Institute for Advanced Biosciences, Grenoble Alpes University/National Institute of Health and Medical Research U1209/National Center for Scientific Research UMR5309, La Tronche, France.
Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland.
Ann Neurol. 2019 Mar;85(3):406-420. doi: 10.1002/ana.25415. Epub 2019 Feb 4.
The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.
APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.
APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.
Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.
两个相关的肿瘤坏死因子成员增殖诱导配体（APRIL）和 B 细胞激活因子（BAFF）目前被作为 B 细胞调节剂靶向用于自身免疫性疾病。在多发性硬化症（MS）中，联合 APRIL/BAFF 阻断导致患者中枢神经系统（CNS）中意外的炎症加剧。在这里，我们研究了 APRIL/BAFF 轴在 CNS 中的作用。
通过免疫组织化学分析 MS 病变中的 APRIL 表达。通过实验性自身免疫性脑脊髓炎（EAE）评估 APRIL 在小鼠 MS 模型中的体内作用。使用人源和鼠源星形胶质细胞进行功能体外研究。
APRIL 在 EAE 病变中表达。缺乏 APRIL 时，疾病最严重。MS 患者的病变在巨噬细胞浸润时也显示 APRIL 表达。值得注意的是，这些巨噬细胞分泌的所有 APRIL 都特异性靶向星形胶质细胞。反应性星形胶质细胞中软骨素硫酸盐蛋白聚糖的上调，有时带有 E 糖基的软骨素硫酸盐，与 APRIL 结合，解释了后者的选择性。星形胶质细胞通过产生足够量的 IL-10 来抑制抗原特异性 T 细胞增殖和致病性细胞因子分泌来对 APRIL 作出反应。最后，在疾病发作前向脊髓内递送重组 APRIL，可迅速减轻 EAE 症状。在疾病发作前甚至开始时重复静脉注射重组 APRIL 也有效果。
我们的数据表明，APRIL 介导 MS 病变中星形胶质细胞的抗炎反应。这种保护作用与 BAFF 不同。神经病学年鉴 2019；85：406-420。
