Establishment of a polyreactive T cell clone from Asian type multiple sclerosis patients and identification of the responsible antigens

亚洲型多发性硬化症患者多反应性 T 细胞克隆的建立及相关抗原的鉴定

• 批准号: 10470154
• 负责人: KIRA Jun-ichi
• 金额: $ 6.08万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470154/
• 关键词: multiple sclerosis; opticospinal; myelin protein; autoreactive T cell; HLA-class II; epitope spreading; HLA; 髄鞘; T細胞; Myelin basic protein; Proteolipid protein; Myelin oligodendrocyte glycoprotein; 脊髄

In Japanese, we previously reported the existence of two subtypes of multiple sclerosis (MS), namely, Asian type MS, in which the clinically estimated lesions are confined to the optic nerves and spinal cord, and Western type MS showing disseminated lesions in the CNS including the cerebrum, cerebellum and brainstem. In the present study, sixty-four myelin overlapping peptides consisting of 16-21 residues which correspond to the human MBP, PLP and MOG sequences were synthesized and myelin peptide specific autoreactive CD4+T cell lines were established by stimulating PBMC with these peptides from MS patients and healthy controls. MS patients tended to show epitope spreading in autoreactive CD4+T cell lines as compared with healthy controls. Reactivity against the mixture of overlapping peptides derived from each myelin proteins was then determined. The results indicated that reactivity to MOG was predominant as Asian type MS. On the other hand, Western type MS showed response to all mye … More lin proteins examined. It has been previously reported that the lesions were confined to the optic nerves and spinal cord in BN rats sensitized with MOG. These findings may indicate that predominant reactivity to MOG in Asian type MS may contribute to the development of opticospinal from MS. Furthermore, DP5(DPA1ィイD1*ィエD102022/DPBAィイD1*ィエD10501) restricted autoreactive CD4+T cell clone (SS1. 2) was established in Asian type MS. SS1.2 recognized 196MBP peptide p74-93 and 170MPB peptide p47-67 and responded to the recombinant 170MBP protein. We investigated responses of SS1.2 to analog peptides with single amino acid substitution. It was found that residues 84 (position 1(p1)), 86(p3), 87(p4), 89(p6) and 90(p7) of the peptide were critical for its binding to DP5 molecule and recognition by TCR. On the basis of these observations, we are going to establish an expression library system for searching peptides recognized by the autoreactive CD4+T cells from DP5 positive Asian type MS patients, we expect that specific antigens in Asian type MS could be explored by such a system in future, Less

在日本，我们之前报道了多发性硬化症（MS）的两种亚型的存在，即亚洲型MS，其临床估计的病变局限于视神经和脊髓，而西方型MS表现为弥散性病变，包括大脑，小脑和脑干。在本研究中，我们合成了64个由16-21个残基组成的髓磷脂重叠肽，它们对应于人MBP、PLP和MOG序列，并通过这些肽刺激MS患者和健康对照的PBMC建立髓磷脂肽特异性自身反应性CD4+T细胞系。与健康对照相比，MS患者倾向于在自身反应性CD4+T细胞系中显示表位扩散。然后测定了对来自每种髓磷脂蛋白的重叠肽混合物的反应性。结果表明，亚洲型MS对MOG的反应性较强，而西方型MS对所有蛋白均有反应。先前有报道称，MOG致敏BN大鼠的病变局限于视神经和脊髓。这些发现可能表明，亚洲型MS中对MOG的主要反应性可能有助于MS的光脊髓的发展。此外，DP5（DPA1 D1* D102022/DPBA D1* D10501）限制了自身反应性CD4+T细胞克隆（SS1）。2)在亚洲型ms中建立SS1.2识别196MBP肽p74-93和170MPB肽p47-67，并对重组170MBP蛋白有应答。我们研究了SS1.2对单氨基酸取代的类似肽的反应。发现该肽的第84位（位置1(p1)）、第86位（p3）、第87位（p4）、第89位（p6）和第90位（p7）是其与DP5分子结合并被TCR识别的关键。在此基础上，我们将建立一个寻找DP5阳性亚洲型MS患者自身反应性CD4+T细胞识别肽的表达文库系统，期望该系统能够在未来探索亚洲型MS的特异性抗原

项目成果

三野原元澄、吉良潤一: "多発性硬化症"生体の科学. 50. 371-372 (1999)

Motosumi Minohara、Junichi Kira：“多发性硬化症”生物科学 50. 371-372 (1999)。

三野原元澄、吉良潤一、他: "多発性硬化症"臨床検査. 43. 1648-1655 (1999)

Motosumi Minohara、Junichi Kira 等：“多发性硬化症”临床检查。43。1648-1655 (1999)。

吉良潤一: "多発性硬化症の最新治療情報"難病と在宅ケア. 11. 12-15 (1998)

Junichi Kira：“多发性硬化症的最新治疗信息”难治性疾病和家庭护理。11. 12-15 (1998)。

Kira J, Kawano Y, et al: "Multiple sclerosis with mite antigen specific IgE"J Neurol Sci. 157. 138-142 (1998)

Kira J、Kawano Y 等人：“螨抗原特异性 IgE 引起的多发性硬化症”J Neurol Sci。

Ito H., Yamasaki K, Kawano Y, Horiuchi I, Yun C. NishimuraY, Kira J.: "HLA-DP-associated susceptibility to optico-spinal form of multiple sclerosis in the Japanese"Tissue Antigens. 52. 179-182 (1998)

Ito H.、Yamasaki K、Kawano Y、Horiuchi I、Yun C. NishimuraY、Kira J.：“日本人中多发性硬化症视神经脊髓形式的 HLA-DP 相关易感性”组织抗原。