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Ligation of cd180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

Cellular & Molecular Immunology 2017年第2期14卷 192-202页

作者： Ming You Guanjun Dong Fanlin Li Feiya Ma Jing Ren Yujun Xu Huimin Yue Ruijing Tang Deshan Ren Yayi Hou The State Key Laboratory of Pharmaceutical Biotechnology Division of Immunology Medical School Nanjing University Nanjing 210093 People's Republic of China Jiangsu Key Laboratory of Molecular Medicine Medical School Nanjing University Nanjing 210093 People's Republic of China oth Ming You and Guanjun Dong contributed equally to this work

A hallmark of systemic lupus erythematosus （SLE） is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-α（IFN-α） signaling is highly activated in SLE B cells and plays a vital role in the antibody response by B cells. Previous studies have shown that cd180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies. However, the association between cd180 and IFN-αsignaling remains unknown. In the present study, we explored the effect of cd180 on regulating the activation of IFN-α signaling in B cells. We found that the number of cd180-negative B cells was increased in MRIJMp-Fas（Ipr/Ipr） lupus-prone mice compared with wild-type mice. Phenotypic analysis showed that cd180-negative B cells comprised cd138＋ plasmablast/plasma cells and GL-7＋ germinal center （GC） B cells. Notably, ligation of cd180 significantly inhibited the I FN-α-induced phosphorylation of signal transducer and activator of transcription 2 （STAT-2） and expression of IFN-stimulated genes （ISGs） in a Lyn-PI3K-BTK-dependent manner in vitro. Moreover, ligation of cd180 could also inhibit IFN-α-induced ISG expression in B cells in vivo. Furthermore, the Toll-like receptor 7 and Toll-like receptor 9 signaling pathways could significantly downregulate cd180 expression and modulate the inhibitory effect of cd180 signaling on the activation of I FN-a signaling. Collectively, our results highlight the close association between the increased proportion of cd180-negative B cells and the activation of IFN-α signaling in SLE. Our data provide molecular insight into the mechanism of IFN-α signaling activation in SLE B cells and a potential therapeutic approach for SLE treatment.

关键词： B cells cd180 IFN-α SLE

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cd180在SLE B细胞的异常表达及其抑制IFN-α通路的机制研究

Cd180在SLE B细胞的异常表达及其抑制IFN-α通路的机制研究

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作者：尤明南京大学

学位级别：硕士

系统性红斑狼疮(Systemic lupus erythematosus, SLE)是一种慢性的、累及多器官多系统的自身免疫性疾病,其主要特征是患者血清中存在大量的IFN-α和自身抗体。B细胞作为抗体产生细胞,其异常活化在SLE的发病过程中发挥关键作用,然而其异... 详细信息

系统性红斑狼疮(Systemic lupus erythematosus, SLE)是一种慢性的、累及多器官多系统的自身免疫性疾病,其主要特征是患者血清中存在大量的IFN-α和自身抗体。B细胞作为抗体产生细胞,其异常活化在SLE的发病过程中发挥关键作用,然而其异常活化的分子机制仍不完全清楚。许多研究报道,SLE的B细胞中IFN-α通路是高度活化的,且IFN-α可通过直接或间接的方式参与B细胞的生存与功能,进而参与SLE的病程发展;在SLE患者体内,cd180-B细胞数量明显增加,并且参与自身抗体的产生,提示cd180可能参与SLE中B细胞的异常活化。那么,cd180的表达变化是否影响IFN-α通路活化?导致cd180表达变化的原因又是什么?因此,本研究针对上述问题,分析了cd180在SLE来源B细胞的表达变化,鉴定了cd180-B细胞的表型,探讨了cd180调控IFN-α通路影响B细胞的分子机制。1.发现SLE来源B细胞低表达cd180,且cd180-B细胞可能由生发中心B细胞和浆细胞组成;我们首先各取5例正常人与SLE患者外周血进行流式分析,验证SLE患者外周血cd180-B细胞异常增多;从分选出B细胞后检测cd180 mRNA水平,发现cd180表达水平在SLE患者中是显著降低的。表明cd180-B细胞的增多可能是由于某些原因导致的B细胞cd180表达降低有关。接下来我们在狼疮模型小鼠中进行了验证,发现在狼疮小鼠脾脏、外周血和骨髓中,cd180-B细胞数量都是明显增加,且分选出的脾脏B细胞的cd180表达降低。我们进一步研究了cd180-B细胞的表型,发现cd180-B细胞可能由生发中心B细胞和浆细胞组成。2.发现激活cd180能够显著抑制B细胞的IFN-α通路活化,提示anti-cd180可能是治疗SLE的潜在策略：我们探讨了cd180与IFN-α通路的关系及影响其表达变化的原因,发现激活cd180在体外和体内均能显著抑制B细胞IFN-α通路的活化并降低IFN-α下游基因的表达。其具体机制是cd180通过lyn-PI3K-BTK这一级联通路引起IFN-α下游STAT-2磷酸化水平下降,进而影响IFN-α通路的活化。进一步发现,用TLR7配体R848和TLR9配体CpG刺激小鼠脾脏B细胞能显著抑制cd180的表达,并调节cd180对IFN-α通路的抑制作用。综上所述,我们证实了MRL/lpr小鼠中cd180-B细胞显著增多;发现激活cd180能够显著抑制IFN-α通路的活化;还发现SLE来源B细胞cd180的表达变化可能归因于TLR7和TLR9通路活化。由于靶向IFN-α治疗SLE具有很大的前景,我们的发现提示,anti-cd 180可能是治疗SLE的潜在策略。

