TM9SF1 expression correlates with autoimmune disease activity and regulates antibody production through mTOR-dependent autophagy.

IF 7 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL
Juan Xiao, Zhenwang Zhao, Fengqiao Zhou, Jinsong Xiong, Zean Yang, Baoxian Gong, Lei Xiang, Mingming Liu, Fengsheng Cao, Hong Xiao, Huabo Chen, Anbing Zhang, Ke Wang
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引用次数: 0

Abstract

Background: Transmembrane 9 superfamily member 1 (TM9SF1) is involved in inflammation. Since both inflammatory and autoimmune diseases are linked to immune cells regulation, this study investigated the association between TM9SF1 expression and autoimmune disease activity. As B cell differentiation and autoantibody production exacerbate autoimmune disease, the signaling pathways involved in these processes were explored.

Methods: Tm9sf1-/- mouse rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) models were used to verify the relationship between gene expression and disease severity. Peripheral blood mononuclear cells (PBMCs) from 156 RA and 145 SLE patients were used to explore the relationship between TM9SF1 expression and disease activity. The effectiveness of TM9SF1 as a predictor of disease activity was assessed using multiple logistic regression and receiver operating characteristic (ROC) curves. The signaling pathways regulated by TM9SF1 in B cell maturation and antibody production were conducted by plasma cell induction experiment in vitro.

Results: The Tm9sf1-/- RA and SLE model mice produced fewer autoantibodies and showed reduced disease severity relative to wild-type (WT) mice. TM9SF1 levels in PBMCs of patients were higher than those in healthy controls, and were reduced in patients with low disease activity relative to those with active RA and SLE. Furthermore, TM9SF1 levels were positively linked with autoantibody titers and pro-inflammatory cytokine levels in both diseases. ROC analyses indicated TM9SF1 outperformed several important clinical indicators in predicting disease activity (area under the curve (AUC) were 0.858 and 0.876 for RA and SLE, respectively). In vitro experiments demonstrated that Tm9sf1 knockout blocked differentiation of B cells into antibody-producing plasma cells by activating mTOR and inhibiting autophagy, and mTOR inhibitors such as rapamycin could reverse this effect.

Conclusions: The primary finding was the identification of the molecular mechanism underlying autophagy regulation in B cells, in which Tm9sf1 knockout was found to modulate mTOR-dependent autophagy to block B cell differentiation into antibody-secreting plasma cells. It was also found that TM9SF1 expression level in PBMCs was an accurate indicator of disease activity in patients with RA and SLE, suggesting its clinical potential for monitoring disease activity in these patients.

TM9SF1 的表达与自身免疫性疾病的活动相关,并通过 mTOR 依赖性自噬调节抗体的产生。
背景:跨膜 9 超家族成员 1(TM9SF1)与炎症有关。由于炎症性疾病和自身免疫性疾病都与免疫细胞的调节有关,本研究调查了 TM9SF1 表达与自身免疫性疾病活动之间的关联。由于B细胞分化和自身抗体的产生会加剧自身免疫性疾病,本研究探讨了参与这些过程的信号通路:方法:使用 Tm9sf1-/- 小鼠类风湿性关节炎(RA)和系统性红斑狼疮(SLE)模型来验证基因表达与疾病严重程度之间的关系。研究人员利用 156 名 RA 患者和 145 名系统性红斑狼疮患者的外周血单核细胞(PBMCs)来探讨 TM9SF1 表达与疾病活动性之间的关系。采用多元逻辑回归和接收者操作特征曲线(ROC)评估了 TM9SF1 作为疾病活动性预测因子的有效性。通过体外浆细胞诱导实验研究了TM9SF1在B细胞成熟和抗体产生过程中调控的信号通路:结果:与野生型(WT)小鼠相比,Tm9sf1-/- RA和系统性红斑狼疮模型小鼠产生的自身抗体更少,疾病严重程度也更低。与健康对照组相比,患者白细胞介体中的 TM9SF1 水平较高,与活动性 RA 和系统性红斑狼疮患者相比,疾病活动性低的患者白细胞介体中的 TM9SF1 水平较低。此外,在这两种疾病中,TM9SF1 水平与自身抗体滴度和促炎细胞因子水平呈正相关。ROC分析表明,TM9SF1在预测疾病活动性方面优于几种重要的临床指标(RA和SLE的曲线下面积(AUC)分别为0.858和0.876)。体外实验表明,Tm9sf1基因敲除可通过激活mTOR和抑制自噬阻止B细胞分化为产生抗体的浆细胞,而雷帕霉素等mTOR抑制剂可逆转这种效应:主要发现是确定了 B 细胞自噬调控的分子机制,其中发现 Tm9sf1 基因敲除可调节 mTOR 依赖性自噬,从而阻止 B 细胞分化为分泌抗体的浆细胞。研究还发现,TM9SF1在PBMCs中的表达水平是衡量RA和系统性红斑狼疮患者疾病活动性的准确指标,这表明TM9SF1具有监测这些患者疾病活动性的临床潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMC Medicine
BMC Medicine 医学-医学:内科
CiteScore
13.10
自引率
1.10%
发文量
435
审稿时长
4-8 weeks
期刊介绍: BMC Medicine is an open access, transparent peer-reviewed general medical journal. It is the flagship journal of the BMC series and publishes outstanding and influential research in various areas including clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. In addition to research articles, the journal also publishes stimulating debates, reviews, unique forum articles, and concise tutorials. All articles published in BMC Medicine are included in various databases such as Biological Abstracts, BIOSIS, CAS, Citebase, Current contents, DOAJ, Embase, MEDLINE, PubMed, Science Citation Index Expanded, OAIster, SCImago, Scopus, SOCOLAR, and Zetoc.
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