树突状细胞免疫受体是治疗哮喘的新靶点  

Dendritic cells immunal receptor as a promising target in asthma therapy

作　　者：马光宇[1] 吴雅琼[2] 高玉环[1] 

机构地区：[1]河北医科大学第四医院东院区血液内科,石家庄050035 [2]河北医科大学第四医院心血管内科,石家庄050011

出　　处：《免疫学杂志》2014年第4期282-287,共6页Immunological Journal

基　　金：河北省医学科学研究重点课题计划(20120125;20120128)

摘　　要：目的探讨树突状细胞(dendritic cells,DCs)表面表达的Ⅱ型膜蛋白——树突状细胞免疫受体(dendritic cells immunal receptor,Dcir)在哮喘中的作用。方法使用卵清蛋白(OV-albumin,OVA)同时诱导Dcir-/-小鼠和野生型小鼠发生哮喘,通过对比2种小鼠模型气管中嗜酸性粒细胞的浸润、血清中抗体的产生、肺的病理表现和淋巴结细胞中Th2细胞因子的释放,来阐明Dcir在哮喘中的作用。为了证明Dcir在哮喘中的作用是通过DC细胞介导的免疫应答而非直接影响T细胞免疫实现的,我们使用含有OVA特异性T细胞受体的转基因小鼠DO11.10与DO11.10×Dcir-/-小鼠进行对比;并通过体外实验验证了Dcir缺失对na觙ve T细胞产生Th2细胞因子以及conventional DC(cDC)和plasmacytoid DC(pDC)增殖速度的影响。结果在OVA诱导的小鼠哮喘模型中,Dcir-/-小鼠气管内嗜酸性粒细胞的浸润较野生型小鼠亢进;Dcir-/-小鼠血清中抗体的产生较野生型小鼠增加;肺部的病理结果显示,相对于野生型小鼠,Dcir-/-小鼠的肺部有更多的浸润细胞、黏液分泌和更为严重的气管纤维化;Dcir-/-小鼠淋巴结细胞释放的Th2细胞因子较野生型小鼠升高。在诱导DO11.10和DO11.10×Dcir-/-小鼠的哮喘模型时,两者的各项指标之间没有明显差异,说明Dcir参与的哮喘恶性化是通过DC细胞介导的免疫应答实现的。在DC细胞与抗原和na觙ve T细胞共同培养的过程中,Dcir-/-小鼠来源的DC细胞诱导了更多的Th2细胞产生。在将骨髓细胞(BMC)诱导为cDC和pDC的体外实验中,Dcir-/-小鼠对GM-CSF的信号和Flt-3 ligand的信号感受性均增强,从而诱导出了比野生型小鼠更多的cDC和pDC。结论 Dcir-/-小鼠增加了OVA诱导的哮喘模型的恶性度。Dcir-/-小鼠对哮喘模型恶性度的增加是由过度增殖的DC细胞介导的免疫应答而并非直接影响T细胞的感受性。在哮喘模型中Dcir通过抑制树突状细胞对GM-CSF和对Flt-3 ligand的信号�Dendritic cell immunoreceptor （Dcir） is a type II transmembrane protein which mainly expressed on dendritic cells surface. To investigate functions of Dcir in asthma, we induced mouse asthma model in Dcir-/- mice and wild-type mice with ovalbumin （OVA）, and compared them in this study. We found that in the OVA-induced asthma model, eosinophils infiltration in Dcir-/- mice was more severe than that in wild-type mice; serum antibodies production in Deir-/- mice was elevated compared with wild-type mice; Th2 cytokine secretion of lymph node cells from Dcir-/- mice were higher than that from wild type mice. Furthermore, lung pathology results showed that, compared to wild-type mice, more lung invasion cells, more mucus secretion and more severe airway fibrosis were found in Dcir-/- mice, therefore, Dcir-/- mice increased malignancy of the OVA-induced asthma model. To confirm the increased malignancy was due to DCs over proliferation by lacking Dcir, OVA transgenic mice （DO11.10.）, which containing OVA specific T cell receptor （TCR）, were introduced, and normal DOll.10 mice and DO11.10x Dcir-/- mice were induced into asthma model. The results showed that there were no significantly differences between the two kinds mice, indicating that Dcir deficiency increased malignancy degree of asthma is due to excessive DCs proliferation but not directly affect T cell susceptibility. Moreover, with in vitro experiments, we confirmed that both conventional DC （cDC） and plasmacytoid DC （pDC） proliferation were enhanced in Dcir^- mice compared with wild-type mice, which indicated that Dcir played an inhibiting role not only in GM-CSF signaling pathway but also in Fh-3 ligand signaling pathway. In summary, Dcir plays an important role in asthma due to controlling DCs proliferation by inhibiting GM-CSF and Fh-3 ligand signaling pathways. Therefore, Dcir ligands may be useful as a treatment method for asthma in the future.

关 键 词：树突状细胞免疫受体 哮喘 基因敲除小鼠 OVA诱导的哮喘模型 

分 类 号：R562.25[医药卫生—呼吸系统]