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Although elevated interleukin-7 (IL-7) levels have been reported in patients with primary Sjögren′s syndrome (SS), the role of IL-7 in this disease remains unclear. We undertook this study to characterize the previously unexplored role of IL-7 in the development and onset of primary SS using the C57BL/6.NOD-Aec1Aec2(B6.NOD-Aec) mouse model, which recapitulates human primary SS.For gain-of-function studies, recombinant IL-7 or control phosphate buffered saline was injected intraperitoneally (IP) into 12-week-old B6.NOD-Aecmice for 8 weeks. For loss-of-function studies, anti–IL-7 receptor α-chain (anti–IL-7Rα) antibody or its isotype control IgG was administered IP into 16-week-old B6.NOD-Aecmice. Salivary flow measurement, histologic and flow cytometric analysis of salivary glands, and serum antinuclear antibody assay were performed to assess various disease parameters.Administration of exogenous IL-7 accelerated the development of primary SS, whereas blockade of IL-7Rα signaling almost completely abolished the development of primary SS, based on salivary gland inflammation and apoptosis, autoantibody production, and secretory dysfunction. IL-7 positively regulated interferon-γ (IFNγ)–producing Th1 and CD8+ T cells in the salivary glands without affecting IL-17. Moreover, IL-7 enhanced the expression of CXCR3 ligands in a T cell– and IFNγ-dependent manner. Accordingly, IFNγ induced a human salivary gland epithelial cell line to produce CXCR3 ligands. IL-7 also increased the level of tumor necrosis factor α, another Th1-associated cytokine that can facilitate tissue destruction and inflammation.IL-7 plays a pivotal pathogenic role in SS, which is underpinned by an enhanced Th1 response and IFNγ/CXCR3 ligand–mediated lymphocyte infiltration of target organs. These results suggest that targeting the IL-7 pathway may be a potential future strategy for preventing and treating SS.