Martino G, Filippi M, Martinelli V, Brambilla E, Comi G, Grimaldi L M
Department of Biotechnology, University of Milano, San Raffaele Scientific Institute, Italy.
Neurology. 1996 May;46(5):1416-21. doi: 10.1212/wnl.46.5.1416.
T lymphocytes are the main cellular mediators in MS pathogenesis, and their activity is modulated by a complex cytokine network in which gamma-interferon (gamma-IFN) is considered essential. We have recently identified a new transplasmalemma Ca2+ influx activated by gamma-IFN in T lymphocytes (mainly CD4+) from patients with MS that makes T cells more susceptible to proliferation. To define the possible role of this Ca2+ influx as a marker of disease activity, we correlated its appearance with clinical and MRI findings in a cross-sectional study of 67 patients with relapsing-remitting MS (RR-MS). We also conducted a short-term longitudinal evaluation (every 15 days over a 5- to 7-month period) in three of the RR-MS patients. Sixty-five percent of all clinically active RR-MS patients showed the gamma-IFN-activated Ca2+ influx. However, positivity was higher in the first week (78%) after the onset of a clinical exacerbation than the second (57%) and third (44%) weeks. The influx was also detected in 45% of clinically stable RR-MS patients, 30% of RR-MS patients with a "benign" course of the disease, 14% of the other active autoimmune or neurologic disease patients, and 9% of healthy subjects (RR-MS versus control subjects, p < 0.001). Brain-MRI gadolinium-enhancing lesions were more frequently found in influx-positive (72%) than in influx-negative (47%) patients (p < 0.005). In the longitudinal study, we recorded five intracellular Ca2+ ([Ca2+]i) elevations and three clinical attacks (one per patient). A peak increase of [Ca2+]i due to the gamma-IFN-activated Ca2+ influx always preceded the clinical attacks from 4 to 45 days and coincided to MRI evidence of inflammation. [Ca2+]i had returned to baseline levels by the time of the onset of two clinical attacks. This finding may account for the lack of detection of the gamma-IFN-activated Ca2+ influx in some RR-MS patients during the first week after clinical onset. The strong association between the influx and clinical and MRI evidence of disease activity supports its role in the early phases of cellular immune activation leading to demyelination in MS. The detection of [Ca2+]i elevations due to the gamma-IFN-activated Ca2+ influx may represent a valuable prognostic marker of disease activity and may be useful to monitor immunologic studies of MS patients in future clinical trials.
T淋巴细胞是多发性硬化症发病机制中的主要细胞介质，其活性受复杂的细胞因子网络调节，其中γ干扰素（γ-IFN）被认为至关重要。我们最近在多发性硬化症患者的T淋巴细胞（主要是CD4+）中发现了一种由γ-IFN激活的新的跨质膜Ca2+内流，这种内流使T细胞更容易增殖。为了确定这种Ca2+内流作为疾病活动标志物的可能作用，我们在一项对67例复发缓解型多发性硬化症（RR-MS）患者的横断面研究中，将其出现情况与临床和MRI结果进行了关联。我们还对3例RR-MS患者进行了短期纵向评估（在5至7个月的时间内每15天评估一次）。所有临床活动期的RR-MS患者中有65%显示出γ-IFN激活的Ca2+内流。然而，临床加重发作后第一周的阳性率（78%）高于第二周（57%）和第三周（44%）。在45%的临床稳定的RR-MS患者、30%病程“良性”的RR-MS患者、14%其他活动性自身免疫性或神经系统疾病患者以及9%的健康受试者中也检测到了这种内流（RR-MS患者与对照受试者相比，p<0.001）。脑MRI钆增强病变在有内流阳性的患者中（72%）比内流阴性的患者中（47%）更常见（p<0.005）。在纵向研究中，我们记录到5次细胞内Ca2+（[Ca2+]i）升高和3次临床发作（每位患者1次）。γ-IFN激活的Ca2+内流导致的[Ca2+]i峰值增加总是在临床发作前4至45天出现，并且与MRI炎症证据相符。在两次临床发作开始时，[Ca2+]i已恢复到基线水平。这一发现可能解释了为什么在临床发作后的第一周，一些RR-MS患者未检测到γ-IFN激活的Ca2+内流。这种内流与疾病活动的临床和MRI证据之间的强烈关联支持了其在导致多发性硬化症脱髓鞘的细胞免疫激活早期阶段的作用。检测由γ-IFN激活的Ca2+内流引起的[Ca2+]i升高可能代表一种有价值的疾病活动预后标志物，并且在未来的临床试验中可能有助于监测多发性硬化症患者的免疫学研究。
