Comparative analysis of molecular immunopathogenesis in optic-spinal and conventional multiple sclerosis

我们分析了在日本相对常见的视神经脊髓多发性硬化（OSMS）和在西方国家常见的常规MS（CMS）的分子免疫发病机制。1)应用敏感的等电聚焦法检测OB，发现CMS中OB的频率为67.9%，OSMS中OB的频率为10%。2)我们用CDR 3谱分析研究了复发过程中克隆扩增的T细胞。Vβ5.2在CSF和血液中均频繁扩增。然而，没有OSMS特异性Vβ扩增。在Vβ5.2扩增的病例中检测到相同的CDR 3氨基酸序列，提示致病相关性。3)MS脑中趋化因子和受体的免疫组织化学分析表明CMS是Th 1优势状态。相反，CCR 5/CCR 3比值在CSF CD 4+细胞中OSMS显著低于CMS。4)NKT细胞可能抑制MS，但在某些患者中，这些淋巴细胞在NKT细胞的CD 1d的配体α-GalCer存在下不能增殖。5)在抗原呈递和免疫记忆中起关键作用的CCR 7+细胞可见于斑块邻近区域，并且CCR 7配体SLC在血管内皮细胞中表达。这些分子可能参与白细胞向病变的迁移。6)我们用噬菌体展示技术研究了脑脊液IgG抗原表位。在每种情况下，检测到共同的氨基酸序列，他们往往是同源的疱疹病毒蛋白。然而，每个患者的这些序列都是独特的。脑脊液中IgG的吸收不改变OB的带型。因此，OB的每条带可能由多种抗体组成。我们的研究表明OSMS在OB和Th 1应答方面与CMS不同。我们还对CMS中的淋巴细胞和与CSF IgG反应的肽进行了表征。

We analyzed the molecular immunopathogeneses of optic-spinal multiple sclerosis (OSMS) relatively common in Japan and conventional MS (CMS) commonly seen in Western countries. 1) We applied the sensitive isoelectric focusing method to detect OB and found that the frequencies of OB were 67.9% in CMS and 10% in OSMS. 2) We studied clonally expanded T cells during relapse with the CDR3 spectratyping. Vβ5.2 was frequently expanded in both CSF and blood. However, there was no OSMS-specific Vβ expansion. Identical amonoacid sequences in CDR3 were detected in cases with Vβ5.2 expansion, suggesting the pathogenetic association. 3) The immunohistochemical analyses of chemokines and the receptors in MS brains showed that CMS was a Th1-dominant condition. In contrast, the CCR5/CCR3 ratio in the CSF CD4+cells was significantly lower in OSMS than in CMS. 4) NKT cells probably suppress MS, but these lymphocytes failed to proliferate in the presence of α-GalCer, a ligand of CD1d of NKT cells, in some patients. 5) CCR7+cells, which play a pivotal role in antigen presentation and immunological memory, were seen in the region adjacent to the plaques, and SLC, a CCR7 ligand, was expressed in the vascular endothelial cells. These molecules may be involved in the migration of leukocytes to the lesions. 6) We studied the CSF IgG epitopes with the phage display method. Common aminoacid sequences were detected in each case, and they were frequently homogenous to herpes viral proteins. However, those sequences in each patient were unique. The absorption of CSF IgG reacted to the sequences presented by the phages did not change the banding pattern of OB. Therefore, each band of OB probably consists of multiple antibodies. Our study demonstrated that OSMS was distinct from CMS in OB and Th1 responses. We also characterized the lymphocytes and the peptides reacting to CSF IgG in CMS.