title: Interleukin-7 enhances the Th1 response to promote the development of Sjögren's syndrome-like autoimmune exocrinopathy in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  For gain-of-function studies, recombinant IL-7 or control phosphate buffered saline was injected intraperitoneally (IP) into 12-week-old B6.NOD-Aec mice 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-Aec mice. Salivary flow measurement, histologic and flow cytometric analysis of salivary glands, and serum antinuclear antibody assay were performed to assess various disease parameters.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Forsyth Institute, Cambridge, MA 02142, USA.
authors.forename: Jun-O
authors.initials: JO
authors.lastname: Jin
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kawai
authors.forename: Seunghee
authors.initials: S
authors.lastname: Cha
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D007274:Injections, Intraperitoneal; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D020395:Receptors, Interleukin-7 / Q000276:immunology; D011994:Recombinant Proteins; D012472:Salivation / Q000187:drug effects; D012859:Sjogren's Syndrome; D013363:Submandibular Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
chemical_list: D000906:Antibodies; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; D011994:Recombinant Proteins; C415350:interleukin-7 receptor, alpha chain