High frequency of circulating non-classical monocytes is associated with stable remission in relapsing-remitting multiple sclerosis

‘No evidence of disease activity (NEDA)’, judged by clinical and radiological findings, is a therapeutic goal in patients with multiple sclerosis (MS). It is, however, unclear if distinct biological mechanisms contribute to the maintenance of NEDA. To clarify the immunological background of long-term disease stability defined by NEDA, circulating immune cell subsets in patients with relapsing-remitting MS (RRMS) were analyzed using flow cytometry. Patients showing long-term NEDA (n = 31) had significantly higher frequencies of non-classical monocytes (NCMs) (6.1% vs 1.4%) and activated regulatory T cells (Tregs; 2.1% vs 1.6%) than those with evidence of disease activity (n = 8). The NCM frequency and NCMs to classical monocytes ratio (NCM/CM) positively correlated with activated Treg frequency and duration of NEDA. Co-culture assays demonstrated that NCMs could increase the frequency of activated Tregs and the expression of PD-L1, contributing to development of Tregs, was particularly high in NCMs from patients with NEDA. Collectively, NCMs contribute to stable remission in patients with RRMS, possibly by increasing activated Treg frequency. In addition, the NCM frequency and NCM/CM ratio had high predictive values for disease stability (AUC = 0.97 and 0.94, respectively), suggesting these markers are potential predictors of a long-term NEDA status in RRMS.以临床与影像学结果判定的无疾病活动证据（No evidence of disease activity, NEDA）是多发性硬化（multiple sclerosis, MS）患者的治疗目标。然而目前尚不明确是否存在独特的生物学机制参与维持无疾病活动状态。为阐明以无疾病活动证据定义的长期疾病稳定的免疫学背景，研究人员采用流式细胞术（flow cytometry）对复发缓解型多发性硬化（relapsing-remitting multiple sclerosis, RRMS）患者的循环免疫细胞亚群进行了分析。与存在疾病活动证据的患者（n=8）相比，长期维持无疾病活动状态的患者（n=31）的非经典单核细胞（non-classical monocytes, NCMs）占比（6.1% vs 1.4%）与活化调节性T细胞（activated regulatory T cells, Tregs）占比（2.1% vs 1.6%）均显著更高。非经典单核细胞占比及其与经典单核细胞的比值（NCM/CM）与活化调节性T细胞占比及无疾病活动状态持续时长呈正相关。共培养实验证实，非经典单核细胞可升高活化调节性T细胞的占比；且来自无疾病活动状态患者的非经典单核细胞的程序性死亡受体配体1（Programmed death-ligand 1, PD-L1）表达水平显著更高，该分子可促进调节性T细胞的发育。综上，非经典单核细胞可能通过提升活化调节性T细胞占比，参与促进复发缓解型多发性硬化患者的稳定缓解。此外，非经典单核细胞占比及其与经典单核细胞的比值对疾病稳定具有较高的预测价值（曲线下面积（Area Under the Curve, AUC）分别为0.97与0.94），提示上述指标可作为复发缓解型多发性硬化患者长期维持无疾病活动状态的潜在预测标志物。