Proinflammatory cytokines regulate antigen-independent T-cell activation by two separate calcium-signaling pathways in multiple sclerosis patients.
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-gamma), tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-2, and IL-6 leads to the activation of most peripheral T cells (mainly CD4 memory) by promoting a persistent intracellular calcium increase via two independent signaling pathways. The activation of these pathways, one activated by IFNgamma and the other by the combination TNFalpha/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.
Martino
G
G
DIBIT, Department of Neurology, University of Milano, San Raffaele Scientific Institute, Italy.
Grohovaz
F
F
Brambilla
E
E
Codazzi
F
F
Consiglio
A
A
Clementi
E
E
Filippi
M
M
Comi
G
G
Grimaldi
L M
LM
D000941:Antigens / Q000502:physiology; D001773:Blood Cells / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D004357:Drug Synergism; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology / Q000502:physiology*; D007425:Intracellular Membranes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D009103:Multiple Sclerosis / Q000097:blood / Q000503:physiopathology*; D009186:Myelin Sheath / Q000276:immunology; D009994:Osmolar Concentration; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*
D000941:Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D002118:Calcium