A study on pathogenesis and therapy of the lysosomal storage disease using ON-OFF (inducible transgeneic expression) system

我们试图利用可诱导的转基因基因表达系统，以进行性神经疾病模型Sandhoff病小鼠为研究对象，探讨溶酶体贮积病的发病机制和治疗方法。由于在我们的动物研究设施中发生了病毒和细菌感染，我们无法很好地构建系统。相反，我们碰巧发现了自身免疫特征，这在山德霍夫病的发病和发展中非常重要。Sandhoff小鼠迅速发展为神经节苷脂GM2和GA2储存的进行性神经疾病。目前的研究表明，该模型中的疾病状态与抗神经节苷脂自身抗体的出现有关。在Sandhoff病晚期小鼠中发现血清抗神经节苷脂自身抗体升高和IgG沉积到中枢神经系统神经元，这些小鼠的血清转移显示IgG与神经元结合。为了确定这些自身抗体的作用，在Sandhoff小鼠中，Fc受体γ基因（FcRgamma）被额外破坏，因为它在免疫复合物介导的自身免疫性疾病中起关键作用。FcRgamma缺失组的临床症状得到改善，寿命延长。Sandhoff小鼠的凋亡细胞数量也明显减少。然而，神经节苷脂的积累水平并没有改变。在尸检的SD患者的大脑中也证实了IgG的沉积。综上所述，这些发现表明自身抗体的产生在桑德霍夫病神经病变的发病机制中起着重要作用，因此为新疗法提供了靶点。

We attemted to find the pathogenesis and therapy of the lysosomal storage disease using Sandhoff disease mice model, a model of progressive neurologic disease, via inducible transgenic gene expression system. Because of the viral and bacterial infections occured in our animal research facility, we could not build the system well.Instead, we happen to find the autoimmune features, that is very important, in the pathogenesis and development of the Sandhoff diease.Sandhoff mice rapidly develop a progressive neurologic disease of ganglioside GM2 and GA2 storage. The present study reveals that the disease-states in this model are associated with the appearance of anti-ganglioside autoantibodies. Both elevation of serum anti-ganglioside autoantibodies and IgG deposition to CNS neurons were found in the advanced stages of the Sandhoff disease in mice and serum transfer from these mice showed IgG binding to neurons. To determine the role of these autoantibodies, the Fc receptor gamma gene (FcRgamma) was additionally disrupted in Sandhoff mice, as it plays a key role in immune complex mediated autoimmune diseases. Clinical symptoms were improved and lifespans were extended in the FcRgamma deleted. Sandhoff mice and the number of apoptotic cells were also decreased. The level of ganglioside accumulation, however, did not change. IgG deposition was also confirmed in the brain of an autopsied SD patient. Taken together, these findings suggest that the production of autoantibodies plays an important role in the pathogenesis of neuropathy in Sandhoff disease and therefore provides a target for novel therapies.