Daoussis Dimitrios, Tsamandas Athanassios, Antonopoulos Ioannis, Filippopoulou Alexandra, Papachristou Dionysios J, Papachristou Nicholaos I, Andonopoulos Andrew P, Liossis Stamatis-Nick
Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, Rion, Patras, 26504, Greece.
Department of Patholology, Patras University Hospital, University of Patras Medical School, Patras, Greece.
Arthritis Res Ther. 2016 May 21;18(1):118. doi: 10.1186/s13075-016-1017-y.
Rituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (SSc); however, the underlying molecular mechanisms remain unknown. We aimed to explore the hypothesis that RTX may mediate its antifibrotic effects by regulating the expression of Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway.
Fourteen patients with SSc and five healthy subjects were recruited. Dkk-1 expression was immunohistochemically assessed in skin biopsies obtained from 11 patients with SSc (8 treated with RTX and 3 with standard treatment), whereas DKK1 gene expression was assessed in 3 patients prior to and following RTX administration.
In baseline biopsies obtained from all patients with SSc but not in healthy subjects, Dkk-1 was undetectable in skin fibroblasts. Following RTX treatment, four out of eight patients had obvious upregulation of Dkk-1 skin expression. Similarly, RTX treatment correlated with a significant 4.8-fold upregulation of DKK1 gene expression (p = 0.030). In contrast, TGFβ expression in the upper dermis was significantly attenuated following treatment. Moreover, this decreased expression of TGFβ in the skin was significantly more pronounced in the subgroup of patients with Dkk-1 upregulation. In this subgroup TGFβ was downregulated by 50.88 % in contrast to only 15.98 % in patients who did not have Dkk-1 upregulation (p = 0.022).
This is the first study demonstrating a link between B cell depletion and skin Dkk-1 upregulation in patients with SSc. RTX-mediated B cell depletion may mechanistically function via the recently established TGFβ-Dkk-1 axis in improving skin fibrosis.
利妥昔单抗（RTX）可能对系统性硬化症（SSc）患者的皮肤和肺部纤维化产生有益影响；然而，其潜在的分子机制仍不清楚。我们旨在探讨RTX可能通过调节Wnt通路抑制剂Dickkopf-1（Dkk-1）的表达来介导其抗纤维化作用这一假说。
招募了14例SSc患者和5名健康受试者。对11例SSc患者（8例接受RTX治疗，3例接受标准治疗）的皮肤活检标本进行免疫组织化学评估Dkk-1表达，而对3例患者在RTX给药前后评估DKK1基因表达。
在所有SSc患者的基线活检标本中，而非健康受试者中，皮肤成纤维细胞中未检测到Dkk-1。RTX治疗后，8例患者中有4例Dkk-1皮肤表达明显上调。同样，RTX治疗与DKK1基因表达显著上调4.8倍相关（p = 0.030）。相比之下，治疗后上真皮层中的TGFβ表达显著减弱。此外，在Dkk-1上调的患者亚组中，皮肤中TGFβ的这种降低表达更为明显。在该亚组中，TGFβ下调了50.88%，而在未发生Dkk-1上调的患者中仅下调了15.98%（p = 0.022）。
这是第一项证明SSc患者B细胞耗竭与皮肤Dkk-1上调之间存在联系的研究。RTX介导的B细胞耗竭可能通过最近建立的TGFβ-Dkk-1轴在改善皮肤纤维化中发挥机制作用。
