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The Mucosal Immune Response to Laryngopharyngeal Reflux

¹ Laryngeal Research Group, and ² Medical and Veterinary Sciences, University of Bristol, Bristol, United Kingdom; ³ Division of Medicine, University of Liverpool, Liverpool, United Kingdom; ⁴ Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin; ⁵ Voice Institute of New York, New York, New York; and ⁶ Center for Voice and Swallowing Disorders, Department of Otolaryngology, Medical College of Georgia, Augusta, Georgia

Correspondence and requests for reprints should be addressed to Martin A. Birchall, M.A., M.D. (Cantab.), F.R.C.S., Professor of Laryngology, Laryngeal Research Group, University of Bristol, Langford House, Bristol, UK BS40 5DU. E-mail: martin.birchall{at}bristol.ac.uk

Rationale: Laryngopharyngeal reflux (LPR) affects up to 20% of Western populations. Although individual morbidity is usually moderate, treatment costs are high and there are associations with other diseases, including laryngeal cancer. To date, there have been no studies of the mucosal immune response to this common inflammatory disease.

Objectives: To determine the mucosal immune response to LPR.

Methods: We performed a prospective immunologic study of laryngeal biopsies from patients with LPR and control subjects (n = 12 and 11, respectively), and of primary laryngeal epithelial cells in vitro.

Measurements and Main Results: Quantitative multiple-color immunofluorescence, using antibodies for lymphocytes (CD4, CD8, CD3, CD79, CD161), granulocytes (CD68, EMBP), monocytic cells (CD68, major histocompatibility complex [MHC] class II), and classical and nonclassical MHC (I, II, β₂-microglobulin, CD1d). Univariate and multivariate analysis and colocalization measurements were applied. There was an increase in percentage area of mucosal CD8⁺ cells in the epithelium (P < 0.005), whereas other leukocyte and granulocyte antigens were unchanged. Although epithelial MHC class I and II expression was unchanged by reflux, expression of the nonclassical MHC molecule CD1d increased (P < 0.05, luminal layers). In vitro, laryngeal epithelial cells constitutively expressed CD1d. CD1d and MHC I expression were inversely related in all subjects, in a pattern which appears to be unique to the upper airway. Colocalization of natural killer T (NKT) cells with CD1d increased in patients (P < 0.01).

Conclusions: These data indicate a role for the CD1d–NKT cell axis in response to LPR in humans. This represents a useful target for novel diagnostics and treatments in this common condition.

Key Words: laryngopharyngeal reflux • CD1d • natural killer T cells • epithelial cells

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Laryngopharyngeal reflux affects up to 20% of the United States population. Although morbidity is low, treatment costs are high, and it is associated with other diseases, including mucosal cancer. What This Study Adds to the Field The nonclassical major histocompatibility complex molecule CD1d appears to be involved in the response to laryngopharyngeal reflux. This finding suggests novel approaches to the diagnosis and treatment of this common condition.