title: A CEACAM6-High Airway Neutrophil Phenotype and CEACAM6-High Epithelial Cells Are Features of Severe Asthma.
abstract: Severe asthma represents a major unmet clinical need; understanding the pathophysiology is essential for the development of new therapies. Using microarray analysis, we previously found three immunological clusters in asthma: Th2-high, Th17-high, and Th2/17-low. Although new therapies are emerging for Th2-high disease, identifying molecular pathways in Th2-low disease remains an important goal. Further interrogation of our previously described microarray dataset revealed upregulation of gene expression for carcinoembryonic Ag cell adhesion molecule (CEACAM) family members in the bronchi of patients with severe asthma. Our aim was therefore to explore the distribution and cellular localization of CEACAM6 using immunohistochemistry on bronchial biopsy tissue obtained from patients with mild-to-severe asthma and healthy control subjects. Human bronchial epithelial cells were used to investigate cytokine and corticosteroid in vitro regulation of CEACAM6 gene expression. CEACAM6 protein expression in bronchial biopsies was increased in airway epithelial cells and lamina propria inflammatory cells in severe asthma compared with healthy control subjects. CEACAM6 in the lamina propria was localized to neutrophils predominantly. Neutrophil density in the bronchial mucosa was similar across health and the spectrum of asthma severity, but the percentage of neutrophils expressing CEACAM6 was significantly increased in severe asthma, suggesting the presence of an altered neutrophil phenotype. CEACAM6 gene expression in cultured epithelial cells was upregulated by wounding and neutrophil elastase. In summary, CEACAM6 expression is increased in severe asthma and primarily associated with airway epithelial cells and tissue neutrophils. CEACAM6 may contribute to the pathology of treatment-resistant asthma via neutrophil and airway epithelial cell-dependent pathways.
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester LE3 9QP, United Kingdom.
authors.forename: Aarti
authors.initials: A
authors.lastname: Shikotra
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080.
authors.forename: David F
authors.initials: DF
authors.lastname: Choy
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester LE3 9QP, United Kingdom.
authors.forename: Salman
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester LE3 9QP, United Kingdom.
authors.forename: Greer
authors.identifier: 0000-0002-4849-4076
authors.initials: G
authors.lastname: Arthur
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Deepti R
authors.initials: DR
authors.lastname: Nagarkar
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Guiquan
authors.initials: G
authors.lastname: Jia
authors.affiliation: University Hospitals of Leicester National Health Service Trust, Glenfield Hospital, Leicester LE3 9QP, United Kingdom; and.
authors.forename: Adam K A
authors.initials: AK
authors.lastname: Wright
authors.affiliation: University Hospitals of Leicester National Health Service Trust, Glenfield Hospital, Leicester LE3 9QP, United Kingdom; and.
authors.forename: Chandra M
authors.initials: CM
authors.lastname: Ohri
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast BT9 7AE, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Doran
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast BT9 7AE, United Kingdom.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Butler
authors.affiliation: University Hospitals of Leicester National Health Service Trust, Glenfield Hospital, Leicester LE3 9QP, United Kingdom; and.
authors.forename: Beverley
authors.identifier: 0000-0003-0246-6130
authors.initials: B
authors.lastname: Hargadon
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Alexander R
authors.identifier: 0000-0003-2600-810X
authors.initials: AR
authors.lastname: Abbas
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Janet
authors.identifier: 0000-0002-6225-6170
authors.initials: J
authors.lastname: Jackman
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast BT9 7AE, United Kingdom.
authors.forename: Liam G
authors.identifier: 0000-0002-9176-5564
authors.initials: LG
authors.lastname: Heaney
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester LE3 9QP, United Kingdom; pb46@le.ac.uk.
authors.forename: Peter
authors.identifier: 0000-0001-8403-0319
authors.initials: P
authors.lastname: Bradding
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000276:immunology*; D001249:Asthma / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000276:immunology*; D059467:Transcriptome
chemical_list: D015703:Antigens, CD; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins