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Mechanisms of Tumor Necrosis Factor α Antagonist–Induced Lupus in a Murine Model
Author(s) -
Xu Yuan,
Zhuang Haoyang,
Han Shuhong,
Liu Chao,
Wang Hai,
Mathews Clayton E.,
Massini John,
Yang Lijun,
Reeves Westley H.
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38882
Subject(s) - systemic lupus erythematosus , tumor necrosis factor alpha , immunology , autoantibody , pristane , b cell activating factor , rheumatoid arthritis , inflammation , medicine , interferon , autoimmunity , endocrinology , chemistry , b cell , immune system , antibody , disease , hydrocarbon , organic chemistry
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. Conclusion 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.