Interferon-gamma induced increases in intracellular calcium in T lymphocytes from patients with multiple sclerosis precede clinical exacerbations and detection of active lesions on MRI

BACKGROUND:Interferon (IFN)-gamma exerts a multiplicity of actions potentially relevant for the pathogenesis of multiple sclerosis, including the expression of a transplasmalemma calcium (Ca2+) influx leading to an intracellular Ca2+ ([Ca2+]i) increase able to lower T lymphocyte threshold of excitability. It has been previously shown in a cross sectional cumulative study that this influx is associated with clinical and MRI evidence of disease activity.METHODS:To evaluate the temporal relation between disease activity and the IFN-gamma activated Ca2+ influx in individual patients, a fluorimetric analysis was performed on peripheral blood lymphocytes from eight patients with relapsing-remitting multiple sclerosis every 15 days for one year.RESULTS:Fluctuations of the influx were correlated with clinical events and monthly enhanced brain MRI. The influx was detected a mean of 10.4 (range 7-17) times per patient during our analysis. In 61% of the occasions, influx induced [Ca2+]i increases were recorded in each patient in more than two consecutive measurements, determining sustained [Ca2+]i increases lasting for a mean of 31.5 days. Peak [Ca2+]i increases preceded clinical attacks (P=0.04) or maximal detection of brain MRI enhancing lesions (P=0.05) by a mean of 30.8 and 34.2 days respectively. Spectral analysis of time series further indicated that the fluctuation frequency of [Ca2+]i increases due to the influx over time were superimposable on the appearance of new MRI lesions in all patients and confirmed that in two thirds of the patients these [Ca2+]i increases occurred significantly before (P<0.005) or concurred with new lesion appearance. Finally, the overall presence of the influx throughout the follow up period correlated (P=0.03) with the patients' exacerbation rates.CONCLUSIONS:Intracellular events leading to T lymphocyte activation in multiple sclerosis occur in the peripheral blood before CNS specific events become evident and are, in part, sustained by cytokine induced Ca2+ mediated phenomena.