Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Front Immunol. 2019 Apr 30;10:835. doi: 10.3389/fimmu.2019.00835. eCollection 2019.
The clinical course of multiple sclerosis ranges from benign with little disease progression and minimal disability, to severe disease requiring intensive medical treatment. There are no reliable circulating biomarkers for predicting disease outcome. Co-inhibitory receptors regulate the termination of effective immune responses to infections while limiting autoimmunity and/or immunopathology. Based on this, we studied the potential of circulating co-inhibitory receptor levels as predictive biomarkers of multiple sclerosis outcome. Co-inhibitory receptor [TIGIT (T cell immunoreceptor with Ig and ITIM domains), TIM-3 (T-cell immunoglobulin and mucin domain-containing 3), LAG-3 (lymphocyte activation gene 3), PD-1 (programmed cell death 1), CTLA-4 (cytotoxic T-lymphocyte-associated protein 4)] expression levels in peripheral blood mononuclear cells (PBMCs) were measured using reverse transcription-PCR in 19 healthy controls and 57 patients with untreated multiple sclerosis. All patients were evaluated for disease outcome and paraclinical measures during the following 9-10 years [progression index, Expanded Disability Status Scale (EDSS) score, number of relapses, number of disease modifying therapies (DMTs), baseline brain magnetic resonance imaging T2 lesion volume, and oligoclonal bands (OCBs)]. Patients had significantly lower TIGIT and LAG-3 levels than the controls ( < 0.02 and < 0.04, respectively). TIM-3 levels were significantly lower in patients with high vs. low disability index and in patients with SPMS diagnosis compared to patients who remained in the relapsing stage of the disease at final visit (both, < 0.02). LAG-3 levels were significantly higher in patients with low disability index vs. non-low disability index multiple sclerosis ( < 0.05). TIM-3 and LAG-3 expression levels correlated significantly with 1-year progression index ( = 0.076, < 0.05; 0.087, < 0.04, respectively) and EDSS score at final visit ( = 0.31, < 0.04; 0.320.088, < 0.04, respectively). Lower LAG-3 levels were associated with higher DMT switching ( = 0.67, < 0.05). Compared to the paraclinical and clinical parameters alone, the combined data of the baseline co-inhibitory receptor expression levels and the paraclinical and clinical parameters were superior for predicting the patients that would progress to secondary progressive multiple sclerosis (SPMS). This is an initial exploration of the utility of CTLA-4, PD-1, TIM-3, LAG-3, and TIGIT expression levels as prognostic indicators in untreated, recently diagnosed multiple sclerosis. Our results support the value of decreased PBMC expression levels of TIM-3 and LAG-3 at diagnosis as an unfavorable prognostic factor, which is to be confirmed in further studies.
多发性硬化症的临床病程从良性（疾病进展和残疾程度较小）到严重（需要强化治疗）不等。目前尚无可靠的循环生物标志物可用于预测疾病结局。共抑制受体调节有效免疫反应的终止，以防止感染，但同时也限制了自身免疫和/或免疫病理学。基于这一点，我们研究了循环共抑制受体水平作为多发性硬化症结局预测生物标志物的潜力。
使用逆转录-PCR 测量了外周血单核细胞（PBMC）中[共抑制受体（T 细胞免疫受体与 Ig 和 ITIM 结构域）、TIM-3（T 细胞免疫球蛋白和粘蛋白结构域 3）、LAG-3（淋巴细胞激活基因 3）、PD-1（程序性细胞死亡 1）、CTLA-4（细胞毒性 T 淋巴细胞相关蛋白 4）]表达水平，纳入了 19 名健康对照者和 57 名未经治疗的多发性硬化症患者。在接下来的 9-10 年内，所有患者均进行疾病结局和临床前评估[进展指数、扩展残疾状态量表（EDSS）评分、复发次数、疾病修正治疗（DMT）次数、基线脑磁共振成像 T2 病变体积和寡克隆带（OCBs）]。
与对照组相比，患者的 TIGIT 和 LAG-3 水平显著降低（<0.02 和<0.04，分别）。TIM-3 水平在高残疾指数患者和 SPMS 诊断患者中显著低于低残疾指数患者，且在最终随访时仍处于疾病复发阶段的患者中（均<0.02）。LAG-3 水平在低残疾指数多发性硬化症患者中显著高于非低残疾指数多发性硬化症患者（<0.05）。TIM-3 和 LAG-3 表达水平与 1 年进展指数（=0.076，<0.05；=0.087，<0.04，分别）和最终随访时的 EDSS 评分（=0.31，<0.04；=0.320.088，<0.04，分别）显著相关。较低的 LAG-3 水平与更高的 DMT 转换相关（=0.67，<0.05）。与临床前和临床参数单独相比，基线共抑制受体表达水平和临床前和临床参数的联合数据更适合预测进展为继发性进展性多发性硬化症（SPMS）的患者。
这是首次探索 CTLA-4、PD-1、TIM-3、LAG-3 和 TIGIT 表达水平作为未经治疗、新近诊断的多发性硬化症患者预后指标的效用。我们的结果支持在诊断时 PBMC 中 TIM-3 和 LAG-3 表达水平降低作为不利预后因素的价值，这需要在进一步研究中得到证实。
