Molecular mechanisms of immune diseases.

免疫疾病的分子机制。

• 批准号: 05272105
• 负责人: OKUMURA Ko
• 金额: $ 127.74万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05272105/
• 关键词: gene; signal transduction; autoantibody; B cell; MHC; transplantation; HIV; アポトーシス; FasL; IL-5リセプター; ADF; Lyn; SLE; 抗原ペプチド; TcR; DR; HSI; B70; NZB; 移植拒絶; IL-5; I-E

All members of this group are involved in the analysis of the relationships between immune dysfunction and disease on a genetic level. From antibodies and thymocytes to signal transduction mechanisms, this group study a wide range of subjects related to pathological causation. 1.) This group discovered the existence of linkage between an unusual MHC haplotype and the abnormal increase in B1 cells, which are important autoimmune antibody secreting B cells. They also reported that the novel gene, which was dubbed Imh-1, is closely linked to the TNF receptor family located on the end of the 4th chromosome. In addition, the group found that the Mott-1 gene, expressed in Mott cells, which are terminally differentiated from B1 lineage cells and present in patients with immune diseases and BCLL,is linked to the Imh-1 locus on the 4th chromosome. 2.) This group reported that B Cell specific bluton kinase (Brk) and JAK2 kinase can be activated via stimulation with IL5. The group also reported t … More hat irregularities in the IL-5R signal transduction pathway are responsible for the weak response of B cells to IL-5 stimulation in XID mice. 3.) This group was successful in cloning the gene which encodes CD86, a molecule which functions as a costimulatory molecule for T cell activation. By decreasing CD28/CD80 and CD86 signal expression, specific tolerance can be induced. In animal models of SLE,rheumatoid arthritis and atopic dermatitis which already show abnormal immune reactivity, they observed a significant suppression of the abnormal immune reactivity by decreasing CD28/CD80 and CD86 signal expression. 4.) In its continued investigation of the role of intracellular signaling in the activation of lymphocytes, this group, by developing Lyn kinase and HS1 deficient mice, analyzed the effects of dysregulation of these molecules on a molecular level. The group also determined the structure of tyrosine phosphory lated HS1 protein. 5.) This group showed that substitution of amino acids in sntigenic peptides altered the immune response to the antigenic peptides. 6.) This group demonstrated that HIV env protein gp 160 can bind to CaM,producing a dimmer that causes apoptosis due to intracellular accumulation of Ca2+. Furthermore, this group observed that binding of the env protein gp 120 to CD4 cells causes FasL production and an induction of apoptosis in CD4 and CD8 cells. Less

该小组的所有成员都参与分析免疫功能障碍与遗传水平疾病之间的关系。从抗体、胸腺细胞到信号转导机制，这个小组研究了与病理原因有关的广泛主题。1.）的人。本研究组发现了异常的MHC单倍型与重要的自身免疫抗体分泌B细胞B1细胞的异常增加之间存在联系。他们还报告说，这种被称为Imh-1的新基因与位于第4号染色体末端的TNF受体家族密切相关。此外，研究小组发现，Mott-1基因在Mott细胞中表达，Mott细胞是从B1谱系细胞终末分化而来的，存在于免疫疾病和BCLL患者中，与第4号染色体上的Imh-1基因座相关。2.）的情况。该小组报道了B细胞特异性bluton激酶（Brk）和JAK 2激酶可以通过用IL 5刺激而被激活。该组织还报告说， ...更多信息 IL-5 R信号转导通路的不规则性是XID小鼠中B细胞对IL-5刺激的弱反应的原因。3.）第三章这个小组成功地克隆了编码CD 86的基因，CD 86是一种作为T细胞活化的共刺激分子的分子。通过降低CD 28/CD 80和CD 86信号表达，可以诱导特异性耐受。在已经显示出异常免疫反应性的SLE、类风湿性关节炎和特应性皮炎的动物模型中，他们观察到通过降低CD 28/CD 80和CD 86信号表达来显著抑制异常免疫反应性。4.）在对细胞内信号传导在淋巴细胞活化中的作用的继续研究中，该小组通过开发林恩激酶和HS 1缺陷小鼠，在分子水平上分析了这些分子失调的影响。该小组还确定了酪氨酸磷酸化的HS 1蛋白的结构。5.）这组研究表明，抗原肽中氨基酸的取代改变了对抗原肽的免疫应答。6.）这个小组证明了HIV env蛋白gp 160可以与CaM结合，产生二聚体，由于细胞内Ca 2+的积累而引起细胞凋亡。此外，该小组观察到env蛋白gp 120与CD 4细胞的结合导致FasL产生并诱导CD 4和CD 8细胞的凋亡。少

项目成果

Nishizumi H., et al.: "Impaired proliferation of peripheral B cells and indication of autoimmune disease in lym-deficient mice." Immunity. 3. 549-560 (1995)

Nishizumi H. 等人：“淋巴缺陷小鼠的外周 B 细胞增殖受损以及自身免疫性疾病的迹象。”

Kamoshita,K.: "Calcium requirement and inhibitor spectrum for intracellular HIV type 1 gp160 processing in cultured HeLa cells and CD4^+ lymphocytes: similarity to those of viral envelope glycoprotein maturase." J. Biochem.117. 1244-1253 (1995)

Kamoshita,K.：“培养的 HeLa 细胞和 CD4^ 淋巴细胞中细胞内 HIV 1 型 gp160 处理的钙需求和抑制剂谱：与病毒包膜糖蛋白成熟酶的相似性。”

Hara,H.: "Detection of human T lymphotropic Virus Type (HTLV-I) proviral DNA and analysis of T cell receptor Vβ CDR3 sequenccs in spinal cord lesions of HTLV-I associated myelopathy/Tropical spastic paraparesis." J.Experimental Medicine. 180. 831-839 (199

Hara, H.：“HTLV-I 相关脊髓病/热带痉挛性截瘫脊髓病变中人类 T 淋巴细胞病毒型 (HTLV-I) 前病毒 DNA 的检测和 T 细胞受体 Vβ CDR3 序列的分析。” 180.831-839 (199

Kikuchi Y.: "CD38 ligation induces Btk activation and enhanced expression of IL-5 receptor a chain." Proc.Natl.Acad.Sci.USA. 92. 10879-10883 (1995)

Kikuchi Y.：“CD38 连接诱导 Btk 激活并增强 IL-5 受体 a 链的表达。”

Nishizumi H.: "Impaired proliferation of peripheral B cells and indication of autoimmune disease in lym-deficient mice." Immunity. 3. 549-560 (1995)

Nishizumi H.：“淋巴缺陷小鼠的外周 B 细胞增殖受损以及自身免疫性疾病的迹象。”