the barrier and reducing the inflammation

So why do people react so differently to the same exposure to allergens? The scientists believe it could come down to a person’s individual genes. Ongoing studies can impact how patients are treated for their symptoms.

“Regardless of cause, biomarkers that track the resilient, adaptive and maladaptive phenotypes have utility in personalizing the care of patients, as those with the maladaptive phenotype may require therapies to both reduce inflammation and repair the disrupted epithelial barrier,” Dr. Jacobs added.

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases

Alisha M. Smith, PhD, Nathan Harper, MS, Justin A. Meunier, BS,  Anne P. Branum, BS, Fabio Jimenez, BS, Lavanya Pandranki, MS, Andrew Carrillo, BS, Charles S. Dela Cruz, MD, PhD, Marcos I. Restrepo, MD, PhD, Diego J. Maselli, MD, Cynthia G. Rather, CCRC, Anna H. Heisser, MD, Daniel A. Ramirez, MD, Weijing He, MD, Robert A. Clark, MD, Charles P. Andrews, MD, Scott E. Evans, MD, Jacqueline A. Pugh, MD, Nu Zhang, PhD, Grace C. Lee, PharmD, PhD, Alvaro G. Moreira, MD, Leopoldo N. Segal, MD, Robert M. Ramirez, MD, Robert L. Jacobs, MD, Muthu Saravanan Manoharan, MS, Jason F. Okulicz, MD, and Sunil K. Ahuja, MD

First published: August 2021, Journal of Allergy and Clinical Immunology

Large-scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma.

Alisha M. Smith, PhD, Robert M. Ramirez, MD, Nathan Harper, MS, Fabio Jimenez, BS, Anne P. Branum, BS, Justin A. Meunier, BS, Lavanya Pandranki, MS, Andrew Carrillo, BS, Caitlyn Winter, MS, Lauryn Winter, MS, Cynthia G. Rather, CCRC, Daniel A. Ramirez, MD, Charles P. Andrews, MD, Marcos I. Restrepo, MD, PhD, Diego J. Maselli, MD, Jacqueline A. Pugh, MD, Robert A. Clark, MD, Grace C. Lee, PharmD, PhD, Alvaro G. Moreira, MD, Muthu Saravanan Manoharan, MS, Jason F. Okulicz, MD, Robert L. Jacobs, MD, ⱡ Sunil K. Ahuja, MD

First published: October 2021, Allergy

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