Georgescu L, Vakkalanka R K, Elkon K B, Crow M K
Specialized Center of Research (SCOR) in Systemic Lupus Erythematosus, Hospital for Special Surgery, New York, USA.
J Clin Invest. 1997 Nov 15;100(10):2622-33. doi: 10.1172/JCI119806.
Immune function in SLE is paradoxically characterized by active T cell help for autoantibody production, along with impaired T cell proliferative and cytokine responses in vitro. To reconcile these observations, we investigated the possibility that the accelerated spontaneous cell death of SLE lymphocytes in vitro is caused by an activation-induced cell death process initiated in vivo. 27 SLE patients, three patients with systemic vasculitis, seven patients with arthritis, and 14 healthy subjects were studied. Patients with clinically active SLE or systemic vasculitis had accelerated spontaneous death of PBMC with features of apoptosis at day 5 of culture. A prominent role for IL-10 in the induction of apoptosis was observed, as neutralizing anti-IL-10 mAb markedly reduced cell death in the active SLE patients by 50%, from 22.3 +/- 5.2% to 11.2 +/- 2.8%, and the addition of IL-10 decreased viability in the active SLE group, but not in the control group, by 38%. In addition, apoptosis was shown to be actively induced through the Fas pathway. The potential clinical relevance of T cell apoptosis in active SLE is supported by the correlation of increased apoptosis and IL-10 levels in vitro with low lymphocyte counts in vivo. We conclude that the spontaneous cell death observed in vitro in lymphocytes from patients with SLE and other systemic autoimmune disorders results from in vivo T cell activation, is actively induced by IL-10 and Fas ligand, and reflects pathophysiologically important events in vivo. Activation-induced cell death in vivo provides a pathogenic link between the aberrant T helper cell activation and impaired T cell function that are characteristic features of the immune system of patients with SLE.
系统性红斑狼疮（SLE）的免疫功能呈现出矛盾的特征，一方面是T细胞对自身抗体产生的积极辅助作用，另一方面是体外T细胞增殖和细胞因子反应受损。为了协调这些观察结果，我们研究了SLE淋巴细胞在体外加速的自发细胞死亡是否由体内启动的激活诱导细胞死亡过程所导致。我们对27例SLE患者、3例系统性血管炎患者、7例关节炎患者和14名健康受试者进行了研究。临床活动期的SLE患者或系统性血管炎患者的外周血单个核细胞（PBMC）在培养第5天出现具有凋亡特征的加速自发死亡。观察到IL-10在诱导凋亡中起重要作用，因为中和性抗IL-10单克隆抗体可使活动期SLE患者的细胞死亡显著减少50%，从22.3±5.2%降至11.2±2.8%，并且添加IL-10可使活动期SLE组的细胞活力降低38%，而对照组则无此现象。此外，凋亡显示是通过Fas途径被积极诱导的。体外凋亡增加和IL-10水平与体内低淋巴细胞计数之间的相关性支持了活动期SLE中T细胞凋亡的潜在临床相关性。我们得出结论，SLE患者和其他系统性自身免疫性疾病患者淋巴细胞在体外观察到的自发细胞死亡是由体内T细胞激活引起的，由IL-10和Fas配体积极诱导，并反映了体内病理生理学上的重要事件。体内激活诱导的细胞死亡在异常的辅助性T细胞激活和T细胞功能受损之间提供了一个致病联系，而这正是SLE患者免疫系统的特征。
