Possible role of Fas and FasL soluble forms in the pathogenesis of the Multiple Sclerosis

Possible role of Fas and FasL soluble forms in the pathogenesis of Multiple Sclerosis Eleonora Palella, F. Salmeri, S. Marino, P. Bramanti, V. Sofo IRCCS Centro Neurolesi - Messina - Messina Dipartimento di Protezionistica - Università degli Studi di Messina - Messina IRCCS Centro Neurolesi "Bonino Pulejo" - IRCCS - Messina IRCCS Centro Neurolesi "Bonino Pulejo" - IRCCS - Messina Dipartimento di Protezionistica - Università degli Studi di Messina - Messina Background and objectives: In multiple sclerosis (MS) T cells autoreactive to myelin antigens as well as non myelin-specific peripheral blood mononuclear cells escape to activation induced cell death (AICD), migrate and infiltrate the CNS. Membrane-bound forms of Fas (mFas) and FasL (mFasL) are able to induce apoptosis of T cells, while their soluble forms (sFas and sFasL) inhibit apoptotic events. The soluble forms may be produced by mRNA alternative splicing and/or released by membrane cleavage. The aim of this study is to verify whether the modifications of membrane-bound molecules observed in our previous work (1) may depend on sFas and sFasL generation. Subjects and methods: 50 patients (30 with active and 20 with stable MS), 14 males and 36 females, aged 22-60 years, were enrolled. The disease was classified as active in presence of a clinical relapse at the time of blood sampling and a history of at least another clinical relapse during the previous 12 months. Blood samples were collected during the clinical worsening and the detection of new enhancing lesions at MRI in clinically active patients, and after a 12 months observation period free of relapses and new active lesions at MRI in clinically stable patients. 16 aged and sex matched healthy controls (HC) were used. Serum samples obtained from the patients and HC were immediately frozen and stored at -70C° until the time of assay. sFas and sFasL determinations were performed in triplicate samples by ELISA. Results: sFas values were overlapping to HC (4931.3±517pg/ml) in stable phases (5227.6±428pg/ml), whereas increased in active MS (8341.8±635pg/ml). sFasL values in stable disease (151.2±17pg/ml) were almost overlapping to HC (121.2±15pg/ml) and dramatically increased in MS active phases (322.3±28pg/ml). Discussion: AICD is the homeostatic mechanism used by the immune system to control T-cell responses, promote tolerance to self-antigens and prevent autoimmunity. Our results showed a strong increase of both sFas and sFasL only in MS active phases. The soluble forms are known to exert an anti-apoptotic effect (2). Then, overproduction of sFas might antagonize mFas function and play a role as a biologic decoy. sFasL down-regulates FasL activity in vivo, either by reducing levels of its membranous form and by generating an antagonist that competes with the mFasL for the binding with mFas. The soluble form overproduction in MS active phases may play a role in the AICD-resistance of autoreactive T cells and represent a major pathogenetic mechanism in MS. Topic: Sclerosi multipla References: V. Sofo, F.M. Salmeri, P. Di Bella, E. Sessa, G. D’Aleo, G. Trimarchi, P. Bramanti. Impairment of membrane markers on peripheral blood mononuclear cells and imbalance of cytokine secretion in the pathogenesis of multiple sclerosis active phases. J. Interferon Cyt. Res. 2005; 25: 661-5. S. Rinta, H. Kuusisto, M. Raunio, R. Paalavuo, M. Levula, T. Lehtimäki, I. Elovaara. Apoptosis-related molecules in blood in multiple sclerosis. Journal of Neuroimmunology 2008; 205: 135–141.