Department of Neurology, University Hospital Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
Neurochem Int. 2010 Nov;57(4):446-50. doi: 10.1016/j.neuint.2010.02.012. Epub 2010 Feb 21.
A hallmark of multiple sclerosis (MS) is the occurrence of focal inflammatory demyelinating lesions in the central nervous system. The prevailing view that activated anti-myelin T cells inherently mediate these lesions has been challenged after observations that these T cells, which are part of the normal immune repertoire, can also intermittently become activated in healthy people and subjects with other diseases. Astrocytes in the white matter of subjects with MS are deficient in beta(2) adrenergic receptors. Stimulation of beta(2) adrenergic receptors increases cAMP, leading to activation of protein kinase A (PKA). beta(2) adrenergic receptor deficiency will reduce the suppressive action of PKA on coactivator class II transactivator (CIITA), which is a key regulator of interferon gamma-induced major histocompatibility (MHC) class II molecule transcription. The expression of MHC class II may deviate astrocytes to function as facultative antigen presenting cells, which can then initiate the inflammatory cascade. In a proof of concept study in MS subjects it was shown that fluoxetine, which activates PKA in astrocytes, reduced the development of focal inflammatory lesions. If confirmed and extended by additional studies, suppressing the antigen presenting capacity of astrocytes could be a novel therapeutic option for the treatment of MS.
多发性硬化症（MS）的一个特点是中枢神经系统中出现局灶性炎症性脱髓鞘病变。在观察到这些 T 细胞（属于正常免疫谱系的一部分）也可以在健康人和患有其他疾病的人中间歇性地被激活之后，激活抗髓鞘 T 细胞固有地介导这些病变的流行观点受到了挑战。多发性硬化症患者的白质星形胶质细胞中缺乏β2 肾上腺素能受体。β2 肾上腺素能受体的刺激会增加 cAMP，从而激活蛋白激酶 A（PKA）。β2 肾上腺素能受体缺乏会降低 PKA 对共激活因子 II 类转激活物（CIITA）的抑制作用，CIITA 是干扰素 γ 诱导主要组织相容性（MHC）II 类分子转录的关键调节剂。MHC II 类的表达可能使星形胶质细胞偏离功能，成为兼性抗原提呈细胞，从而引发炎症级联反应。在 MS 患者的概念验证研究中表明，氟西汀可激活星形胶质细胞中的 PKA，从而减少局灶性炎症病变的发生。如果通过额外的研究得到证实和扩展，抑制星形胶质细胞的抗原提呈能力可能成为治疗 MS 的一种新的治疗选择。
