Sibbitt W L, Mathews P M, Bankhurst A D
J Clin Invest. 1983 May;71(5):1230-9. doi: 10.1172/jci110872.
Spontaneous cytotoxicity mediated by natural killer (NK) cells is impaired in several human diseases including systemic lupus erythematosus (SLE). The precise mechanism(s) by which NK activity is suppressed in patients with SLE is generally unknown. The present study was designed to focus on cellular defects per se in NK cells from patients with SLE. It was observed that the usual enhancing effect of interferon (IF) and IF inducers was markedly impaired in SLE patients. Of 24 SLE patients studied, 17 had significantly decreased NK activity relative to controls. NK activity had a significant negative correlation with clinical activity score (r = -0.56, P less than 0.005) but was not correlated with corticosteroid dose, antinuclear antibody titers, total hemolytic complement (CH50), or sedimentation rate. Furthermore, significant depressions in NK activity correlated with variations in disease activity in six patients followed serially. Depressed NK function could not be reversed by prolonged in vitro incubation at 37 degrees C or with protease treatment. Furthermore, depressed NK activity was not altered by removal of glass adherent cells nor was a suppression of NK activity in normal controls seen by the addition of SLE peripheral mononuclear cells. No reversal of depressed activity to normal levels was seen by the addition of indomethacin nor did the supernatants from SLE cell cultures cause a suppression of normal NK function. NK activity in SLE patients did not respond normally to IF inducers (poly-I:C and concanavalin A) even if the SLE patients had normal NK function. The response of SLE cells to exogenous IF was also impaired. The number of effector-target conjugates was quantitated with several target cells (K562, Yac-1, Fravel) in SLE patients and controls. A significant correlation between the proportion of glass nonadherent mononuclear cells that formed effector-target conjugates with these various targets and the magnitude of NK lysis was observed. However, SLE and normal subjects had equal numbers of effector-target conjugates independent of NK function. Release of a soluble cytotoxic factor was induced with concanavalin A, and was markedly impaired in SLE patients relative to normal controls. Thus, impaired NK cell function in SLE does not appear to be related to cell-mediated suppressive mechanisms or to the deletion of effector cells; rather, the decreased NK activity may be related to an impaired release of a soluble cytotoxic factor.
自然杀伤（NK）细胞介导的自发细胞毒性在包括系统性红斑狼疮（SLE）在内的多种人类疾病中受损。SLE患者中NK活性被抑制的确切机制通常尚不清楚。本研究旨在聚焦SLE患者NK细胞本身的细胞缺陷。据观察，干扰素（IF）和IF诱导剂的通常增强作用在SLE患者中明显受损。在研究的24例SLE患者中，17例相对于对照组NK活性显著降低。NK活性与临床活动评分呈显著负相关（r = -0.56，P小于0.005），但与皮质类固醇剂量、抗核抗体滴度、总溶血补体（CH50）或血沉无关。此外，在连续随访的6例患者中，NK活性的显著降低与疾病活动的变化相关。NK功能降低不能通过在37℃长时间体外培养或蛋白酶处理来逆转。此外，去除玻璃黏附细胞不会改变NK活性降低的情况，添加SLE外周单个核细胞也不会使正常对照的NK活性受到抑制。添加消炎痛不会使降低的活性恢复到正常水平，SLE细胞培养上清液也不会抑制正常NK功能。即使SLE患者具有正常的NK功能，其NK活性对IF诱导剂（聚肌胞苷酸和刀豆球蛋白A）也无正常反应。SLE细胞对外源性IF的反应也受损。用几种靶细胞（K562、Yac-1、Fravel）对SLE患者和对照组的效应细胞 - 靶细胞结合物数量进行了定量。观察到与这些不同靶细胞形成效应细胞 - 靶细胞结合物的玻璃非黏附单个核细胞比例与NK裂解程度之间存在显著相关性。然而，无论NK功能如何，SLE患者和正常受试者的效应细胞 - 靶细胞结合物数量相等。用刀豆球蛋白A诱导可溶性细胞毒性因子的释放，与正常对照相比，SLE患者明显受损。因此，SLE中NK细胞功能受损似乎与细胞介导的抑制机制或效应细胞的缺失无关；相反，NK活性降低可能与可溶性细胞毒性因子的释放受损有关。