关键词：系统性红斑狼疮 B细胞 IFN-α cd180

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Identification of a three-gene prognostic signature for radioresistant esophageal squamous cell carcinoma

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World Journal of Clinical Oncology 2023年第1期14卷 13-26页

作者： Xiao-Yan Wang Narasimha M Beeraka Nan-Nan Xue Hui-Ming Yu Ya Yang Mao-Xing Liu Vladimir N Nikolenko Jun-Qi Liu Di Zhao Department of Endocrinology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052Henan ProvinceChina Department of Radiation Oncology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052Henan ProvinceChina Department of Human Anatomy I.M.Sechenov First Moscow State Medical UniversityMoscow 119991Russia Department of Pharmaceutical Chemistry JSS College of PharmacyMysuru 570015India Department of Radiation Oncology Peking University Cancer Hospital&InstituteBeijing 065005China Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education) Department of Gastrointestinal Surgery ⅣPeking University Cancer Hospital&InstituteBeijingChina M.V.Lomonosov Moscow State University Moscow 119991Russia

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is causing a high mortality rate due to the lack of efficient early prognosis markers and suitable therapeutic regimens.The prognostic role of genes responsible for the acquisition of radioresistance in ESCC has not been fully elucidated.AIM To establish a prognostic model by studying gene expression patterns pertinent to radioresistance in ESCC patients.METHODS Datasets were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases.The edgeR,a Bioconductor package,was used to analyze mRNA expression between different groups.We screened genes specifically responsible for radioresistance to estimate overall survival.Pearson correlation analysis was performed to confirm whether the expression of those genes correlated with each other.Genes contributing to radioresistance and overall survival were assessed by the multivariate Cox regression model through the calculation ofβi and risk score using the following formula:∑^(n)_(i=1)βi×PSI.RESULTS We identified three prognostic mRNAs(cathepsin S[CTSS],cluster of differentiation 180[cd180],and SLP adapter and CSK-interacting membrane protein[SCIMP])indicative of radioresistance.The expression of the three identified mRNAs was related to each other(r>0.70 and Pcd180,and SCIMO for ESCC,which may facilitate the prediction of early prognosis of this malignancy.

关键词： Esophageal squamous cell carcinoma CTSS cd180 SCIMP Radioresistance TNM stage Prognosis

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Roles of plasmablasts in IgG4-related disease and various immune-based diseases

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World Journal of Rheumatology 2016年第1期6卷 16-22页

作者： Syuichi Koarada Yoshifumi Tada Department of Rheumatology Faculty of MedicineSaga University

IgG4-related disease(IgG4-RD) is a systemic fibroinflammatory disease with multiple organ disorders.Recently,in IgG4-RD,increased circulating plasmablasts have been found.The subsets of plasmablasts are negative for RP105(cd180).A large population of B cells lacking RP105(RP105-negative B cells) are found inpatients with active with systemic lupus erythematosus and other systemic autoimmune diseases,including dermatomyositis,and Sj?gren's syndrome.In other conditions,such as neuromyelitis optica,Kawasaki's disease,primary biliary cirrhosis and aging,RP105 expression on B cells and monocytes also alters.We review the basic science and clinical significance of RP105-negative B cells including plasmablasts in various immune-based diseases.RP105-negative B cells,especially plasmablasts,play crucial roles in both systemic and organ-specific autoimmune and inflammatory disorders.

关键词： Plasmablast cd180 IgG4-related disease Autoimmune disease

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