Human Airway Epithelial BAFF is Reduced in Early Life but Virally-induced via JAK/STAT

Elizabeth Chorvinsky, Center for Genetic Medicine Research, Children's Research Institute, Washington, D.C., U.S.A.
Surajit Bhattacharya, Center for Genetic Medicine Research, Children's Research Institute, Washington, D.C., U.S.A.
Kyle Salka, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, N.Y., U.S.A.
Bethlehem Solomon Bera, Center for Genetic Medicine Research, Children's Research Institute, Washington, D.C., U.S.A.
Allison Welham, Center for Genetic Medicine Research, Children's Research Institute, Washington, D.C., U.S.A.
Ethan Mondell, Johns Hopkins University School of Medicine, Baltimore, M.D., U.S.A.
Geovanny F. Perez, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, N.Y., U.S.A; Division of Pediatric Pulmonology and Sleep Medicine, Oishei Children's Hospital, Buffalo, N.Y., U.S.A.
Dinesh Pillai, Division of Pediatric Pulmonary and Sleep Medicine, Children's National Hospital, Washington, D.C., U.S.A; Department of Pediatrics, George Washington University School of Medicine, Washington, D.C., U.S.A.
Jyoti Jaiswal, Center for Genetic Medicine Research, Children's Research Institute, Washington, D.C., U.S.A; Department of Pediatrics, George Washington University School of Medicine, Washington, D.C., U.S.A.
Gustavo Nino, Center for Genetic Medicine Research, Children's Research Institute, Washington, D.C., U.S.A; Division of Pediatric Pulmonology and Sleep Medicine, Oishei Children's Hospital, Buffalo, N.Y., U.S.A; Division of Pediatric Pulmonary and Sleep Medicine, Children's National Hospital, Washington, D.C., U.S.A; Department of Pediatrics, George Washington University School of Medicine, Washington, D.C., U.S.A.
Maria J. Gutierrez, Division of Pediatric Allergy, Immunology and Rheumatology, Johns Hopkins University School of Medicine, Baltimore, M.D., U.S.A. Electronic address: mgutie10@jhmi.edu.

Document Type

Journal Article

Publication Date

5-21-2025

Journal

The Journal of allergy and clinical immunology

DOI

10.1016/j.jaci.2025.04.034

Keywords

Airway Epithelium; Airway antibody-mediated immunity; B-cell activating factor; BAFF; Early Life; IFN signaling; JAK/STAT signaling; Respiratory viral infections

Abstract

BACKGROUND: Early infancy is marked by high susceptibility to severe viral respiratory infections and reduced protective antibody responses, making rapid development of local airway immunity essential. Despite this, the developmental dynamics of human airway B-cells and their interaction with airway epithelial cells (AECs) in early life remain poorly understood. OBJECTIVE: To study the developmental dynamics of human airway B-cell populations, the variation in AEC-derived B cell survival and maturation factors with age, and how viral respiratory infections influence their production. METHODS: Changes in human airway B-cell populations and survival receptors across different pediatric age groups were analyzed using a single-cell RNA sequencing dataset. The production of B-cell Activating Factor (BAFF) and other B-cell survival and maturation factors by human AECs was assessed in infants (<12 months) and older children, both at baseline and following viral stimulation in vitro. Additional in vivo validation studies assessed airway BAFF production at baseline and during PCR-confirmed viral respiratory infections across pediatric age groups. RESULTS: We observed age-dependent shifts in airway B-cell composition, identifying the BAFF/BAFF-receptor axis as critical for B-cell maturation and survival in early life. Although BAFF production in AECs is initially reduced in infants (<12 months), it can be activated by viral stimuli both in vivo and in vitro. Mechanistic studies showed that BAFF production in human infant AECs is induced by type-I and III interferons (IFN) via JAK/STAT signaling. CONCLUSION: Human AEC JAK/STAT signaling activation regulates the early maturation of airway B-cell responses via local BAFF induction, particularly during viral infections.

Department

Pediatrics

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