ANTIGEN-INDIPENDENT PERIPHERAL ACTIVATION PRECEDES CLINICAL EVIDENCE OF DISEASE ACTIVITY IN MS

Central nervous system (CNS) lesions ~ypical of multiple sclerosis (MS) are characterized by demyelinating inflammatory infiltrates that contain few CNS antigen-specific autoreactive T cells and a multitude of pathogenic non-specific lymphocytes. We report that in patients with MS the combined action of interferon-y, tumor necrosis factor a, interleukin (IL)-2 and IL-6 leads to the activation of the majority of peripheral T cells (mainly CD4- memory) by promoting a persistent intracellular calcium increase via two indipendent signaling pathways. The activation of ~hese pathways, which is indipendent f=om myelin antigens, precedes by two wee~s phases of d~s~as~ activity (e.q. clinical relapses and/or appearance of gadolinium-enhancing lesions on brain magnetic resonance imaging scans). Our results indicate that an appropriate combination of four cytokines, three with a proinflammatory profile and one necessary for T cell growth and differentiation, can activate in an antigen- indipendent fashion the majority of peripheral T cell from MS ,patients. This mechanism is likely to contribute td the recruitment of non-specific lymphocytes required for CNS demyelination and may represent a major ~arget for ir~mune-in~ervention in MS.