Mechanisms of Tumor Necrosis Factor alpha Antagonist-Induced Lupus in a Murine Model

作者：Xu Yuan; Zhuang Haoyang; Han Shuhong; Liu Chao; Wang Hai; Mathews Clayton E; Massini John; Yang Lijun; Reeves Westley H^*

来源：Arthritis & Rheumatology, 2015, 67(1): 225-237.

DOI：10.1002/art.38882

Objective. Tumor necrosis factor alpha (TNF alpha) 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 TNF alpha 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 TNF alpha (TNF alpha(-/-)) or TNF alpha-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 TNF alpha on type I IFN-producing plasmacytoid dendritic cells (PDCs), Ly-6C(high) monocytes, and TNF alpha-producing neutrophils were determined.
Results. TNF alpha(-/-) mice did not spontaneously develop autoantibodies or clinical manifestations of lupus, suggesting that TNF alpha deficiency alone is insufficient to cause lupus. Although the levels of type I IFN were comparable between untreated TNF alpha(-/-) and wildtype control mice, untreated TNF alpha(-/-) 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, TNF alpha(-/-) 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 TNF alpha(-/-) 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 TNF alpha 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 auto-immunity 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 TNF alpha, may influence who will develop lupus following treatment with TNF alpha inhibitors.

• 出版日期2015-1