INTERLEUKIN-10 PROMOTES ACTIVATION-INDUCED CELL-DEATH OF SLE LYMPHOCYTES MEDIATED BY FAS LIGAND

Immune function in SLE is paradoxically characterized by active T cell help for autoantibody production, along with impaired T cell prolifer ative and cytokine responses in vitro, To reconcile these observations , we investigated the possibility that the accelerated spontaneous cel l 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 healt hy subjects were studied. Patients with clinically active SLE or syste mic vasculitis had accelerated spontaneous death of PBMC with features of apoptosis at day 5 of culture, A prominent role for IL-10 in the i nduction of apoptosis was observed, as neutralizing anti-IL-10 mAb mar kedly 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 viabili ty in the active SLE group, but not in the control group, by 38%, In a ddition, apoptosis was shown to be actively induced through the Fas pa thway, The potential clinical relevance of T cell apoptosis in active SLE is supported by the correlation of increased apoptosis and IL-10 l evels in vitro with low lymphocyte counts in vivo, We conclude that th e spontaneous cell death observed in vitro in lymphocytes from patient s with SLE and other systemic autoimmune disorders results from in viv o T cell activation, is actively induced by IL-10 and Fas ligand, and reflects pathophysiologically important events in vivo. Activation-ind uced cell death in vivo provides a pathogenic link between the aberran t T helper cell activation and impaired T cell function that are chara cteristic features of the immune system of patients with SLE.