Table_1_Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis.docx

Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.

多发性硬化（multiple sclerosis, MS）患者随年龄增长会出现早期免疫衰老过程，该过程可影响治疗应答并增加感染风险。本研究探讨了与高炎症性MS相关的脂质特异性寡克隆IgM条带（lipid-specific oligoclonal IgM bands, LS-OCMB）是否会改变MS患者因年龄诱导的免疫谱特征。本横断面研究共纳入263例MS患者，根据LS-OCMB的存在情况分为两组：LS-OCMB阳性组（M+, n=72）与LS-OCMB阴性组（M-, n=191）。研究对脑脊液（cerebrospinal fluid, CSF）细胞亚群及与免疫衰老相关的分子进行了检测分析。

在M-患者中，衰老可显著降低脑脊液中CD4+和CD8+ T淋巴细胞（包括Th1细胞与Th17细胞）以及分泌肿瘤坏死因子-α（tumor necrosis factor-α, TNF-α）的B细胞的绝对计数；同时升高血清抗巨细胞病毒IgG抗体滴度（免疫衰老的标志性指标）及脑脊液几丁质酶3样蛋白1（chitinase 3-like 1, CHI3L1）水平（与星形胶质细胞活化密切相关）。与之相反，M+患者的T细胞耗竭生物标志物T细胞免疫球蛋白黏蛋白分子3（TIM-3, T-cell immunoglobulin and mucin-domain containing-3）随年龄升高，且CHI3L1水平也有所上升，该变化与年龄无关。

最后，两组患者的脑脊液中程序性死亡受体配体1（PD-L1, programmed death-ligand 1，T细胞耐受的诱导因子）及激活素A（activin A，属于衰老相关分泌组且与炎症衰老相关）的水平均随年龄升高，且上述变化与疾病病程无关，最终导致残疾程度加重。

综上，所有MS患者随年龄增长均会出现轻度的T细胞耐受诱导及先天免疫激活，进而导致残疾程度升高。此外，M-患者的脑脊液淋巴细胞数量显著降低，这可能会增加感染风险。由此可见，年龄与免疫状态对于制定MS的个体化有效治疗方案至关重要。