Small Molecule Inhibitors of Nuclear Export and the Amelioration of Lupus by Modulation of Plasma Cell Generation and Survival.
Small Molecule Inhibitors of Nuclear Export and the Amelioration of Lupus by Modulation of Plasma Cell Generation and Survival.
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DOI：
10.1002/art.42128
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发表时间：
2022-08
影响因子：
13.3
通讯作者：
Anolik, Jennifer H.
中科院分区：
文献类型：
--
作者：
Rangel-Moreno, Javier;Garcia-Hernandez, Maria de la Luz;Owen, Teresa;Barnard, Jennifer;Becerril-Villanueva, Enrique;Kashyap, Trinayan;Argueta, Christian;Gamboa-Dominguez, Armando;Tamir, Sharon;Landesman, Yosef;Goldman, Bruce I.;Ritchlin, Christopher T.;Anolik, Jennifer H.
研究最近批准用于治疗难治性浆细胞（PC）恶性肿瘤的选择性核输出抑制剂（SINE）可能具有治疗狼疮的潜力的假设。用SINE或溶剂对照处理NZB/NZW雌性小鼠。收获组织并使用标准标志物通过流式细胞术进行分析。通过评价蛋白尿和肾脏组织学分析监测肾炎。采用酶联免疫吸附试验（ELISA）检测血清抗双链DNA抗体（anti-dsDNA）水平，采用酶联免疫斑点试验（ELISA）检测血清总IgG和dsDNA抗体分泌细胞（ASC）。SINE在疾病的早期和晚期都消除了小鼠狼疮肾炎，并迅速削弱了老年中心（GC）中自身反应性PC的产生。SINE抑制基质细胞产生NF-κ B驱动的稳态趋化因子，改变脾B和T细胞的战略定位，并显著减少T滤泡辅助细胞（TFH）、GC B细胞和自身反应性PC。SINE还降低了狼疮易感小鼠肾脏中参与PC存活和募集的细胞因子/趋化因子。在人扁桃体的GC、狼疮患者的脾B细胞和狼疮肾炎患者的肾脏中的多个B细胞亚群中检测到SINE靶标Exportin 1。我们的集体结果支持SINE通过靶向狼疮发病机制中关键的几种分子和细胞途径（包括浆细胞产生的自身抗体）的治疗潜力。
To investigate the hypothesis that selective inhibitors of nuclear export (SINE), recently approved for the treatment of refractory plasma cell (PC) malignancy, may have potential in the treatment of lupus. NZB/NZW female mice were treated with SINE or vehicle control. Tissue was harvested and analyzed by flow cytometry using standard markers. Nephritis was monitored by evaluation for proteinuria and by histologic analysis of kidneys. Serum anti– double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay (ELISA) and total IgG and dsDNA antibody-secreting cells (ASC) by enzyme-linked immunospot assay. SINE abrogated murine lupus nephritis at both early and late stages of the disease and rapidly impaired generation of autoreactive PC in germinal centers (GC). SINE inhibited the production of the NF-κB-driven homeostatic chemokines by stromal cells, altering splenic B and T cell strategic positioning and significantly reducing T follicular helper cells (TFH), GC B cells, and autoreactive PC. SINE also decreased cytokines/chemokines involved in PC survival and recruitment in the kidney of lupus-prone mice. Exportin 1, the SINE target, was detected in GC of human tonsils, splenic B cells of lupus patients, and multiple B cell subsets in the kidney of patients with lupus nephritis. Our collective results support the therapeutic potential of SINE via targeting several molecular and cellular pathways critical in lupus pathogenesis, including autoantibody production by plasma cells.
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DOI：
10.3904/kjim.2017.383
发表时间：
2018-03
期刊：
The Korean journal of internal medicine
影响因子：
--
作者：
Kwok SK;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
11.4
作者：
Etchin, J.;Sun, Q.;Kentsis, A.;Farmer, A.;Zhang, Z. C.;Sanda, T.;Mansour, M. R.;Barcelo, C.;McCauley, D.;Kauffman, M.;Shacham, S.;Christie, A. L.;Kung, A. L.;Rodig, S. J.;Chook, Y. M.;Look, A. T.
通讯作者：
Look, A. T.
影响因子：
13.6
作者：
Crispín JC;Liossis SN;Kis-Toth K;Lieberman LA;Kyttaris VC;Juang YT;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
3.7
作者：
Lugar PL;Love C;Grammer AC;Dave SS;Lipsky PE
通讯作者：
Lipsky PE
影响因子：
--
作者：
Looney, RJ;Anolik, JH;Sanz, I
通讯作者：
Sanz, I