Systemic IFN-beta treatment induces apoptosis of peripheral immune cells in MS patients.
ABSTRACT 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-beta (IFN-beta) 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-beta 1a 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-beta 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-beta 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-beta in vivo. These findings indicate that immunomodulatory IFN-beta 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-beta treatment.
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ABSTRACT: Multiple sclerosis is a clinically heterogeneous autoimmune disease leading to severe neurological disability. Although during the last years many disease-modifying agents as treatment options for multiple sclerosis have been made available, their mechanisms of action are still not fully determined. In the present study radiosensitivity in lymphocytes of patients with relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis and healthy controls was investigated. Whole blood cultures from multiple sclerosis patients and healthy controls were used to analyse the spontaneous and radiation-induced micronuclei in binucleated lymphocytes. A subgroup of patients with relapsing-remitting multiple sclerosis was treated with immunomodulatory agents, interferon β or glatiramer acetate. The secondary progressive multiple sclerosis patients group was not receiving any treatment. Our results reveal that the basal DNA damage was not different between relapsing-remitting and secondary progressive multiple sclerosis patients, and healthy controls. No differences between gamma-irradiation induced micronuclei frequencies in binucleated cells from relapsing-remitting and secondary progressive multiple sclerosis patients, and healthy controls were found either. Nevertheless, when we compared the radiation induced DNA damage in binucleated cells from healthy individuals with the whole group of patients, a reduction in the frequency of micronuclei was obtained in the patients group. Induced micronuclei yield was significantly lower in the irradiated samples from treated relapsing-remitting multiple sclerosis patients than in healthy controls and relapsing-remitting not treated patients. Intrinsic sensitivity of lymphocytes subpopulations to the apoptotic effect of immunomodulatory treatment could be responsible for this result.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2013; · 4.44 Impact Factor
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ABSTRACT: Objective: To elucidate the role of tumor necrosis factor (TNF) receptor signal transduction in multiple sclerosis (MS). Methods: We performed a cross-sectional analysis of the gene expression of TRAF2 (TNF receptor-associated factor 2) and RIP (receptor-interacting protein) in peripheral blood leukocytes of 23 relapsing-remitting (RR), 19 secondary progressive (SP) and 12 primary progressive (PP) MS patients as well as of 29 healthy controls by quantitative RT-PCR. Additionally, we monitored a subgroup of 15 RRMS patients longitudinally every 3 months over a 9-month time period. Results: TRAF2 expression was significantly elevated in RRMS patients compared to the other disease courses (p < 0.005, respectively) and the control group (p < 0.009). RIP expression was significantly elevated in the patient groups compared to the healthy group (phealthy-RR < 0.002; phealthy-PP < 0.003; phealthy-SP < 0.06). Neither variable changed over the 9-month time course. Conclusion: TRAF2 and RIP1 elevation in leukocytes might be interpreted as the molecular equivalent of an elevated general inflammatory activity in MS patients compared to healthy control persons. TRAF2 elevation in RRMS reinforces the concept that different pathophysiological and immunological processes sustain RRMS and SPMS or PPMS.NeuroImmunoModulation 04/2013; 20(3):177-183. · 1.84 Impact Factor