de Andrés Clara, Fernández-Paredes Lidia, Tejera-Alhambra Marta, Alonso Bárbara, Ramos-Medina Rocío, Sánchez-Ramón Silvia
Department of Neurology, Hospital General Universitario Gregorio Marañón , Madrid , Spain.
Department of Clinical Immunology, IdISSC, Hospital Clínico San Carlos , Madrid , Spain.
Front Immunol. 2017 Feb 23;8:196. doi: 10.3389/fimmu.2017.00196. eCollection 2017.
A striking common feature of most autoimmune diseases is their female predominance, with at least twice as common among women than men in relapsing-remitting multiple sclerosis (MS), the prevailing MS clinical form with onset at childbearing age. This fact, together with the protective effect on disease activity during pregnancy, when there are many biological changes including high levels of estrogens and progesterone, puts sex hormones under the spotlight. The role of natural killer (NK) and NKT cells in MS disease beginning and course is still to be elucidated. The uterine NK (uNK) cells are the most predominant immune population in early pregnancy, and the number and function of uNK cells infiltrating the endometrium are sex-hormones' dependent. However, there is controversy on the role of estrogen or progesterone on circulating NK (CD56 and CD56) and NKT cells' subsets. Here, we show a significantly increased activation of CD3CD56CD8 cells in pregnant MS women (MSP) compared with non-pregnant MS women (NPMS) ( < 0.001) and even with respect to healthy pregnant women (HP, < 0.001), remaining increased even after delivery. The dynamics of expression of early activation marker CD69 on CD3CD56CD8 cells showed a progressive statistically significant increase along the gestation trimesters (T) and at postpartum (PP) with respect to NPMS (1T: = 0.018; 2T: = 0.004; 3T: < 0.001; PP: = 0.001). In addition, early activation expression of CD69 on CD3CD56CD8 cells was higher in MSP than HP in the first two trimesters of gestation ( = 0.004 and = 0.015, respectively). NPMS showed significantly increased cytotoxic/regulatory NK ratio compared with healthy controls ( < 0.001). On the other hand, gender studies showed no differences between MS women and men in NK and CD3CD56CD8 cells' subsets. Our findings may add on the understanding of the regulatory axis in MS during pregnancy. Further studies on specific CD8 NKT cells function and their role in pregnancy beneficial effects on MS are warranted to move forward more effective MS treatments.
大多数自身免疫性疾病的一个显著共同特征是女性居多，在复发缓解型多发性硬化症（MS）中，女性患者至少是男性患者的两倍，MS是一种常见的临床类型，发病于育龄期。这一事实，再加上孕期对疾病活动的保护作用，孕期会发生许多生物学变化，包括高水平的雌激素和孕激素，使得性激素成为关注焦点。自然杀伤（NK）细胞和NKT细胞在MS疾病起始和病程中的作用仍有待阐明。子宫NK（uNK）细胞是妊娠早期最主要的免疫细胞群体，浸润子宫内膜的uNK细胞数量和功能依赖于性激素。然而，雌激素或孕激素对循环NK（CD56bright和CD56dim）细胞和NKT细胞亚群的作用存在争议。在此，我们发现与未孕MS女性（NPMS）相比，孕MS女性（MSP）中CD3CD56CD8细胞的活化显著增加（P<0.001），甚至与健康孕妇（HP）相比也增加（P<0.001），产后仍保持增加。CD3CD56CD8细胞上早期活化标志物CD69的表达动态显示，与NPMS相比，在妊娠各期（T）和产后（PP）均有统计学意义的逐渐增加（1T：P=0.018；2T：P=0.004；3T：P<0.001；PP：P=0.001）。此外，在妊娠的前两个阶段，MSP中CD3CD56CD8细胞上CD69的早期活化表达高于HP（分别为P=0.004和P=0.015）。与健康对照组相比，NPMS的细胞毒性/调节性NK比值显著增加（P<0.001）。另一方面，性别研究显示MS女性和男性在NK细胞和CD3CD^{+}56^{+}CD8^{+}细胞亚群上没有差异。我们的发现可能有助于加深对孕期MS调节轴的理解。有必要进一步研究特定CD8^{+} NKT细胞功能及其在孕期对MS有益作用中的作用，以推进更有效的MS治疗。
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