Central Nervous System Destruction Mediated by Glutamic Acid Decarboxylase-Specific CD4+ T Cells
Central Nervous System Destruction Mediated by Glutamic Acid Decarboxylase-Specific CD4+ T Cells
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DOI：
10.4049/jimmunol.0903728
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发表时间：
2010-05-01
影响因子：
4.4
通讯作者：
Vignali, Dario A. A.
中科院分区：
文献类型：
--
作者：
Burton, Amanda R.;Baquet, Zachary;Vignali, Dario A. A.
抗谷氨酸脱羧酶（GAD）65的高滴度自身抗体通常在患有1型糖尿病以及僵人综合征（SPS）（一种影响CNS的疾病）和SPS的变体（具有强直和肌阵挛的进行性脑脊髓炎）的患者中观察到。虽然有大量的数据集中在GAD 65特异性CD 4（+）T细胞在1型糖尿病中的作用，但对其在SPS中的作用知之甚少。在这项研究中，我们发现，小鼠具有单克隆GAD 65特异性CD 4（+）T细胞群（4 B5，PA 19.9G11，或PA 17.9G7）发展一个致命的脑脊髓炎样疾病在没有任何其他T细胞或B细胞。GAD 65反应性CD 4（+）T细胞在整个CNS中发现，与GAD 65表达和激活的小胶质细胞直接一致：在脑实质和血脑屏障之间的界面处靠近脑室周围器官。在存在B细胞的情况下，产生了高滴度的抗GAD 65自身抗体，但这些抗体对疾病的发生率或严重程度没有影响。此外，从脑中分离的GAD 65特异性CD 4（+）T细胞被激活并产生IFN-γ。这些发现表明，GAD 65反应性CD 4（+）T细胞单独介导的致死性脑脊髓炎样疾病，可能作为一个有用的模型，研究GAD 65介导的疾病的中枢神经系统。免疫学杂志，2010，184：4863-4870。
High titers of autoantibodies against glutamic acid decarboxylase (GAD) 65 are commonly observed in patients suffering from type 1 diabetes as well as stiff-person syndrome (SPS), a disorder that affects the CNS, and a variant of SPS, progressive encephalomyelitis with rigidity and myoclonus. Although there is a considerable amount of data focusing on the role of GAD65-specific CD4(+) T cells in type 1 diabetes, little is known about their role in SPS. In this study, we show that mice possessing a monoclonal GAD65-specific CD4(+) T cell population (4B5, PA19.9G11, or PA17.9G7) develop a lethal encephalomyelitis-like disease in the absence of any other T cells or B cells. GAD65-reactive CD4(+) T cells were found throughout the CNS in direct concordance with GAD65 expression and activated microglia: proximal to the circumventricular organs at the interface between the brain parenchyma and the blood-brain barrier. In the presence of B cells, high titer anti-GAD65 autoantibodies were generated, but these had no effect on the incidence or severity of disease. In addition, GAD65-specific CD4(+) T cells isolated from the brain were activated and produced IFN-gamma. These findings suggest that GAD65-reactive CD4(+) T cells alone mediate a lethal encephalomyelitis-like disease that may serve as a useful model to study GAD65-mediated diseases of the CNS. The Journal of Immunology, 2010, 184: 4863-4870.