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T follicular helper 1 cells in blood potentially mirror salivary gland-infiltrating T cells in Sjögren’s disease

ABSTRACT: Understanding the intricate relationship between peripheral blood immune profiles and the inflammatory environment within affected tissues is pivotal for uncovering mechanisms driving autoimmune diseases. This study aimed to characterize CD4+ T cell subsets in peripheral blood that mirror the inflammatory milieu of labial salivary glands (LSG) in primary Sjögren’s disease (pSjD). Using multicolor flow cytometry and T cell receptor (TCR) sequencing, we identified CXCR3+CXCR5+ T follicular helper 1 (Tfh1) cells as significantly elevated in the circulation of pSjD patients and even more prominently increased in the LSG, with blood PD-1+ICOS+ Tfh1 cells positively correlating with titers of antinuclear, anti-SS-A, and anti-SS-B antibodies. In contrast, CXCR3+CXCR5− Th1 cells were enriched in LSG but reduced in circulation. TCR analysis demonstrated that circulating Tfh1 cells shared extensive clonal similarity with LSG T cells. In the LSG, cytokines such as IL-6, IL-12, IL-21, and TGF-β were upregulated, with TGF-β and TCR recognition promoting Tfh1 differentiation. This microenvironment led to increased production of IL-2, TNF-α, and IL-21, promoting the expansion of CD19+CD38+ B cells. These findings underscore circulating Tfh1 cells as reflections of glandular inflammation and highlight TGF-β as a key driver of Tfh1 differentiation, presenting a potential therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307781 | GEO | 2026/07/02

REPOSITORIES: GEO

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Project description:<Objective> To compare gene expression in labial salivary glands (LSG) of IgG4-related disease (IgG4-RD) with SjM-CM-6grenM-bM-^@M-^Ys syndrome (SS). <Methods> Gene expression was analyzed by DNA microarray in LSG of IgG4-RD (n=5), SS (n=5), and healthy controls (n=3). Differentially expressed genes (DEGs) in IgG4-RD and SS were identified, and gene-annotation enrichment analysis of these DEGs was performed using Gene Ontology (GO) annotation. Validation of the result was performed by quantitative PCR using LSG from IgG4-RD (n=9), SS (n=10), and controls (n=4). <Results> Gene expression patterns in IgG4-RD, SS, and healthy controls were quite different with each other in hierarchical clustering as well as principal component analysis. In IgG4-RD, 1771 up-regulated probe sets (corresponding to 1321 up-regulated genes) and 1785 down-regulated probe sets (corresponding to 1320 down-regulated genes) were identified as DEGs (false discovery rate <0.05). GO term analysis indicated that the up-regulated set of DEGs in IgG4-RD encoded proteins that function in cell proliferation, extracellular matrix organization, and organ development. PCR validated significantly higher expression of lactotransferrin (LTF) in IgG4-RD than SS (P<0.05), and chemokine (C-C motif) ligand 18 (CCL18) in IgG4-RD than SS and controls (P<0.05). <Conclusion> The results clearly showed that the gene expression pattern in LSG of IgG4-RD is different from that of SS. LSG samples were collected from 5 Japanese patients with IgG4-RD, as well as from 5 Japanese patients with SS who had been followed up at University of Tsukuba Hospital (Ibaraki, Japan). All patients with IgG4-RD satisfied the comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD) 2011 proposed by the All Japan IgG4 team [3]. The diagnosis of IgG4-RD was based on the presence of all three items; 1) clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs, 2) Hematological examination shows elevated serum IgG4 concentrations (135 mg/dl), 3) Histopathologic examination shows: (1) Marked lymphocyte and plasmacyte infiltration and fibrosis. (2) Infiltration of IgG4+ plasma cells: ratio of IgG4+/IgG+ cells > 40% and >10 IgG4+ plasma cells/HPF. All patients with SS satisfied the Japanese Ministry of Health criteria for the diagnosis of SS (1999) [4]. These criteria included four clinicopathological findings: lymphocytic infiltration of the salivary or lacrimal glands, dysfunction of salivary secretion, keratoconjunctivitis sicca, and presence of anti-SS-A or SS-B antibodies. The diagnosis of SS was based on the presence of two or more of the above four items. Approval for this study was obtained from the local ethics committee and a signed informed consent was obtained from each subject.

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T follicular helper 1 cells in blood potentially mirror salivary gland-infiltrating T cells in Sjögren’s disease

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