Systemic IFN-β treatment induces apoptosis of peripheral immune cells in MS patients

In multiple sclerosis (MS), an impaired apoptotic deletion of activated CNS-specific immune cells, leading to their pathogenic persistence, has been suggested to maintain chronic brain inflammation. We here investigated whether interferon-β (IFN-β) therapy induces apoptosis of peripheral immune cells. Serial blood samples from 127 relapsing–remitting MS patients were analyzed prior to the initiation of a weekly IFN-β1a therapy and 4, 26, and 52 weeks thereafter. Peripheral immune cells were investigated for apoptosis and for the expression of apoptosis-regulatory genes CD95, CD95 ligand, FLIP, Bcl-2, Bcl-X L, Bag-1, and caspase 3 by quantitative real-time PCR. Biological efficacy of IFN-β treatment was checked by quantification of Mx expression (ELISA and real-time PCR). We found a significant increase in the apoptosis rate of immune cells in response to IFN-β treatment, compared to baseline levels. While Bcl-2 levels were permanently and Bag-1 levels transiently elevated upon therapy, other apoptosis-regulatory genes revealed no alterations. Upregulation of Mx expression confirmed the activity of IFN-β in vivo. These findings indicate that immunomodulatory IFN-β therapy involves the induction of apoptotic cell death with the observed RNA upregulation of Bcl-2 family members rather reflecting a possible compensatory mechanism. The increased apoptosis susceptibility of peripheral immune cells may contribute to the known reduction of brain inflammatory lesions during IFN-β treatment.