Basile Maria Sofia, Mazzon Emanuela, Mangano Katia, Pennisi Manuela, Petralia Maria Cristina, Lombardo Salvo Danilo, Nicoletti Ferdinando, Fagone Paolo, Cavalli Eugenio
Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy.
IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.
Brain Sci. 2020 Jan 17;10(1):52. doi: 10.3390/brainsci10010052.
Tetraspanins are a conserved family of proteins involved in a number of biological processes. We have previously shown that Tetraspanin-32 (TSPAN32) is significantly downregulated upon activation of T helper cells via anti-CD3/CD28 stimulation. On the other hand, TSPAN32 is marginally modulated in activated Treg cells. A role for TSPAN32 in controlling the development of autoimmune responses is consistent with our observation that encephalitogenic T cells from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mice exhibit significantly lower levels of TSPAN32 as compared to naïve T cells. In the present study, by making use of ex vivo and in silico analysis, we aimed to better characterize the pathophysiological and diagnostic/prognostic role of TSPAN32 in T cell immunity and in multiple sclerosis (MS). We first show that TSPAN32 is significantly downregulated in memory T cells as compared to naïve T cells, and that it is further diminished upon ex vivo restimulation. Accordingly, following antigenic stimulation, myelin-specific memory T cells from MS patients showed significantly lower expression of TSPAN32 as compared to memory T cells from healthy donors (HD). The expression levels of TSPAN32 was significantly downregulated in peripheral blood mononuclear cells (PBMCs) from drug-naïve MS patients as compared to HD, irrespective of the disease state. Finally, when comparing patients undergoing early relapses in comparison to patients with longer stable disease, moderate but significantly lower levels of TSPAN32 expression were observed in PBMCs from the former group. Our data suggest a role for TSPAN32 in the immune responses underlying the pathophysiology of MS and represent a proof-of-concept for additional studies aiming at dissecting the eventual contribution of TSPAN32 in other autoimmune diseases and its possible use of TSPAN32 as a diagnostic factor and therapeutic target.
四跨膜蛋白是一类保守的蛋白质家族，参与多种生物学过程。我们之前已经表明，通过抗CD3/CD28刺激激活T辅助细胞后，四跨膜蛋白32（TSPAN32）显著下调。另一方面，TSPAN32在活化的调节性T细胞中仅有轻微调节。TSPAN32在控制自身免疫反应发展中的作用与我们的观察结果一致，即与未活化的T细胞相比，来自髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE）小鼠的致脑炎性T细胞中TSPAN32水平显著降低。在本研究中，我们利用体外和计算机分析，旨在更好地描述TSPAN32在T细胞免疫和多发性硬化症（MS）中的病理生理以及诊断/预后作用。我们首先表明，与未活化的T细胞相比，记忆T细胞中TSPAN32显著下调，并且在体外再刺激后进一步降低。因此，抗原刺激后，与健康供体（HD）的记忆T细胞相比，MS患者的髓鞘特异性记忆T细胞中TSPAN32的表达显著降低。与HD相比，未经药物治疗的MS患者外周血单核细胞（PBMC）中TSPAN32的表达水平显著下调，与疾病状态无关。最后，与疾病稳定期较长的患者相比，比较处于早期复发的患者时，在前一组患者的PBMC中观察到TSPAN32表达水平中等但显著降低。我们的数据表明TSPAN32在MS病理生理基础的免疫反应中发挥作用，并为进一步研究提供了概念验证，这些研究旨在剖析TSPAN32在其他自身免疫性疾病中的最终作用以及其作为诊断因子和治疗靶点的潜在用途。
