COMPARATIVE ANALYSIS OF CLINICAL AND MOLECULAR IMMUNOLOGICAL PATHOGENESES IN SUBTYPES OF MULTIPLE SCLEROSIS IN JAPAN

多发性硬化症（MS）分为两种亚型：1)常规多发性硬化症（CMS），脱髓鞘病变弥散在中枢神经系统；2)视神经-脊髓多发性硬化症（OSMS），以选择性累及视神经和脊髓为特征。我们在日本研究了这两种亚型的临床和分子免疫学发病机制。120例患者中MS亚型的比例如下：CMS（60.8%）、OSMS（22.5%）、脊柱MS（7.5%）、继发性进展性MS（5.0%）和原发性进展性MS（4.1%）。与CMS相比，OSMS均无进展。脑脊液中CCR5+CD4+细胞亚群%和IgG1%在OSMS中明显低于CMS，提示OSMS的Th1免疫功能较弱。OSMS不同于CMS的病理特征是组织破坏严重，巨噬细胞明显浸润，免疫球蛋白和活化补体在血管中沉积。寡克隆带阳性CMS最特征性病变为脑室周围病变。CMS中CSF IgG噬菌体展示分析显示，与疱疹病毒高度同源的序列通常作为与患者IgG.6结合的肽段。MS中的CDR3谱型分析显示Vβ5.2+T细胞克隆频繁扩增，提示T细胞在MS发病机制中的重要性。间接免疫荧光法对患者血清和小鼠脑组织的染色显示出OSMS及其高危组特有的独特染色模式。血清自身抗体命名为NMO-IgG，并与CNS微血管、pia、pia下组织和Virchow-Robin空隙结合。NMO-IgG7s在OSMS早期诊断中的作用及其在发病机制中的作用有待进一步研究。

Multiple sclerosis (MS) is classified into two subtypes, 1)conventional MS (CMS) in which demyelinating lesions are disseminated in the central nervous system and 2)optic-spinal MS (OSMS) characterized by the selective involvement of the optic nerves and spinal cord. We investigated clinical and molecular immunological pathogeneses of these two subtypes in Japan.1.The percentages of MS subtypes in our 120 cases were as follows, CMS (60.8%), OSMS(22.5%), spinal MS(7.5%), secondary progressive MS(5.0%), and primary progressive MS(4.1%). In contrast to CMS, none of OSMS was progressive.2.The CCR5+CD4+cell subset% and IgG1% in the cerebrospinal fluid (CSF) were significantly lower in OSMS than in CMS, suggesting less Th1 immunity in OSMS.3.Pathological features of OSMS distinct from CMS were severe tissue destruction, marked macrophage infiltration, and deposition of immunoglobulins and activated complements in the blood vessels.4.The most characteristic lesions in oligoclonal bands-positive CMS were the periventricular lesions.5.Phage display analysis of CSF IgG in CMS showed that the sequences highly homologous to herpes viruses were commonly detected as the peptides bound to the patients'IgG.6.CDR3 spectratyping analysis in MS revealed a frequent expansion of Vβ5.2+T cell clones suggesting the importance of the T cells in the pathogenesis of MS.7.Indirect immunofluorescence method with patients' sera and mouse brain tissue demonstrated a unique staining pattern specifically seen in OSMS and its high-risk group. The serum autoantibody was named NMO-IgG, and it was shown to bind to CNS microvessels, pia, subpial tissue and Virchow-Robin space. Further studies are needed to analyze NMO-IgG7s useful for early diagnosis of OSMS and its role in the pathogenesis.