Studies on the pathogenesis of immunological disorders by the analysis of molecules concerning the differentiation and function of lymphocytes.

通过分析有关淋巴细胞分化和功能的分子来研究免疫性疾病的发病机制。

• 批准号: 06454296
• 负责人: YATA Junichi
• 金额: $ 4.35万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06454296/
• 关键词: severe combined immunodeficiency; hyper-IgM syndrome; Wiskott-Aldrich syndrome; gene abnormality; mast cell; Fcepsilon receptor; allergy; 接着分子; 遺伝子異常; インターロイキン4; IgE; IL-2レセプターγ鎖; 免疫グロブリン遺伝子; B細胞; Fcεレセプター; IL-4

Pathogenesis of the immunological disorders such as congenital immunodeficiency diseases and allergy was analyzed on the basis of the molecules concerning with the differentiation and function of lymphocytes. X-linked severe combined immunodeficiency is caused by the gene abnormality of cytokine receptor gamma-chain common for IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. WE analyzed the gene from Japanese patients and found some new mutations. T and NK cells are defective, while B cells are normally present in this disease. However, we found that immunoglobulin gene rearrangement in variable region of the patient B cells stays at immature stage and that these genes show few mutation which should be observed in mature B cells. These abnormalities were not corrected even after reconstitution of T cells by bone marrow transplantation, which indicated that these are caused by the defect of B cells themselves. X-linked hyper-IgM syndrome is the result of the gene abnormality of CD40 ligand. … More We analyzed the gene in 13 Japanese patients and found some new mutations. In one case 2 different mRNAs were transcribed from 1 abnormal gene. This was the first observation in this disease. Prenatal diagnosis by the gene analysis using amniotic cells was performed and the result was confirmed to be correct after birth, which shows that prenatal gene diagnosis is practically available in this disease. WASP gene abnormality causes Wiskott-Aldrich syndrome. Eight Japanese cases were analyzed for the gene and 3 new mutations were found. Aggregation of actin fibers in cytoplasma was found to be impaired in the cells transfected with mutant WASP gene, which indicated that WASP molecule is related to cell configuration. Mast cells bear Fcepsilon receptors and are triggered to release chemical mediators when IgE bound to the receptors reacts with antigen. We disclosed that transcription of Fcepsilon receptor gene is enhansed by IL-4. IL-4 also incleased anhesiveness of mast cells by integrin. These observations indicated that IL-r has a role acting on mast cells besides inducing IgE production. Less

免疫疾病的发病机理，例如先天性免疫缺陷疾病和过敏，基于与淋巴细胞分化和功能的分子分析。 X连锁的严重合并免疫缺陷是由IL-2，IL-4，IL-7，IL-9和IL-15受体共同的细胞因子受体γ-链的基因异常引起的。我们分析了日本患者的基因，并发现了一些新的突变。 T和NK细胞有缺陷，而B细胞通常存在于该疾病中。但是，我们发现患者B细胞可变区域中的免疫球蛋白基因重排位于未成熟阶段，并且这些基因显示的突变很少，在成熟的B细胞中应观察到​​。即使通过骨髓移植重新结构T细胞后，这些异常也无法纠正，这表明这些异常是由B细胞本身的缺陷引起的。 X连锁的高IGM综合征是CD40配体基因异常的结果。 …更多我们分析了13名日本患者的基因，并发现了一些新的突变。在一种情况下，从1个异常基因转录不同的mRNA。这是该疾病的第一个观察结果。进行了使用羊膜细胞的基因分析进行产前诊断，并确认结果是正确的，这表明在该疾病中实际上可以使用产前基因诊断。黄蜂基因异常会导致Wiskott-Aldrich综合征。分析了8例日本病例，发现了3个新突变。发现细胞质中肌动蛋白的聚集在用突变体WASP基因转染的细胞中受损，这表明WASP分子与细胞构型有关。肥大细胞带有fcepsilon受体，并触发与受体结合与抗原反应的IgE时释放化学介质。我们透露，FCEPSILON受体基因的转录被IL-4增强。 IL-4还通过整联蛋白提高了肥大细胞的诱饵。这些观察结果表明，除了诱导IgE产生外，IL-R在肥大细胞上起作用。较少的

项目成果

Hagasawa,M.,Maeda,H.,Okawa,H.and Yata,J.: "Pulmonary miliary tuberculosis and T cell abnormalities in a severe combined immunodeficiency patient reconstituted with haploidentical bone marrow transplantation." International Journal of Hematology. 59. 303-3

Hagasawa,M.、Maeda,H.、Okawa,H. 和 Yata,J.：“通过单倍相合骨髓移植重建的严重联合免疫缺陷患者的肺粟粒性结核和 T 细胞异常。”

Kawabata, K., Nagasawa, M., Morio, T., Okawa, H.and Yata, J.: "Decreased alpha/beta heterodimer among CD8 molecules of peripheral blood T cells in Wiskott-Aldrich syndrome." Clin.Immunol.Immunopathol.81 (2). 129-135 (1996)

Kawabata, K.、Nagasawa, M.、Morio, T.、Okawa, H. 和 Yata, J.：“Wiskott-Aldrich 综合征中外周血 T 细胞 CD8 分子的 α/β 异二聚体减少。”

Minegishi, Y., Ishii, N., Tsuchida, M., Okawa, H., Sugamura, K.and Yata, J.: "T cell reconstitution by haploidentical BMT does not restore the diversification of the Ig heavy chain gene in patients with X-linked SCID." Bone Marrow Transplant.16 (3). 801-8

Minegishi, Y.、Ishii, N.、Tsuchida, M.、Okawa, H.、Sugamura, K. 和 Yata, J.：“通过半相合 BMT 重建 T 细胞并不能恢复患者 Ig 重链基因的多样化

Nagasawa, M., Maeda, H., Okawa H.and Yata, J.: "Pulmonary miliary tuberculosis and T cell abnormalities in a servere combined immunodeficiency patent reconstituted with haploidentical bone marrow transplantation." Int.J.Hemat.59 (4). 303-309 (1994)

Nagasawa, M.、Maeda, H.、Okawa H. 和 Yata, J.：“用单倍相合骨髓移植重建严重联合免疫缺陷患者中的肺粟粒性结核和 T 细胞异常。”

Hagasawa,M.,Okawa,H.and Yata,J.: "Deletorious effect of high dose γ-globulin therapy on patients with hemophagocytic syndrome." International Journal of Hematology. 60. 91-93 (1994)

Hagasawa, M.、Okawa, H. 和 Yata, J.：“高剂量 γ-球蛋白治疗对噬血细胞综合征患者的有害作用。”国际血液学杂志 60. 91-93 (1994)。