Desplat-Jégo Sophie, Feuillet Lionel, Creidy Rita, Malikova Irina, Rance Roselyne, Khrestchatisky Michel, Hahm Kyungmin, Burkly Linda C, Pelletier Jean, Boucraut José
Neurobioligie des Interactions Cellulaires et Neurophysiopathologie, CNRS UMR 6184, IFR Jean Roche, 51 Bd Pierre Dramard, 13 916 Marseille Cedex 20, France.
J Leukoc Biol. 2009 Jan;85(1):132-5. doi: 10.1189/jlb.0608347. Epub 2008 Oct 22.
The TNF superfamily ligand, TNF-like weak inducer of apoptosis (TWEAK), regulates cellular responses ranging from proliferation to cell death in a manner highly dependent on the cell type and the microenvironmental context. We have shown previously that treatment of experimental autoimmune encephalomyelitis mice after the priming phase with neutralizing anti-TWEAK antibodies results in a reduction in the severity of the disease and leukocyte infiltration. To further characterize TWEAK/fibroblast growth factor-inducible 14-kDa protein (Fn14) involvement during multiple sclerosis (MS), we evaluated in MS patients and controls: TWEAK and Fn14 expression on PBMC and soluble TWEAK concentration in serum and cerebrospinal fluid (CSF). Thirty-six consecutive patients were enrolled, including 11 patients with relapsing-remitting MS, 11 with a clinical isolated syndrome suggestive of MS (CISSMS), and 14 controls with non-MS diseases. Intracellular TWEAK could be observed in lymphocytes and/or monocytes in all groups of patients. None of the 36 patients displayed TWEAK expression at the cell surface of lymphocytes. In contrast, 12 out of the 36 patients were positive for membrane TWEAK expression on their monocytes. Among these patients, eight were from the CISSMS group. Fn14 was not detected in PBMC. The soluble form of TWEAK is detectable in serum and CSF of patients, and TWEAK concentrations were not statistically different between the disease groups. We demonstrated for the first time that TWEAK is expressed at the cell surface of monocytes during MS, especially in the CISSMS group. Our results support the proposal that TWEAK could be a target for antibody therapy in MS.
肿瘤坏死因子（TNF）超家族配体——肿瘤坏死因子样凋亡微弱诱导剂（TWEAK），以高度依赖细胞类型和微环境背景的方式调节从增殖到细胞死亡的细胞反应。我们之前已经表明，在启动期后用中和性抗TWEAK抗体治疗实验性自身免疫性脑脊髓炎小鼠，会导致疾病严重程度降低和白细胞浸润减少。为了进一步明确TWEAK/成纤维细胞生长因子诱导的14 kDa蛋白（Fn14）在多发性硬化症（MS）中的作用，我们在MS患者和对照组中评估了：外周血单个核细胞（PBMC）上TWEAK和Fn14的表达以及血清和脑脊液（CSF）中可溶性TWEAK的浓度。连续纳入了36例患者，包括11例复发缓解型MS患者、11例临床孤立综合征提示MS（CISSMS）患者和14例非MS疾病对照组。所有患者组的淋巴细胞和/或单核细胞中均可观察到细胞内TWEAK。36例患者中无一例在淋巴细胞表面显示TWEAK表达。相反，36例患者中有12例单核细胞膜TWEAK表达呈阳性。在这些患者中，8例来自CISSMS组。PBMC中未检测到Fn14。患者血清和CSF中可检测到可溶性TWEAK形式，疾病组之间TWEAK浓度无统计学差异。我们首次证明，MS期间TWEAK在单核细胞表面表达，尤其是在CISSMS组。我们的结果支持TWEAK可能成为MS抗体治疗靶点的提议。
