Research Spotlight: Understanding More About the Genetic Drivers of Airway Defects in Job Syndrome

Hongmei Mou, PhD, an investigator in the Mucosal Immunology and Biology Research Center, is the senior author of a new article in the Journal of Allergy and Clinical Immunology, STAT3 Mutation-Associated Airway Epithelial Defects in Job Syndrome.

What Question Were You Investigating?

Autosomal dominant hyper-IgE syndrome (AD-HIES), also known as Job Syndrome, is caused by de novo STAT3 mutation. Patients with Job Syndrome often suffer chronic lung infections and pneumonia.

Since airway epithelial cells play a central role as the first line of defense against pathogenic infection and express high levels of STAT3, we sought to determine whether and how AD-HIES STAT3 mutations impact innate host defense and regeneration of airway epithelial cells. 

What Approach Did You Use?

We quantitatively analyzed cell proliferation, differentiation, barrier function, bacterial elimination, and innate immune responses to pathogenic infection in healthy and job syndrome airway epithelial cells that harbor various AD-HIES STAT3 mutations.

What Were Your Findings?

AD-HIES STAT3 mutation significantly reduces STAT3 protein stability and transcription activity. As a consequence, it confers numerous defects in airway epithelial cells. Airway epithelial cells of Job Syndrome feature mucous hyperplasia and a loss of coordinated mucociliary clearance.

Notably, they are defective in bacterial killing and fail to initiate vigorous pro-inflammatory responses and neutrophil recruitment in response to Pseudomonas aeruginosa infection.

What are the Clinical Implications?

Previously, defective adaptive immunity is believed to primarily account for the lung manifestations in Job Syndrome.

We uncovered an assortment of abnormalities and immunodeficiencies in airway epithelial cells, adding to our understanding of the complex biology of this disease.

We suggest that more broadly considered therapeutic approaches for Job Syndrome treatment including, at least, therapies that encompass both the epithelial cells and immune cells should be pursued.

Paper cited: Zhang, Y., Lin, T., Leung, H. M., Zhang, C., Wilson-Mifsud, B., Feldman, M. B., Puel, A., Lanternier, F., Couderc, L. J., Danion, F., Catherinot, E., Salvator, H., Tcherkian, C., Givel, C., Xu, J., Tearney, G. J., Vyas, J. M., Li, H., Hurley, B. P., & Mou, H. (2023). STAT3 Mutation-Associated Airway Epithelial Defects in Job Syndrome. The Journal of allergy and clinical immunology, S0091-6749(23)00007-6. Advance online publication. https://doi.org/10.1016/j.jaci.2022.12.821

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