Trabattoni Daria, Saresella Marina, Pacei Michela, Marventano Ivana, Mendozzi Laura, Rovaris Marco, Caputo Domenico, Borelli Manuela, Clerici Mario
Department of Immunology, University of Milano, Milan, Italy.
J Immunol. 2009 Oct 15;183(8):4984-93. doi: 10.4049/jimmunol.0901038. Epub 2009 Sep 30.
T lymphocytes costimulatory molecules, including CD80, CD86, CD28, CTLA4, PD-1, PD-L1, and B7-H3, are associated with the preferential production of pro- or anti-inflammatory cytokines. We analyzed the expression of these molecules and myelin basic protein (MBP)-specific IL-10 and IFN-gamma production in patients with multiple sclerosis (MS) with relapsing-remitting acute (AMS, n = 40) or stable (SMS, n = 38). Twenty-two patients successfully undergoing therapy with glatimer acetate (n = 12) or IFNbeta (n = 10) were also analyzed. MBP-specific and PD-1-expressing T lymphocytes, PD-L1-expressing CD19(+) cells, and PD-L1(+)/IL-10(+)/CD14(+) and CD19(+) cells were significantly augmented in SMS patients. Additionally, MBP-specific and annexin V-expressing CD4(+) and CD8(+) (apoptotic) T lymphocytes were augmented and pAkt-positive (proliferating) cells were decreased in SMS compared with AMS patients. PD-1 ligation resulted in the increase of pAkt(+) lymphocytes in AMS patients alone. B7-H3 expression and IFN-gamma production were comparable in all individuals but the PD-L1(+)/IL-10(+) over B7-H3(+)/IFN-gamma(+) ratio was significantly lower in AMS compared with SMS patients. Finally, PD-L1 expression on immune cells was reduced in treated patients, suggesting that therapy-induced disease remission is not associated with the modulation of the expression of this molecule. The PD-1/PD-L1 pathway plays an important role in modulating immune functions in MS patients; monitoring and targeting these proteins could offer diagnostic and therapeutic advantages.
T淋巴细胞共刺激分子，包括CD80、CD86、CD28、CTLA4、PD-1、PD-L1和B7-H3，与促炎或抗炎细胞因子的优先产生有关。我们分析了复发缓解型急性多发性硬化症（AMS，n = 40）或稳定型多发性硬化症（SMS，n = 38）患者中这些分子的表达以及髓鞘碱性蛋白（MBP）特异性白细胞介素-10和干扰素-γ的产生。还分析了22名成功接受醋酸格拉替雷（n = 12）或干扰素β（n = 10）治疗的患者。SMS患者中MBP特异性和表达PD-1的T淋巴细胞、表达PD-L1的CD19(+)细胞以及PD-L1(+)/IL-10(+)/CD14(+)和CD19(+)细胞显著增加。此外，与AMS患者相比，SMS患者中MBP特异性和表达膜联蛋白V的CD4(+)和CD8(+)（凋亡）T淋巴细胞增加，而pAkt阳性（增殖）细胞减少。仅在AMS患者中，PD-1连接导致pAkt(+)淋巴细胞增加。所有个体中B7-H3的表达和干扰素-γ的产生相当，但与SMS患者相比，AMS患者中PD-L1(+)/IL-10(+)与B7-H3(+)/干扰素-γ(+)的比率显著更低。最后，治疗患者免疫细胞上的PD-L1表达降低，这表明治疗诱导的疾病缓解与该分子表达的调节无关。PD-1/PD-L1通路在调节MS患者的免疫功能中起重要作用；监测和靶向这些蛋白质可能具有诊断和治疗优势。
