Proinflammatory cytokines regulate antigen independent T-cell activation by two separate calcium-signaling pathways in multiple sclerosis patients
Proinflammatory cytokines regulate antigen independent T-cell activation by two separate calcium-signaling pathways in multiple sclerosis patients
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DOI：
10.1002/ana.410430312
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发表时间：
1998-03-01
影响因子：
11.2
通讯作者：
Grimaldi, LME
中科院分区：
文献类型：
--
作者：
Martino, G;Grohovaz, F;Grimaldi, LME
多发性硬化症(MS)的典型中枢神经系统(CNS)损害的特点是脱髓鞘的炎性浸润物，其中含有很少的CNS抗原特异性自身反应T细胞和大量致病的非抗原特异性单个核细胞。在这里，我们报道了在MS患者中，干扰素-伽马、肿瘤坏死因子-α、白介素2和白介素6的联合作用通过两个独立的信号通路促进持续的细胞内钙升高，从而导致大多数外周T细胞(主要是CD4记忆)的激活。这些通路的激活，一个由干扰素-γ激活，另一个由肿瘤坏死因子-α/白介素2/白介素6组合激活，不依赖于髓鞘抗原，比疾病活动期早两周(例如，临床复发和/或在一年的随访期中在脑磁共振扫描中出现Gd增强的病变)。我们的结果表明，四种细胞因子的适当组合，其中三种具有促炎特征，一种是T细胞生长和分化所必需的，可以以一种不依赖于抗原的方式激活MS患者的大多数外周T细胞。这种机制可能有助于将非特异性淋巴细胞重新招募到细胞激活过程中，导致中枢神经系统脱髓鞘，并可能是MS免疫干预的主要靶点。
Central nervous system (CNS) lesions typical of multiple sclerosis (MS) are characterized by demyelinating inflammatory infiltrates that contain few CNS antigen-specific autoreactive T cells and a multitude of pathogenic non-antigen-specific mononuclear cells. Here, we report that in patients with MS the combined action of interferon-gamma (IFN gamma), tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-2, and IL-6 leads to the activation of most peripheral T cells (mainly CD4 memory) by promoting a persistent intracellular calcium increase via two independent signaling pathways. The activation of these pathways, one activated by IFN gamma and the other by the combination TNF alpha/IL-2/IL-6, is independent from myelin antigens and precedes by 2 weeks phases of disease activity (eg, clinical relapses and/or appearance of gadolinium-enhancing lesions on brain magnetic resonance imaging scans during 1 year of follow-up). Our results indicate that an appropriate combination of the four cytokines, three with a proinflammatory profile and one necessary for T-cell growth and differentiation, can activate in an antigen-independent fashion most peripheral T cells from MS patients. This mechanism is likely to contribute to the recruitment of nonspecific lymphocytes into the cellular activation processes leading to CNS demyelination and may represent a major target for immune intervention in MS.