Tsujimura Shizuyo, Adachi Tomoko, Saito Kazuyoshi, Tanaka Yoshiya
The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
RMD Open. 2017 Jul 14;3(1):e000423. doi: 10.1136/rmdopen-2016-000423. eCollection 2017.
P-glycoprotein (P-gp) expression on activated lymphocytes in systemic lupus erythematosus (SLE) plays a role in active efflux of intracellular drugs, resulting in drug resistance. The role of P-gp-expressing lymphocytes in the pathogenesis of SLE remains unclear. The aim of this study was to determine the importance of P-gpCD4 cells in organ manifestations in refractory SLE.
The proportion of P-gpCD4 cells was determined by flow cytometry in peripheral blood of patients with SLE (n=116) and healthy adults (n=10). Renal biopsy specimens were examined by immunohistochemistry for P-gp expression.
CD69 is a marker of CD4 cell activation. The proportion of both P-gp-expressing CD4 cells and CD69-expressing CD4 cells in peripheral blood was higher in SLE than control. The proportion of P-gpCD69CD4 cells correlated with Systemic Lupus Erythematosus Disease Activity Index and was higher in poor responders to corticosteroids. Furthermore, the proportion of P-gpCD69CD4 cells was significantly higher in proliferative lupus nephritis (LN) with poor response to corticosteroids. The efficacy of immunosuppressive therapy depended on the regulation of the proportion of P-gpCD69CD4 cells. Marked accumulation of P-gpCD4 cells in renal interstitial tissue and high proportion of peripheral P-gpCD69CD4 cells were noted in patients with proliferative LN.
The results showed high proportion of P-gpCD69CD4 cells in peripheral blood and their accumulation in renal tissue in patients with proliferative LN refractory to CS therapy, suggesting that P-gp expression on activated CD4 T cells is a potentially useful marker for refractoriness to treatment and a novel target for treatment.
系统性红斑狼疮（SLE）中活化淋巴细胞上的P-糖蛋白（P-gp）表达在细胞内药物的主动外排中起作用，导致耐药性。表达P-gp的淋巴细胞在SLE发病机制中的作用仍不清楚。本研究的目的是确定P-gp⁺CD4⁺细胞在难治性SLE器官表现中的重要性。
通过流式细胞术测定SLE患者（n = 116）和健康成年人（n = 10）外周血中P-gp⁺CD4⁺细胞的比例。通过免疫组织化学检查肾活检标本中P-gp的表达。
CD69是CD4⁺细胞活化的标志物。SLE患者外周血中表达P-gp的CD4⁺细胞和表达CD69的CD4⁺细胞的比例均高于对照组。P-gp⁺CD69⁺CD4⁺细胞的比例与系统性红斑狼疮疾病活动指数相关，在对皮质类固醇反应不佳的患者中更高。此外，在对皮质类固醇反应不佳的增殖性狼疮性肾炎（LN）中，P-gp⁺CD69⁺CD4⁺细胞的比例显著更高。免疫抑制治疗的疗效取决于P-gp⁺CD69⁺CD4⁺细胞比例的调节。在增殖性LN患者中，肾间质组织中P-gp⁺CD4⁺细胞明显积聚，外周血中P-gp⁺CD69⁺CD4⁺细胞比例较高。
结果显示，在对CS治疗难治的增殖性LN患者中，外周血中P-gp⁺CD69⁺CD4⁺细胞比例较高，且在肾组织中积聚，提示活化CD4⁺T细胞上的P-gp表达是治疗难治性的潜在有用标志物和新的治疗靶点。
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