178. Longitudinal transcriptomic profiling of nasal epithelium in patients with granulomatosis with polyangiitis
Creators: name: Rhee1, Rennie
name: Zhao2, Fang
name: Garifallou3, James P.
name: Da Silva3, Renata Pellegrino
name: Chou1, Sherry
name: Shubhasree Banerjee1
name: Amudala1, Naomi
name: Sreih1, Antoine G.
name: Cohen1, Noam A.
name: Collman1, Ronald G.
name: Merkel1, Peter A.
name: Grayson4, Peter C.
name: Miner1, Jonathan J.
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Epithelial cells lining the respiratory tract regulate immune responses and modulate host-commensal interactions. In particular, goblet cells and submucosal glands produce a protective layer of mucin-type glycoproteins, which are the primary component of mucus. We aimed to define the longitudinal changes in nasal epithelial gene expression associated with disease activity in patients with granulomatosis with polyangiitis (GPA). <strong>Methods: </strong>Samples of nasal epithelial cells were obtained by nasal cytology brushes collected longitudinally from patients with GPA and healthy controls. Pre-relapse and relapse visits from 7 patients with GPA (“relapsing GPA”) were matched by immunosuppressive therapy to 2 visits each from 7 patients in stable remission (“non-relapsing GPA”). Relapse was defined as BVAS-WG &gt;0. We performed bulk RNA-sequencing and unsupervised hierarchical clustering analysis of differentially expressed genes between relapsing vs non-relapsing GPA. Pathway enrichment analysis was performed using NCATS BioPlanet. Differentially expressed genes were mapped to cells using HuBMAP. <strong>Results: </strong>There were data from a total of 36 visits among the 14 patients with GPA and 10 healthy controls. Among GPA patients, 86% were PR3-ANCA positive, 64% had prior history of sinonasal involvement, 64% had prior history of relapse; these characteristics were not significantly different between relapsing and non-relapsing groups. There were no significant differences between relapsing and non-relapsing GPA groups in use of topical nasal antibiotics, oral antibiotics, or sinus rinse at time of visit. At the relapse visit, 4 of 7 patients with relapse had clinically-apparent sinonasal involvement and 6 of 7 patients with relapse developed extra-rhinologic manifestations related to GPA. We found differential gene expression related to mucus production in the relapsing GPA group compared to the non-relapsing GPA or healthy control groups. For example, upregulation of the genes B3GNT6 (required for mucin-type core 3 O-glycosylation), GALNT6 (initiates mucin-type O-glycosylation), SPDEF (regulates goblet cell differentiation and mucus production), and MUC5AC (major glycoprotein component of mucus) were observed in the relapsing vs non-relapsing GPA groups. Enrichment analysis revealed pathways associated with O-linked glycosylation of mucins and O-glycan biosynthesis. Upregulated genes were mapped to goblet and submucosal gland cells which are known to produce mucins. Notably, the transcriptomic profiles were similar between the relapse and pre-relapse visits (many months before clinical manifestations of relapse occurred) and were similarly expressed in patients with or without sinonasal symptoms at time of relapse. <strong>Conclusions:</strong> While it has been shown that mucus regulates microbiota and inflammation within the intestinal epithelium, a role for mucus in sinonasal autoimmunity has not previously been described. By performing RNA-seq gene expression profiling, we discovered a persistent signature related to mucus production (specifically mucin-type O-glycosylation) in patients with relapsing GPA but not in those in stable remission. This profile is present regardless of sinonasal symptoms and is detectable many months before active disease becomes clinically apparent. Our results suggest that alterations in homeostasis of mucin-producing cells may contribute to relapsing GPA and, given the established role of mucins in regulating microbiota, raise new questions about the role of mucins in mediating pathogenic host-microbial interactions in the sinonasal epithelium of patients with relapsing GPA. <strong>Disclosures:</strong> None