title: Molecular signatures of a disturbed nasal barrier function in the primary tissue of Wegener's granulomatosis.
abstract: Wegener's granulomatosis (WG) is a complex autoimmune disease of unknown etiology, frequently involving localized inflammation of the nasal mucosa as an early manifestation. The current hypothesis suggests that the disease is triggered by a disturbed interaction between genetic and environmental effects, such as an altered microflora at mucosal layers. In this study, a systematic assessment of 49 transcripts with potential pathophysiological relevance was performed using quantitative real-time PCR in nasal mucosa samples of more than 80 individuals, including normal control (NC) individuals and disease controls. In addition, colonization with Staphylococcus aureus was quantified in the same individuals to assess its impact on transcriptomic signatures. Transcription profiles show an increased heterogeneity in diseased individuals. In all, 10 transcripts were identified to be differentially expressed (P≤0.05, false discovery rate ≤0.05) between patients with WG and NC individuals. These transcripts include antimicrobial peptides (human β-defensin (DEFB)1: fold-change WG vs. controls: +4.45, lysozyme: -3.4, DEFB4 and S100A7 (S100 calcium-binding protein A7): both "switched on" in WG), innate immune receptors (Toll-like receptor 4: -2.1, NOD-like receptor C3: -2.1, scavenger receptor CD36: +2.9), and cytokines (interferon-γ: -14, transforming growth factor-β 1: -1.4, interleukin-17D: -2.7). These transcriptional profiles are independent of S. aureus colonization. This study for the first time describes that, on the basis of data obtained from the primary nasal tissue, WG exhibits molecular features that allow its differentiation from other inflammatory disorders with involvement of the nasal mucosa. Further studies based on these findings may enable the identification of subphenotypes, which are currently discussed as an important target for a personalized medicine approach, aiming to reduce side effects and the number of therapy non-responders.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts University, Kiel, Germany. laudien@hno.uni-kiel.de
authors.forename: M
authors.initials: M
authors.lastname: Laudien
authors.forename: R
authors.initials: R
authors.lastname: Häsler
authors.forename: J
authors.initials: J
authors.lastname: Wohlers
authors.forename: J
authors.initials: J
authors.lastname: Böck
authors.forename: S
authors.initials: S
authors.lastname: Lipinski
authors.forename: L
authors.initials: L
authors.lastname: Bremer
authors.forename: R
authors.initials: R
authors.lastname: Podschun
authors.forename: P
authors.initials: P
authors.lastname: Ambrosch
authors.forename: P
authors.initials: P
authors.lastname: Lamprecht
authors.forename: P
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: A
authors.initials: A
authors.lastname: Till
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D014890:Granulomatosis with Polyangiitis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D025341:Principal Component Analysis; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology; D013211:Staphylococcus aureus / Q000502:physiology; D055815:Young Adult