HMG1 protein and its receptor : their distribution and clinical significance

HMG1蛋白及其受体：分布及临床意义

• 批准号: 13470108
• 负责人: OZAKI Shoichi
• 金额: $ 8万
• 依托单位: St. Marianna University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470108/
• 关键词: HMG1; receptor; anti-HMG antibody; Shock; autoimmune disease; ELISA; epitope; RAGE

We isolated high mobility group (HMG) nonhisitone chromosomal proteins 1 and 2 (HMG1/HMG2) as target antigens of anti-neutrophil cytoplasmic antibody (ANCA), and have been analyzing the roles of those autoantibodies as well as the autoantigens. We found the existence of anti-HMG1/HMG2 antibodies in 89% of patients with autoimmune hepatitis. These antibodies seemed to be useful clinical markers in the disease based on the highest prevalence and the correlation with disease activity. We also observed that HMG1 selectively enhanced the proliferation of cholangial cell lines in a dose-dependent manner.We established an ELISA system for soluble HMG1 protein by using both polyclonal and monoclonal anti-HMG1/HMG2 antibody, which enabled us to test a serum HMG1 level as high as 10 micrograms/ml. We found that serum HMG1 reached a detectable level in fatal shock patients as long as we tested. We also established a novel fatal mouse model, in which 90% of the hepatic blood flow was blocked by a surgical procedure. All mice died 60 hr after the ligation, prior to which their serum HMG1 levels significantly increased. The survival rate increased by a simultaneous ip injection of monoclonal anti-HMG1 antibody. Taken together, these data indicates that HMG1 protein may play an important role in a certain fatal condition, and that the intervention of serum HMG1 levels may serve as a new strategy for such a critical state.

我们分离了高迁移率族（HMG）非组蛋白1和2（HMG 1/HMG 2）作为抗中性粒细胞胞浆抗体（ANCA）的靶抗原，并分析了这些自身抗体和自身抗原的作用。我们发现89%的自身免疫性肝炎患者存在抗HMG 1/HMG 2抗体。基于最高患病率和与疾病活动的相关性，这些抗体似乎是该疾病的有用临床标志物。本实验还观察到HMG 1以剂量依赖的方式选择性地促进胆管细胞系的增殖，并建立了可溶性HMG 1蛋白的ELISA检测体系，该体系可检测血清中HMG 1浓度高达10 μ g/ml。我们发现，只要我们检测，致命性休克患者血清HMG 1达到可检测水平。我们还建立了一种新的致命的小鼠模型，其中90%的肝血流被外科手术阻断。所有小鼠在结扎后60小时死亡，在此之前它们的血清HMG 1水平显著增加。同时腹腔注射抗HMG 1单克隆抗体可提高存活率。综上所述，这些数据表明，HMG 1蛋白可能在某种致命性疾病中发挥重要作用，而血清HMG 1水平的干预可能成为这种临界状态的新策略。

项目成果

Tanaka M., Ozaki S., et al.: "Potential preventive effects of follistatin-related protein / TSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis"Int. Immunol.. 15(1). 71-77 (2003)

Tanaka M.、Ozaki S. 等人：“卵泡抑素相关蛋白/TSC-36 对类风湿性关节炎关节破坏及其自身抗体拮抗调节的潜在预防作用”Int。

Akamizu T., Ozaki S., Hiratani H., Uesugi H., Sobagima J., Hataya Y., Kanamoto N., Saijo M., Hattori Y., Moriyama K., Ohmori K and Nakao K.: "Drug-induced neutropenia associated with anti-neutrophil cytoplasmic antibodies (ANCA) : possible involvement of

Akamizu T.、Ozaki S.、Hiratani H.、Uesugi H.、Sobagima J.、Hataya Y.、Kanamoto N.、Saijo M.、Hattori Y.、Moriyama K.、Ohmori K 和 Nakao K.：“药物-

Yahata K., Ozaki S., et al.: "Molecular cloning and expression of a novel klotho-related protein"J. Mol. Med.. 78. 389-394 (2000)

Yahata K.，Ozaki S.，et al.：“新型 klotho 相关蛋白的分子克隆和表达”J.

Akamizu T., Ozaki S., et al.: "Drug-induced neutropenia associated with anti-neutrophil cytoplasrmic antibodies (ANCA) : possible involvement of complement in granulocy tecytotoxicity"Clin Exp Immunol. 127. 92-98 (2002)

Akamizu T.、Ozaki S. 等人：“与抗中性粒细胞胞质抗体 (ANCA) 相关的药物诱导的中性粒细胞减少症：补体可能参与粒细胞毒性”Clin Exp Immunol。

Fida S., Myers A. M., Whittingham S., Rowley j.M., Ozaki S., and Mackay R. I.: "Autoantibodies to the Transcriptional Factor SOX13 in Primary Biliary Cirrhosis Compared with Other Diseases"Journal of Autoimmunity. 19. 251-257 (2002)

Fida S.、Myers A. M.、Whittingham S.、Rowley j.M.、Ozaki S. 和 Mackay R. I.：“与其他疾病相比，原发性胆汁性肝硬化中转录因子 SOX13 的自身抗体”《自身免疫杂志》。