NUCLEOLIN AS THE EARLIEST TARGET MOLECULE OF AUTOANTIBODIES PRODUCED IN MRL/lpr LUPUS PRONE MICE

核仁蛋白是 MRL/lpr 狼疮易感小鼠中产生的自身抗体的最早靶分子

• 批准号: 11670454
• 负责人: MINOTA Seiji
• 金额: $ 2.05万
• 依托单位: JICHI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670454/
• 关键词: systemic lupus erythematosus; autoantibody; MRL; lpr mouse; NZB; NZW F1 mouse; anti-DNA antibody; anti-nucleolin antibody; 1prマウス

To elucidate the autoantigen against which autoantibodies are produced in the earliest phase of the disease process of systemic lupus erythematosus (SLE), serum samples were collected individually and serially from 10 NZB/NZW F1 and 10 MRL/lpr mice. Using immunoblots with mouse thymoma cell (EL-4) lysates as substrates, all mice were found to generate autoantibody against either 150kDa. 110kDa, 75kDa or 55kDa molecule as early as 4 weeks. Anti-DNA antibodies occurred almost at the same time or after those against these four molecules. The number of antigens reactive with autoantibodies in immunoblots increased gradually with age. Antibodies against histone molecules were produced after 8 weeks of age. Among the four antigens, the 110kDa molecule was identified as nucleolin, which is an abundant nucleolar phosphoprotein. Nucleolin binds DNA, RNA and nucleic-acid binding proteins such as histone H1. Nucleolin is a target of granzyme A of cytotoxic T cells, and autoantibodies against it are found in sera from patients with SLE as well as those with various viral infections. These results indicate that nucleolin is one of the immunodominant molecules which break down self-tolerance and initiate autoantibody-spreading in mouse model of SLE.

为阐明系统性红斑狼疮（SLE）发病早期产生自身抗体的自身抗原，分别连续采集10只NZB/NZW F1和10只MRL/lpr小鼠血清。用小鼠胸腺瘤细胞（EL-4）裂解物作为底物的免疫印迹，发现所有小鼠产生抗150 kDa的自身抗体。110 kDa、75 kDa或55 kDa分子。抗DNA抗体几乎同时或在抗这四种分子的抗体之后出现。免疫印迹中与自身抗体反应的抗原数量随着年龄的增长而逐渐增加。抗组蛋白分子的抗体在8周龄后产生。在四种抗原中，110 kDa的分子被鉴定为核仁素，这是一种丰富的核仁磷蛋白。核仁素结合DNA、RNA和核酸结合蛋白，如组蛋白H1。核仁素是细胞毒性T细胞的颗粒酶A的靶点，并且在SLE患者以及具有各种病毒感染的患者的血清中发现针对核仁素的自身抗体。这些结果表明核仁素是SLE小鼠模型中破坏自身耐受和启动自身抗体扩散的免疫优势分子之一。

项目成果

Shimpo, M., Ikeda, U., Maeda, Y., Ueno, S., Ikeda, M., Minota, S., Takizawa, T., Urabe, M., Kume, A., Monahan, J., Ozawa, K.Shimada, K.: "Gene transfer into rat renal cells using adeno-associated virus vectors."Am.J.Nephrol.. 20. 242-247 (2000)

新浦，M.，池田，U.，前田，Y.，上野，S.，池田，M.，美田，S.，泷泽，T.，浦部，M.，久米，A.，莫纳汉，J.，

Okazaki,H.,Sato,H.,Kamimura,T.,Hirata,D.,Iwamoto,M.,Yoshio,T.,Mimori,A.,Masuyama,J.,Kano,S.and Minota,S.: "In vitro and in vivo inhibition of activaaation induced T cell apoptosis by bucillamine."J.Rheumatol.. 27. 1358-1364 (2000)

冈崎 H.、佐藤 H.、上村 T.、平田 D.、岩本 M.、吉雄 T.、三森 A.、增山 J.、卡诺 S. 和美田 S.：

Minota,S.,Horie,S.,Yamada,A.,S Iwamoto,M.,Yoshio,T.,Mimori,A.,Masuyama,J.,Kano,.: "Circulating myeloperoxidase and anti-myeloperoxidase antibody in patients with vasculitis"Scand.J.Rheum.. 28. 94-99 (1999)

Minota,S.、Horie,S.、Yamada,A.、S Iwamoto,M.、Yoshio,T.、Mimori,A.、Masuyama,J.、Kano,.：“患者中的循环髓过氧化物酶和抗髓过氧化物酶抗体

Mimori,A.,Suzuki,T.,Hashimoto,M.,Nara,H.,Yoshio,T.,Masuyama,J.,Okazaki,H.,Hirata,D.,Kano,S.and Minota,S.: "Subarachnoid hemorrhage and systemic lupus erythematosus."Lupus. 9. 521-526 (2000)

三森，A.，铃木，T.，桥本，M.，奈良，H.，吉雄，T.，增山，J.，冈崎，H.，平田，D.，卡诺，S.和美田，S.：

Hirata, D., Iwamoto, M., Yoshio, T., Okazaki, H., Masuyama, J., Mimori, A.and Minota, S.: "Nucleolin as the earliest target molecule of autoantibodies produced in MRL/lpr lupus-prone mice."Clin.Immunol.. 97(1). 50-58 (2000)

Hirata, D.、Iwamoto, M.、Yoshio, T.、Okazaki, H.、Masuyama, J.、Mimori, A. 和 Minota, S.：“核仁素是 MRL/lpr 狼疮中产生的自身抗体的最早靶分子