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Galectin-8 as an immunosuppressor in experimental autoimmune encephalomyelitis and a target of human early prognostic antibodies in multiple sclerosis

机译：Galectin-8作为实验性自身免疫性脑脊髓炎的免疫抑制剂也是人类多发性硬化症早期预后抗体的靶标

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Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 silencing on lymphocyte subpopulations and the development of experimental autoimmune encephalitis (EAE), to then assess the presence and clinical meaning of anti-Gal-8 antibodies in MS patients. Lgals8/Lac-Z knock-in mice lacking Gal-8 expression have higher polarization toward Th17 cells accompanied with decreased CCR6+ and higher CXCR3+ regulatory T cells (Tregs) frequency. These conditions result in exacerbated MOG35-55 peptide-induced EAE. Gal-8 eliminates activated Th17 but not Th1 cells by apoptosis and ameliorates EAE in C57BL/6 wild-type mice. β-gal histochemistry reflecting the activity of the Gal-8 promoter revealed Gal-8 expression in a wide range of CNS regions, including high expression in the choroid-plexus. Accordingly, we detected Gal-8 in human cerebrospinal fluid, suggesting a role in the CNS immune-surveillance circuit. In addition, we show that MS patients generate function-blocking anti-Gal-8 antibodies with pathogenic potential. Such antibodies block cell adhesion and Gal-8-induced Th17 apoptosis. Furthermore, circulating anti-Gal-8 antibodies associate with relapsing-remitting MS (RRMS), and not with progressive MS phenotypes, predicting clinical disability at diagnosis within the first year of follow-up. Our results reveal that Gal-8 has an immunosuppressive protective role against autoimmune CNS inflammation, modulating the balance of Th17 and Th1 polarization and their respective Tregs. Such a role can be counteracted during RRMS by anti-Gal-8 antibodies, worsening disease prognosis. Even though anti-Gal-8 antibodies are not specific for MS, our results suggest that they could be a potential early severity biomarker in RRMS.
机译：Galectin-8（Gal-8）是调节免疫系统等功能的聚糖结合蛋白家族的成员，并且是自身免疫性疾病中抗体的靶标。然而，其在多发性硬化症（MS）（中枢神经系统（CNS）的一种自身免疫性炎性疾病）中的作用仍然未知。我们研究了Gal-8沉默对淋巴细胞亚群的影响以及实验性自身免疫性脑炎（EAE）的发展，然后评估了MS患者中抗Gal 8抗体的存在及其临床意义。缺少Gal-8表达的Lgals8 / Lac-Z敲入小鼠对Th17细胞具有更高的极化作用，伴随着CCR6 + 降低和CXCR3 + 调节性T细胞（Tregs）频率升高。这些条件导致加剧的MOG35-55肽诱导的EAE。 Gal-8可通过凋亡消除激活的Th17细胞，但不能消除Th1细胞，并改善C57BL / 6野生型小鼠的EAE。反映Gal-8启动子活性的β-gal组织化学揭示了Gal-8在广泛的CNS区表达，包括在脉络丛中的高表达。因此，我们在人脑脊髓液中检测到Gal-8，提示其在中枢神经系统免疫监视电路中起作用。此外，我们显示MS患者产生具有致病潜力的功能阻断性抗Gal-8抗体。这样的抗体阻断细胞粘附和Gal-8诱导的Th17凋亡。此外，循环中的抗Gal-8抗体与复发缓解型MS（RRMS）相关，而与进行性MS表型无关，从而预测在随访的第一年内诊断出临床残疾。我们的结果表明，Gal-8对自身免疫性中枢神经系统炎症具有免疫抑制作用，可调节Th17和Th1极化及其各自的Treg的平衡。 RRMS期间抗Gal-8抗体可抵消这种作用，从而恶化疾病的预后。即使抗Gal-8抗体对MS不是特异性的，我们的结果也表明它们可能是RRMS中潜在的早期严重程度生物标志物。

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