Central Nervous System (CNS) lesions typical 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-Antigen-Specific MonoNuclear Cells.
Here, we report that in patients with MS the combined action of Interferon-gamma (IFN-γ), Tumor Necrosis Factor-alpha (TNF), InterLeukin IL-2, and IL-6 leads to the activation of most peripheral T-Cells.
Mainly CD4 Memory Cells, by promoting a persistent IntraCellular Calcium increase via two independent signaling pathways.
The activation of these pathways, one activated by IFN-γ and the other by the combination TNF/IL-2/IL-6, is independent from Myelin Antigens.
And precedes by 2 weeks, phases of disease activity (eg, clinical relapses and/or appearance of Gadolinium enhancing lesions on Brain Magnetic Resonance Imaging scans during 1 year of follow-up).
Our results indicate that an appropriate combination of the four Cytokines, three with a ProInflammatory profile and one necessary for T-Cell growth and differentiation, can activate in an Antigen-Independent fashion most peripheral T-Cells from MS patients.
This mechanism is likely to contribute to the recruitment of NonSpecific Lymphocytes into the cellular activation processes leading to CNS DeMyelination and may represent a major target for Immune intervention in MS.