Interferon-γ induced increases in intracellular calcium in T lymphocytes from patients with multiple sclerosis precede clinical exacerbations and detection of active lesions on MRI
- aNeuroimmunology Unit, Department of Biotechnology (DIBIT), San Raffaele Scientific Institute, Milano, Italy, bDepartment of Neurology, University of Milano, San Raffaele Scientific Institute, Milano, Italy, cBiostatistic Unit, San Raffaele Scientific Institute, Milano, Italy
- Dr Luigi M E Grimaldi, Neuroimmunology Unit - DIBIT, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy.
- Received 29 October 1996
- Revised 9 April 1997
- Accepted 11 April 1997
Abstract
BACKGROUND Interferon (IFN)-γ 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-γ 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+]iincreases were recorded in each patient in more than two consecutive measurements, determining sustained [Ca2+]iincreases 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.
