Full Papers
FMO2+ fibroblasts as a potential disease-associated subset in the submandibular gland of IgG4-related disease: insights from single-cell RNA sequencing comparative analysis with the labial gland in primary Sjögren’s syndrome
H. Lu1, Y. Li2, H. Liu3, H. Li4, J. Meng5
- Department of Rheumatology and Immunology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
- Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, China.
- Department of Rheumatology and Immunology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
- Department of Rheumatology and Immunology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
- Department of Rheumatology and Immunology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. mserena@163.com
CER20148
Full Papers
Received: 19/05/2026
Accepted : 25/07/2026
In Press: 01/10/2026
Abstract
OBJECTIVES:
To perform a comprehensive analysis of the immune landscapes in submandibular glands of IgG4-related disease (IgG4-RD) and labial salivary glands of primary Sjögren’s syndrome (pSS).
METHODS:
Five single-cell transcriptomics datasets of submandibular glands (SG) harvested from IgG4-RD patients and seven single-cell transcriptomics datasets of labial glands (LG) derived from pSS patients were processed and integrated by Seurat and Harmony R packages. After identifying cell types by classic marker genes, differential abundance analysis, functional enrichment and cell-cell communication were performed.
RESULTS:
After integrating single-cell RNA sequencing datasets, thirteen distinct subsets were identified. Differential abundance analysis revealed significant enrichment of LZ_GC B cells, DZ_GC B cells, Naive B cells, IgG4+plasma cells, CD4+DUSP4+MAF+T, CD4+TCM, CD8+TEM, Tfh, Treg, FMO2+ monocytes, M2 macrophages and FMO2+ fibroblasts in SG from patients with IgG4-RD compared to those in LG tissues in patients with pSS. FMO2+ fibroblasts were heterogeneous from other subpopulations with high expression of SELENOP, SEPTIN7, SELENOW, CCN1, LHFPL6, BEX3, CCN2, REX1BD, TMEM35B, TLE5. Gene Ontology (GO) analysis of the differentially expressed genes implicated this population in critical processes, including the humoral immune response, oxidative phosphorylation, and fibroblast proliferation. Moreover, we found the chemerin signalling pathway was the primary ligand-receptor interaction between fibroblasts and macrophages in SG from IgG4-RD. Specifically, Chemerin (encoded by RARRES2), the ligand in the CHEMERIN signalling pathway, was mainly expressed in fibroblasts and its receptors CMKLR1 and CCRL2 were primarily expressed on both macrophages and fibroblasts.
CONCLUSIONS:
FMO2+ fibroblasts emerged as a candidate cell subset potentially associated with the submandibular gland micro-environment in IgG4-RD. These findings provided a foundation for future functional studies to elucidate the potential roles of fibroblast-immune cell interactions in the pathogenesis of IgG4-RD.
