Grimaldi L M, Martino G
Department of Neurology, University of Milano, San Raffaele Scientific Institute, Italy.
Mult Scler. 1995;1 Suppl 1:S38-43.
A central role in the complex immunology of MS is played by activated T lymphocytes. Proper antigenic stimulation, adequate major histocompatibility complex (MHC) coactivation and multiple cytokine signals regulate T-cell activation via the generation of intracellular calcium (Ca2+) transients necessary to up-regulate the genes controlling lymphocyte growth and differentiation. Interferon gamma (IFN-gamma) exerts an autocrine/paracrine control of T-lymphocyte activity and is able to co-mediate most demyelinating events occurring in MS patients. The mechanisms by which IFN-gamma exerts its effects include increased expression of MHC class II molecules on the surface of glial cells and stimulation of macrophage/microglial cell production of molecules toxic to myelin. Most intracellular events regulating these processes in lymphocytes are, however, still unknown. We have reported that in the majority of MS patients T lymphocytes (mainly CD4+) exposed to IFN-gamma show a Ca2+ influx whose ion permeability and pharmacological properties differ from those of all Ca2+ influxes so far described. This IFN-gamma-activated Ca2+ influx, which is probably sustained by a cationic channel, was observed in the majority of patients with MS, but only in a limited number of subjects affected by other neurological, active immune-mediated diseases or healthy control subjects. Moreover, the presence of the influx correlates with clinical and radiological evidence of disease activity and induces T-lymphocyte proliferation even when cells are suboptimally stimulated by activatory stimuli. We conclude that this new IFN-gamma-activated Ca2+ influx seems to be highly specific for MS (especially during its active phase), and could be important for the intracellular regulation of cells involved in demyelination. The presence of the influx in T lymphocytes from MS patients could account for the reported temporal association between infections and clinical relapses.
活化的T淋巴细胞在多发性硬化症复杂的免疫学中起着核心作用。适当的抗原刺激、足够的主要组织相容性复合体（MHC）共激活以及多种细胞因子信号通过产生上调控制淋巴细胞生长和分化的基因所必需的细胞内钙（Ca2+）瞬变来调节T细胞活化。干扰素γ（IFN-γ）对T淋巴细胞活性发挥自分泌/旁分泌控制作用，并能够共同介导多发性硬化症患者发生的大多数脱髓鞘事件。IFN-γ发挥其作用的机制包括胶质细胞表面MHC II类分子表达增加以及刺激巨噬细胞/小胶质细胞产生对髓鞘有毒性的分子。然而，调节淋巴细胞中这些过程的大多数细胞内事件仍然未知。我们已经报道，在大多数多发性硬化症患者中，暴露于IFN-γ的T淋巴细胞（主要是CD4+）会出现Ca2+内流，其离子通透性和药理学特性与迄今为止描述的所有Ca2+内流不同。这种IFN-γ激活的Ca2+内流可能由一个阳离子通道维持，在大多数多发性硬化症患者中都观察到了，但仅在少数受其他神经学、活跃免疫介导疾病影响的受试者或健康对照受试者中观察到。此外，这种内流的存在与疾病活动的临床和放射学证据相关，并且即使在细胞受到激活刺激的亚最佳刺激时也能诱导T淋巴细胞增殖。我们得出结论，这种新的IFN-γ激活的Ca2+内流似乎对多发性硬化症具有高度特异性（尤其是在其活动期），并且可能对参与脱髓鞘的细胞的细胞内调节很重要。多发性硬化症患者T淋巴细胞中存在这种内流可以解释所报道的感染与临床复发之间的时间关联。
