National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China.
Front Immunol. 2021 Dec 21;12:773896. doi: 10.3389/fimmu.2021.773896. eCollection 2021.
Type 1 diabetes (T1D) is an autoimmune disease with a complex aetiology. B cells play an important role in the pathogenesis of T1D. Regulatory B cells (Bregs) are a subset of B cells that produce and secrete the inhibitory factor interleukin-10 (IL-10), thereby exerting an anti-inflammatory effect. It was recently discovered that T-cell immunoglobulin mucin domain 1 (Tim-1) is essential for maintaining Bregs function related to immune tolerance. However, the detailed understanding of Tim-1 Bregs and IL-10 Bregs in T1D patients is lacking. This study aimed to characterize the profile of B cell subsets in T1D patients compared with that in controls and determine whether Tim-1 Bregs and IL-10 Bregs play roles in T1D.
A total of 47 patients with T1D, 30 patients with type 2 diabetes (T2D) and 24 healthy controls were recruited in this study. Flow cytometry was used to measure the levels of different B cell subsets (including B cells, plasmablasts, and Bregs) in the peripheral blood. Radiobinding assays were performed to detect the antibody titres of T1D patients. In addition, the correlations between different B cell subsets and patient parameters were investigated.
Compared with healthy controls, differences in frequency of Tim-1 Bregs were significantly decreased in patients with T1D (36.53 ± 6.51 . 42.25 ± 6.83, =0.02), and frequency of IL-10 Bregs were lower than healthy controls (17.64 ± 7.21. 24.52 ± 11.69, =0.009), the frequency of total Bregs in PBMC was also decreased in patients with T1D (1.42 ± 0.53. 1.99 ± 0.93, =0.002.). We analyzed whether these alterations in B cells subsets were associated with clinical features. The frequencies of Tim-1 Bregs and IL-10 Bregs were negatively related to fasting blood glucose (FBG) (=-0.25 and -0.22; =0.01 and 0.03 respectively). The frequencies of Tim-1 Bregs and IL-10 Bregs are positively correlated with fast C-peptide (FCP) (=0.23 and 0.37; =0.02 and 0.0001, respectively). In addition, the frequency of IL-10 Breg was also negatively related to glycosylated haemoglobin (HbA1c) (=-0.20, =0.04). The frequencies of Tim-1 Bregs, IL-10 Bregs and Bregs in T2D patients were reduced, but no statistically significant difference was found between other groups. Interestingly, there was positive correlation between the frequencies of Tim-1 Bregs and IL-10 Bregs in T1D (=0.37, =0.01). Of note, it is worth noting that our study did not observe any correlations between B cell subsets and autoantibody titres.
Our study showed altered Tim-1 and IL-10 expression in regulatory B cell in T1D patients. Tim-1, as suggested by the present study, is associated with islet function and blood glucose levels. These findings indicate that Tim-1 Bregs and IL-10 Bregs were involved in the pathogenesis of T1D.
1 型糖尿病（T1D）是一种具有复杂病因的自身免疫性疾病。B 细胞在 T1D 的发病机制中起重要作用。调节性 B 细胞（Bregs）是产生和分泌抑制因子白细胞介素-10（IL-10）的 B 细胞亚群，从而发挥抗炎作用。最近发现，T 细胞免疫球蛋白粘蛋白结构域 1（Tim-1）对于维持与免疫耐受相关的 Bregs 功能是必需的。然而，关于 T1D 患者中 Tim-1 Bregs 和 IL-10 Bregs 的详细了解还很缺乏。本研究旨在比较 T1D 患者与对照组之间 B 细胞亚群的特征，并确定 Tim-1 Bregs 和 IL-10 Bregs 是否在 T1D 中发挥作用。
本研究共纳入 47 例 T1D 患者、30 例 2 型糖尿病（T2D）患者和 24 名健康对照者。采用流式细胞术检测外周血中不同 B 细胞亚群（包括 B 细胞、浆母细胞和 Bregs）的水平。放射性配体结合试验检测 T1D 患者的抗体滴度。此外，还研究了不同 B 细胞亚群与患者参数之间的相关性。
与健康对照组相比，T1D 患者 Tim-1 Bregs 的频率明显降低（36.53±6.51 vs. 42.25±6.83，=0.02），IL-10 Bregs 的频率也低于健康对照组（17.64±7.21 vs. 24.52±11.69，=0.009），T1D 患者 PBMC 中的总 Bregs 频率也降低（1.42±0.53 vs. 1.99±0.93，=0.002）。我们分析了这些 B 细胞亚群的改变是否与临床特征有关。Tim-1 Bregs 和 IL-10 Bregs 的频率与空腹血糖（FBG）呈负相关（=-0.25 和-0.22；=0.01 和 0.03）。Tim-1 Bregs 和 IL-10 Bregs 的频率与快速 C 肽（FCP）呈正相关（=0.23 和 0.37；=0.02 和 0.0001）。此外，IL-10 Breg 的频率也与糖化血红蛋白（HbA1c）呈负相关（=-0.20，=0.04）。T2D 患者的 Tim-1 Bregs、IL-10 Bregs 和 Bregs 频率降低，但与其他组之间无统计学差异。有趣的是，在 T1D 患者中，Tim-1 Bregs 和 IL-10 Bregs 的频率呈正相关（=0.37，=0.01）。值得注意的是，本研究未观察到 B 细胞亚群与自身抗体滴度之间的任何相关性。
本研究显示 T1D 患者中 Tim-1 和 IL-10 表达的调节性 B 细胞发生改变。Tim-1 与胰岛功能和血糖水平有关，这表明 Tim-1 Bregs 和 IL-10 Bregs 参与了 T1D 的发病机制。
