Idiopathic subglottic stenosis is associated with activation of the inflammatory IL-17A/IL-23 axis.
Idiopathic subglottic stenosis (iSGS) is a rare and devastating extrathoracic obstruction involving the lower laryngeal and upper tracheal airway. It arises without known antecedent injury or associated disease process. Persistent mucosal inflammation and a localized fibrotic response are hallmarks of the disease. Despite the initial clinical description of iSGS more than 40 year ago, there have been no substantive investigations into the pathogenesis of this enigmatic and progressive airway obstruction. In these studies, we present the initial characterization of the molecular pathogenesis underlying the fibrosing phenotype of iSGS.



Utilizing 20 human iSGS and healthy control specimens, we applied histologic, immunohistochemical, molecular, and immunologic techniques.



We demonstrate significant activation of the canonical IL-23/IL-17A pathway in the tracheal mucosa of iSGS patients, as well as identify γδ T cells as the primary cellular source of IL-17A.



Our results suggest that aberrant mucosal immune activation is a component in of the pathogenesis of iSGS. Most critically, our work offers new targets for future therapeutic intervention.



NA Laryngoscope, 126:E356-E361, 2016.
Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee. alexander.gelbard@vanderbilt.edu.
Alexander
A
Gelbard
Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee.
Nicolas-George
NG
Katsantonis
Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee.
Masanobu
M
Mizuta
Department of Medicine, Division of Pulmonary and Critical Care, Vanderbilt University, Nashville, Tennessee.
Dawn
D
Newcomb
Department of Medicine, Division of Infectious Disease, Vanderbilt University, Nashville, Tennessee.
Joseph
J
Rotsinger
Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee.
Bernard
B
Rousseau
Department of Otolaryngology, University of Virginia Health System, Charlottesville, Virginia.
James J
JJ
Daniero
Department of Medicine, Division of Pulmonary & Critical Care, Mayo Clinic, Rochester, Minnesota.
Eric S
ES
Edell
Department of Otolaryngology, Mayo Clinic, Rochester, Minnesota.
Dale C
DC
Ekbom
Department of Otolaryngology, Mayo Clinic, Rochester, Minnesota.
Jan L
JL
Kasperbauer
Department of Otolaryngology, Johns Hopkins, Baltimore, Maryland.
Alexander T
AT
Hillel
Department of Medicine, New York University School of Medicine, New York, New York, U.S.A.
Liying
L
Yang
Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee.
C Gaelyn
CG
Garrett
Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee.
James L
JL
Netterville
Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee.
Christopher T
CT
Wootten
Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee.
David O
DO
Francis
Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee.
Charles
C
Stratton
Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee.
Kevin
K
Jenkins
Department of Pediatrics, Division of Medical Genetics, Vanderbilt University, Nashville, Tennessee.
Tracy L
TL
McGregor
Department of Medicine, Division of Infectious Disease, Vanderbilt University, Nashville, Tennessee.|Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee.
Jennifer A
JA
Gaddy
Department of Medicine, Division of Pulmonary and Critical Care, Vanderbilt University, Nashville, Tennessee.|Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee.
Timothy S
TS
Blackwell
Department of Medicine, Division of Infectious Disease, Vanderbilt University, Nashville, Tennessee.
Wonder P
WP
Drake
D000402:Airway Obstruction / Q000209:etiology; D016022:Case-Control Studies; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D020381:Interleukin-17 / Q000502:physiology*; D053759:Interleukin-23 / Q000502:physiology*; D007830:Larynx / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D014132:Trachea / Q000378:metabolism / Q000473:pathology; D014135:Tracheal Stenosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology
C508717:IL17A protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D053759:Interleukin-23
IL-17; IL-17A; ISS; iSGS; idiopathic subglottis stenosis; laryngotracheal stenosis; tracheal stenosis