IMMUNE REGULATION BY IMMUNOGLOBULIN-LIKE RECEPTORS

免疫球蛋白样受体的免疫调节

• 批准号: 14207014
• 负责人: TAKAI Toshiyuki
• 金额: $ 19.05万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207014/
• 关键词: Ig-like receptor; PIR; allergy; autoimmunity; transplantation; GVHD; immunoregulation; PIR-B; Th2 response; dendritic cell; MHC class I; IgLR; Allergy; gene targeting

PIRs expressed on B and myeloid cells form a unique 'self' recognition. Activating PIR-A and inhibitory PIR-B were shown to bind various murine MHC class I (H-2) molecules. In vitro H-2 tetramer stimulation of PIRs induced intracellular phosphotyrosine signaling. PIR-B-deficient mice transferred with allogeneic splenocytes showed exacerbated graft-versus-host disease, which was due to the augmented activation of the recipient's dendritic cells (DCs) with the concomitant up-regulation of PIR-A and increased IFN-production. PIR-A-induced DC activation also led to increased proliferation of donor cytotoxic T cells. Thus, PIR-A and PIR-B are counter-acting receptors that play key roles for successful tissue transplantation, and may regulate irrelevant reaction to autologous tissues in a constitutive fashion under physiological circumstances.To analyze the etiology of mild osteopetrosis in DAP12 (DNAX protein 12)-deficient mice, we examined the bone morphology in FcRγ-deficient (FcRγ--) mice and DAP12/FcRγ double deficient (DKO) mice. Histological examination revealed that FcRγ--mice did not show any remarkable osteopetrosis. However, we found that DKO mice exhibited much more severe osteopetrosis than DAP12--mice, suggesting that either DAP12 or FcRγ is required for normal bone remodeling. In osteoclast precursor cells, FcRγ and DAP12 associate with multiple IgLRs including OSCAR and PIR-A ; and TREM-2 and SIRPβ1, respectively, and activate Ca^2 signal through PLCγ. Thus, ITAM-dependent costimulatory signals activated by multiple IgLRs are indispensable for the maintenance of bone homeostasis, indicating that RANK and M-CSF receptor are not sufficient to activate signals required for osteoclastogenesis.

表达在B细胞和髓系细胞上的PIRS形成一种独特的“自我”识别。激活的PIR-A和抑制的PIR-B与多种小鼠MHC I类(H-2)分子结合。体外H-2四聚体刺激PIRS可诱导细胞内磷酸酪氨酸信号转导。移植异基因脾细胞的PIR-B缺陷小鼠表现出移植物抗宿主疾病的加重，这是由于受体的树突状细胞(DC)的增强激活，伴随着PIR-A的上调和干扰素的产生。Pir-A诱导的DC活化也导致供体细胞毒性T细胞的增殖增加。因此，PIR-A和PIR-B是在成功的组织移植中起关键作用的反向作用受体，在生理条件下可能以一种结构性的方式调节与自体组织无关的反应。为了分析DNAX蛋白12(DNAX Protein 12)缺陷小鼠轻度骨化症的病因，我们观察了FcRγ缺陷(Fcrγ-)和DAP12/Fcrγ双缺陷(DKO)小鼠的骨形态。组织学检查显示FCRγ--小鼠未出现明显的骨化病。然而，我们发现DKO小鼠表现出比DAP12-小鼠更严重的骨石化，这表明DAP12或FcRγ是正常骨重建所必需的。在破骨细胞前体细胞中，FcRγ和DAP12分别与OSCAR、PIR-A、TREM-2和Sirpβ1等多种Ig受体结合，并通过PLCγ激活Ca^2信号。因此，由多个IgLR激活的ITAM依赖的共刺激信号对于维持骨内环境的稳定是必不可少的，这表明RANK和M-CSF受体不足以激活破骨细胞形成所需的信号。

项目成果

Yamaguchi A et al.: "Possible role of autoantibody in the pathophysiology of GM2 angliosidoses"J.Clin.Invest.. 113(2). 200-208 (2004)

Yamaguchi A 等人：“自身抗体在 GM2 血管瘤的病理生理学中的可能作用”J.Clin.Invest.. 113(2)。

Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.

• DOI: 10.1172/jci16923
• 发表时间: 2003-02
• 期刊: The Journal of clinical investigation
• 作者: T. Kaifu;J. Nakahara;M. Inui;K. Mishima;T. Momiyama;Mitsuji Kaji;Akiko Sugahara;H. Koito;Azusa Ujik

The pre-B cell receptor signaling for apoptosis is negatively regulated by FcgRIIB.

凋亡相关的前 B 细胞受体信号传导受到 FcgRIIB 的负向调节。

• 发表时间: 2002
• 期刊: J.Immunol. 168
• 作者: Kato I;Takai T;Kudo A.
• 通讯作者: Kudo A.

Akiyama K, et al.: "Targeting of apoptotic tumor cells to Fcγ receptors provides efficient and versatile vaccination against tumors by dendritic cells"J. Immunol. 170(4). 1641-1648 (2003)

Akiyama K 等人：“将凋亡的肿瘤细胞靶向 Fcγ 受体提供了树突状细胞针对肿瘤的有效且多功能的疫苗接种”J.Immunol.170(4)。

Roles of FcγRIIB in nasal eosinophilia and IgE production in murine allergic rhinitis

• 发表时间: 2004
• 期刊: Respiratory Research
• 影响因子: 5.8
• 作者: 渡邉 徹