Researchers show how allergic responses, build up of specific protein can trigger asthma

UNC scientist Mehmet Kesimer, PhD, helps medical colleagues figure out why airborne allergens can cause asthma symptoms in some people but not others. His work implicates an important protein in mucus -- MUC5AC.

Researchers show how allergic responses, build up of specific protein can trigger asthma click to enlarge Mehmet Kesimer, PhD

October 10, 2016

More than 300 million people worldwide are affected by asthma, 25 million in the United States alone, and for most of them, an allergy is an underlying cause. But why do some individuals allergic to airborne allergens develop asthma while many do not? Now, researchers at Massachusetts General Hospital (MGH) and the UNC School of Medicine have used innovative imaging technology and other novel laboratory techniques to identify key differences in both the immune response and the sensitivity of airway cells to inflammation between allergic individuals with and without asthma. Their results were reported in companion papers appearing in Science Translational Medicine

“Our study found that CD4 helper T cells in individuals with asthma had a more potent immune response to airway allergens than did allergic individuals without asthma,” said senior author Andrew Luster, MD, PhD, of MGH’s Center for Immunology and Inflammatory Diseases (CIID). “Second, the airway cells of asthmatic individuals were both structurally different and had a greater response to allergens and to allergy-associated inflammation.” 

This work depended on the ability to analyze the structure and function of the airway smooth muscle cells that contract and obstruct the airway during an asthma attack. This marked the first time such work was accomplished, and it was made possible by a novel imaging technique developed by another Mass General team, led by Melissa Suter, PhD, of the MGH Division of Pulmonary and Critical Care Medicine. Her team developed an advanced version of optical coherence tomography (OCT), which provides high-resolution imaging of the structure of many types of tissue. 

Suter’s team developed a microscopic imaging platform that provides both orientation-resolved OCT (OR-OCT) images, which reveal the amount of airway smooth muscle, and mechano-microscopy, which measures the force with which muscle tissue contracts. After validating the ability of their equipment in lab tests, they collaborated with Luster’s group to assess the structure of airway smooth muscle in six volunteer study participants – three with mild allergic asthma and three with no allergy – and found that airway smooth muscle was two times thicker in participants with asthma. 

Luster’s team used Suter’s technology and several other approaches to investigate differences in the airway response to allergens among 36 participants with mild allergic asthma, 48 with allergies but no history of asthma, and 5 healthy control participants. After initial measurements of participants’ airway smooth muscle using OR-OCT, researchers introduced diluted amounts of the appropriate allergen – either cat dander or dust mites – into a small section of participants’ lungs. They then measured numerous aspects of the immune response within the lungs, with particular attention to inflammation and to characteristics of the CD4 T cells that specifically respond to the allergen in question. 

Allergic patients with and without asthma responded to the allergen challenge with type 2 inflammation – the type that is characteristic of allergy – and both groups were found to have similar levels of several types of T cells. But use of a novel tool developed in the laboratory of James Moon, PhD, in the MGH CIID – an immunologic agent that recognizes allergen-specific T cell receptors – allowed researchers to identify and analyze allergen-specific CD4 T cells in participants’ airways. While participants with and those without asthma had increased levels of allergen-specific CD4 T cells after the allergen challenge, cells in participants with asthma showed markedly higher expression of two receptors for type 2 innate immune signals. 

Then Mehmet Kesimer, PhD, associate professor of pathology and laboratory medicine at UNC, used novel research techniques to analyze both the amount and the consistency of mucus secreted in participants’ airways in response to the allergen challenge. His lab found that asthmatic participants had increased levels of a mucus/gel-forming protein called mucin compared to other allergic and healthy participants. This protein makes mucus thicker and may increase airway hyper-reactivity. In particular, Kesimer, who is a member of the UNC Marsico Lung Institute, found higher levels of a subtype of gel-forming mucins of the lung – MUC5AC – in people with asthma.

“Mucin overexpression, at the gene level, had previously been associated with asthma, but this collaborative study shows their overproduction at the protein level,” Kesimer said. “The MUC5AC subtype could contribute to asthma symptoms, such as congestion and difficulty breathing.

Kesimer added that it could be possible to target the MU5AC protein to create a therapy to help alleviate asthma symptoms or prevent them all together.

UNC media contact: Mark Derewicz, 984-974-1915, mark.derewicz@unch.unc.edu

 

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