title: Mechanisms of tumor necrosis factor α antagonist-induced lupus in a murine model.
abstract: OBJECTIVE
  Tumor necrosis factor α (TNFα) antagonists are effective for treating rheumatoid arthritis and other inflammatory diseases, but their use can be complicated by the development of lupus-like phenomena. This study was undertaken to investigate the role of TNFα in a murine model of lupus.
  
  
  METHODS
  Toll-like receptor 7 (TLR-7) ligand-driven lupus was induced by injection of pristane into C57BL/6 (B6) mice deficient in TNFα (TNFα(-/-) ) or TNFα-intact B6 mice as wild-type controls. Autoantibody and type I interferon (IFN) production was measured in each group of mice, and the effects of the presence or absence of TNFα on type I IFN-producing plasmacytoid dendritic cells (PDCs), Ly-6C(high) monocytes, and TNFα-producing neutrophils were determined.
  
  
  RESULTS
  TNFα(-/-) mice did not spontaneously develop autoantibodies or clinical manifestations of lupus, suggesting that TNFα deficiency alone is insufficient to cause lupus. Although the levels of type I IFN were comparable between untreated TNFα(-/-) and wild-type control mice, untreated TNFα(-/-) mice had increased circulating levels of PDCs and PDC-like cells, which enhanced the potential for production of type I IFN. When treated with pristane, TNFα(-/-) mice developed more severe lupus compared to pristane-treated controls, characterized by increased levels of anti-Sm/RNP autoantibodies, type I IFN, PDCs, and peritoneal inflammatory (Ly-6C(high) ) monocytes. In pristane-treated TNFα(-/-) mice, the numbers of neutrophils, a cell type that promotes resolution of inflammation, were decreased considerably, whereas the responses of inflammatory monocytes and PDCs and the production of type I IFN were increased and prolonged.
  
  
  CONCLUSIONS
  Low levels of TNFα will increase the number of circulating PDCs in mice, thereby enhancing the potential to produce type I IFN. However, this does not necessarily lead to type I IFN production or autoimmunity unless there is concomitant exposure to endogenous TLR-7 ligands, which are released from dead cells following pristane treatment. In humans, the rate of clearance of dead cells, along with the levels of TNFα, may influence who will develop lupus following treatment with TNFα inhibitors.
authors.affiliation: University of Florida, Gainesville.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Haoyang
authors.initials: H
authors.lastname: Zhuang
authors.forename: Shuhong
authors.initials: S
authors.lastname: Han
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.forename: John
authors.initials: J
authors.lastname: Massini
authors.forename: Lijun
authors.initials: L
authors.lastname: Yang
authors.forename: Westley H
authors.initials: WH
authors.lastname: Reeves
mesh_terms: D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000378:metabolism; D003713:Dendritic Cells / Q000473:pathology; D004195:Disease Models, Animal; D007370:Interferon Type I / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D013729:Terpenes / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D007370:Interferon Type I; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; C009042:pristane