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.

NLRC3 is an inhibitory sensor of PI3K–mTOR pathways in cancer

“…A previous study has shown that expression of NLRC3 is down-regulated in patients with the autoimmune disease Wegener’s granulomatosis 24 . Moreover, a loss-of-function mutation in the gene encoding the NLRC3-like protein in zebrafish results in systemic inflammation 25 .…”

Characteristic changes in microbial community composition and expression of innate immune genes in acute appendicitis

“…Analysis of the TaqMan low-density array real-time PCR including cluster analysis was performed as described recently. 18 …”

“…18 A complete list of the genes analyzed and respective real-time PCR assays used in this study are provided in Supplementary Table S1.…”

Orbital complications:diagnosis of different rhinological causes

“…In contrast, therapeutic regimens in rheumatic or lymphatic conditions are based on immuno-, chemo-and radiotherapy [4,5]. Surgical approaches are restricted to histologically evidenced cases to provide immunological trigger effects with a subsequent disease aggravation [6][7][8]. In addition, corticosteroids, a considerable component of anti-inflammatory treatment of orbital complications in acute rhinosinusitis, can mask lymphatic or rheumatic conditions and prolong time to diagnosis dramatically [9].…”