系统性红斑狼疮患者接受贝利尤单抗治疗后 T 细胞分析的高维分析。

High-dimensional analysis of T-cell profiling variations following belimumab treatment in systemic lupus erythematosus.

机构信息

Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan

Clinical Research Management Center, Nagoya City University Hospital, Nagoya, Japan.

出版信息

Lupus Sci Med. 2023 Oct;10(2). doi: 10.1136/lupus-2023-000976.

DOI:10.1136/lupus-2023-000976

PMID:37802602

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10565340/

Abstract

OBJECTIVE

This study sought to elucidate the molecular impacts of belimumab (BEL) treatment on T-cell immune profiling in SLE.

METHODS

We used mass cytometry with 25 marker panels for T-cell immune profiling in peripheral blood T cells (CD3+) from 22 patients with BEL-treated SLE and 20 controls with non-BEL-treated SLE. An unsupervised machine-learning clustering, FlowSOM, was used to identify 39 T-cell clusters (TCLs; TCL01-TCL39). TCLs (% of CD3+) showing significant (p<0.05) associations with BEL treatment (BEL-TCL) were selected by a linear mixed-effects model for comparing groups of time-series data. Furthermore, we analysed the association between BEL treatment and variations in regulatory T-cell (Treg) phenotypes, and the ratio of other T-cell subsets to Treg as secondary analysis.

RESULTS

Clinical outcomes: BEL treatment was associated with a decrease in daily prednisolone use (coef=-0.1769, p=0.00074), and an increase in serum CH50 (coef=0.4653, p=0.003), C3 (coef=1.1047, p=0.00001) and C4 (coef=0.2990, p=0.00157) levels. Molecular effects: five distinct BEL-TCLs (TCL 04, 07, 11, 12 and 27) were identified. Among these, BEL-treated patients exhibited increased proportions in the Treg-like cluster TCL11 (coef=0.404, p=0.037) and two naïve TCLs (TCL04 and TCL07). TCL27 showed increased levels (coef=0.222, p=0.037) inversely correlating with baseline C3 levels. Secondary analyses revealed associations between BEL treatment and an increase in Tregs (coef=1.749, p=0.0044), elevated proportions of the fraction of Tregs with inhibitory function (fTregs, coef=0.7294, p=0.0178) and changes in peripheral helper T cells/fTreg (coef=-4.475, p=0.0319) and T helper 17/fTreg ratios (coef=-6.7868, p=0.0327). Additionally, BEL was linked to variations in T-cell immunoglobulin and mucin domain-containing protein-3 expression (coef=0.2422, p=0.039).

CONCLUSIONS

The study suggests an association between BEL treatment and variations in T cells, particularly Tregs, in SLE pathologies involving various immune cells.

摘要

目的

本研究旨在阐明贝利单抗（BEL）治疗对系统性红斑狼疮（SLE）患者 T 细胞免疫谱的分子影响。

方法

我们使用质谱流式细胞术，对 22 名接受 BEL 治疗的 SLE 患者和 20 名未接受 BEL 治疗的 SLE 患者的外周血 T 细胞（CD3+）进行 25 个标记面板的 T 细胞免疫谱分析。采用无监督机器学习聚类方法 FlowSOM 鉴定 39 个 T 细胞簇（TCL；TCL01-TCL39）。通过线性混合效应模型选择与 BEL 治疗呈显著（p<0.05）关联的 TCL（TCL% of CD3+），用于比较时间序列数据组。此外，我们分析了 BEL 治疗与调节性 T 细胞（Treg）表型变化以及其他 T 细胞亚群与 Treg 比值之间的关联，作为次要分析。

结果

临床结果：BEL 治疗与每日泼尼松使用量减少（系数=-0.1769，p=0.00074）以及血清 CH50（系数=0.4653，p=0.003）、C3（系数=1.1047，p=0.00001）和 C4（系数=0.2990，p=0.00157）水平升高相关。分子效应：鉴定出五个独特的 BEL-TCL（TCL04、07、11、12 和 27）。其中，接受 BEL 治疗的患者 Treg 样簇 TCL11（系数=0.404，p=0.037）和两个幼稚 TCL（TCL04 和 TCL07）的比例增加。TCL27 水平升高（系数=0.222，p=0.037），与基线 C3 水平呈负相关。次要分析显示，BEL 治疗与 Tregs 增加（系数=1.749，p=0.0044）、具有抑制功能的 Tregs 分数（fTregs，系数=0.7294，p=0.0178）和外周辅助性 T 细胞/fTreg（系数=-4.475，p=0.0319）和 T 辅助 17/fTreg 比值（系数=-6.7868，p=0.0327）的变化相关。此外，BEL 与 T 细胞免疫球蛋白和粘蛋白结构域蛋白 3 表达的变化相关（系数=0.2422，p=0.039）。