Pathomechanisms of paraneoplastic neurological syndrome-neuronal damege mediated by cytotoxic T cells

一部分副肿瘤性神经综合征可以用特征性抗神经元抗体诊断，这也可以预测潜在的癌症。尽管在患者的血清和CSF中发现的这些抗体被认为是疾病特异性的，但没有直接证据表明其在神经元损失中的作用。在副肿瘤性小脑变性（PCD）伴抗Yo抗体或抗Hu抗体伴脑脊髓神经病（抗Hu综合征）患者中发现CD 8阳性T细胞浸润，提示HLA-I类限制性细胞毒性T细胞（CTL）可能参与了这些疾病。首先，我们用RT-PCR和单链构象多态性方法检测了浸润淋巴细胞的T细胞受体Vb基因，提示PCD/抗Hu综合征的肿瘤和小脑/后神经节中T细胞的寡克隆扩增，然后，我们用HLA-A24特异性肽检测了HLA-I类限制性细胞毒性T淋巴细胞（CTL）对Yo蛋白肽的活性，结合基序或具有B7超型特异性肽结合基序的Hu蛋白的一些肽。在PCD/抗Hu综合征患者的外周血中，用针对在其表面上表达每种肽的自体成纤维细胞的特异性肽刺激后诱导CTL活性。为了进一步阐明CTL是否真的与神经元损伤有关，需要建立CTL诱导的动物模型。

A part of the paraneoplastic neurological syndrome could be diagnosed with characteristic anti-neuronal antibodies which also give the prediction for underlying cancer. Although these antibodies found in the sera and CSFs of patients is thought to be disease- specific, there is no direct evidence of a role in neuronal loss. Infiltration of CD8-positive T cells in the affected tissue was found in the patient with paraneoplastic cerebellar degeneration(PCD)and anti-Yo antibody or encepahlomyeloneuropathy with anti-Hu antibody(anti-Hu syndrome)which suggested HLA class I restricted cytotoxic T cells(CTL)may be involved in these disorders. First, we examined Vb genes of T cell receptors of infiltrated lymphocytes with RT-PCR and single strand conformational polym orphism method, that suggested the oligoclonal expansions of T cells in the tumor and the cerebellum/posterior ganglions of PCD/anti-Hu syndrome, respectively.Then we examined HLA-class I- restricted cytotoxic T lymphocyte(CTL)activity against a peptid of the Yoprotein with the HLA A24-specific peptide-binding motifs or some peptides of the Hu protein with the B7 supertype-specific peptide binding motifs. CTL activity was induced in the peripheral blood of patients with PCD/anti-Hu syndrome after stimulated with specific peptides against autologous fibroblasts expressing each peptide on their surface. To clarify that CTL might really related to the neuronal damage, CTL induced animal models should be raised.For this purpose, we immunized the mice bering common MHC motifs with these peptides and autologous dendritic cells and obtained T cell clones reactive to each peptides.