Braakman E, van Tunen A, Meager A, Lucas C J
Clin Exp Immunol. 1986 Nov;66(2):285-94.
In order to determine the factors underlying the impaired natural cytotoxic (NC) activity in multiple sclerosis (MS) patients, we have analysed the interleukin 2 (IL-2)-interferon gamma-(IFN gamma)-NC activity regulatory circuit in 40 MS patients and 40 matched healthy controls. Exogenous recombinant IFN gamma (rIFN gamma) enhanced NC activity in peripheral blood lymphocytes (PBL) derived from MS patients and controls equally well. In contrast, PBL from MS patients showed a significantly lower increase of NC activity in response to IL-2 than healthy controls. This defect in responsiveness was independent of the dose of IL-2. Even at the highest dose of rIL-2 (1000 U/ml), MS patients showed a decreased response. PBL from MS patients required a 2 to 10 times higher dose of IL-2 to reach NC activity levels comparable to controls. In healthy individuals IL-2 can act upon both Fc gamma R+ and Fc gamma R- NC precursor cells. The decreased responsiveness to IL-2 is not confined to one subpopulation of IL-2-responsive precursor cells because depletion of Fc gamma R+ cells before culture in the presence of IL-2 revealed no significant differences in the contribution of Fc gamma R+ precursor cells to the IL-2 enhanced NC activity between MS patients and controls. Also the number of IL-2-responsive precursor cells appeared to be normal since the number of Fc gamma R+ cells in MS patients and controls was comparable. PBL from MS patients produced significantly lower amounts of IFN gamma upon stimulation with IL-2. Analysis of the different parameters of the regulatory circuit at the population level showed, both for patients and controls, a significant correlation between IFN gamma production and increase of NC activity induced by IL-2. Also the endogenous NC activity and IFN gamma production, both in patients and controls, were correlated. At the individual level, defects in NC activity could not be linked to another parameter of the regulatory circuit.
为了确定多发性硬化症（MS）患者自然细胞毒性（NC）活性受损的潜在因素，我们分析了40例MS患者和40例匹配的健康对照者的白细胞介素2（IL-2）-干扰素γ（IFNγ）-NC活性调节回路。外源性重组IFNγ（rIFNγ）同样能有效增强MS患者和对照者外周血淋巴细胞（PBL）的NC活性。相比之下，MS患者的PBL对IL-2刺激的NC活性增加明显低于健康对照者。这种反应性缺陷与IL-2的剂量无关。即使在最高剂量的rIL-2（1000 U/ml）下，MS患者的反应仍降低。MS患者的PBL需要比对照者高2至10倍的IL-2剂量才能达到与之相当的NC活性水平。在健康个体中，IL-2可作用于FcγR +和FcγR - NC前体细胞。对IL-2反应性降低并不局限于IL-2反应性前体细胞的一个亚群，因为在IL-2存在下培养前去除FcγR +细胞后发现，MS患者和对照者之间FcγR +前体细胞对IL-2增强的NC活性的贡献没有显著差异。此外，由于MS患者和对照者中FcγR +细胞的数量相当，IL-2反应性前体细胞的数量似乎也正常。MS患者的PBL在IL-2刺激下产生的IFNγ量明显更低。在群体水平上对调节回路的不同参数进行分析表明，对于患者和对照者，IFNγ产生与IL-2诱导的NC活性增加之间均存在显著相关性。患者和对照者的内源性NC活性和IFNγ产生也相关。在个体水平上，NC活性缺陷与调节回路的其他参数没有关联。
