Institute of Neuroscience and Brain Diseases, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, 441021, China.
Department of Rheumatology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, 441021, China.
BMC Med. 2024 Oct 31;22(1):502. doi: 10.1186/s12916-024-03729-w.
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.
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.
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.
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.
跨膜 9 超家族成员 1（TM9SF1）参与炎症反应。由于炎症和自身免疫性疾病都与免疫细胞的调节有关，因此本研究探讨了 TM9SF1 表达与自身免疫性疾病活动之间的关系。由于 B 细胞分化和自身抗体产生会加剧自身免疫性疾病，因此探索了涉及这些过程的信号通路。
使用 Tm9sf1 小鼠类风湿关节炎（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。使用来自 156 例 RA 和 145 例 SLE 患者的外周血单核细胞（PBMC）来探讨 TM9SF1 表达与疾病活动之间的关系。使用多变量逻辑回归和接收者操作特征（ROC）曲线评估 TM9SF1 作为疾病活动预测因子的有效性。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中的调控作用。
与野生型（WT）小鼠相比，Tm9sf1 RA 和 SLE 模型小鼠产生的自身抗体较少，疾病严重程度降低。与健康对照组相比，患者 PBMC 中的 TM9SF1 水平较高，与活动期 RA 和 SLE 患者相比，低疾病活动患者的 TM9SF1 水平降低。此外，TM9SF1 水平与两种疾病中的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 在预测疾病活动方面优于几个重要的临床指标（RA 和 SLE 的 AUC 分别为 0.858 和 0.876）。体外实验表明，Tm9sf1 敲除通过激活 mTOR 并抑制自噬来阻断 B 细胞分化为产生抗体的浆细胞，而雷帕霉素等 mTOR 抑制剂可以逆转这种效应。
本研究的主要发现是确定了 B 细胞中自噬调节的分子机制，其中发现 Tm9sf1 敲除调节 mTOR 依赖性自噬以阻断 B 细胞分化为产生抗体的浆细胞。还发现 PBMC 中 TM9SF1 的表达水平是 RA 和 SLE 患者疾病活动的准确指标，表明其在监测这些患者疾病活动方面具有临床潜力。
