BackgroundData from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target.Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients. We investigated whether siponimod, in addition to its peripheral immune modulation, may exert direct neuroprotective effects in the central nervous system (CNS) of mice with chronic progressive EAE.MethodsMinipumps allowing continuous intracerebroventricular (icv) infusion of siponimod for 4 weeks were implanted into C57BL/6 mice subjected to MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, qPCR experiments, and peripheral lymphocyte counts were performed. In addition, the effect of siponimod on activated microglia was assessed in vitro to confirm the direct effect of the drug on CNS-resident immune cells.ResultsSiponimod administration (0.45 μg/day) induced a significant beneficial effect on EAE clinical scores with minimal effect on peripheral lymphocyte counts. Siponimod rescued defective GABAergic transmission in the striatum of EAE, without correcting the EAE-induced alterations of glutamatergic transmission. We observed a significant attenuation of astrogliosis and microgliosis together with reduced lymphocyte infiltration in the striatum of EAE mice treated with siponimod. Interestingly, siponimod reduced the release of IL-6 and RANTES from activated microglial cells in vitro, which might explain the reduced lymphocyte infiltration. Furthermore, the loss of parvalbumin-positive (PV+) GABAergic interneurons typical of EAE brains was rescued by siponimod treatment, providing a plausible explanation of the selective effects of this drug on inhibitory synaptic transmission.ConclusionsAltogether, our results show that siponimod has neuroprotective effects in the CNS of EAE mice, which are likely independent of its peripheral immune effect, suggesting that this drug could be effective in limiting neurodegenerative pathological processes in MS.
Regulatory T Cells (Tregs) are a T-lymphocyte subset involved in the maintenance of immune peripheral tolerance. Despite evidence of the adaptive immune system’s role in Alzheimer’s Disease (AD), the involvement of Tregs is still not clear. We focused on the Flow-Cytometry analysis of the Treg frequencies and phenotypes in the AD. The aim of the study is to analyse similarities and differences in Tregs profile between Alzheimer’s Disease and Multiple Sclerosis. Regulatory T Cells (CD4+/CD25high/CD127low-neg) were identified using an innovative Flow Cytometry method and subtyped as Resting (analysed CD45RApos/CD25dim), Activated (CD45RAneg/CD25bright) and Secreting (CD45RAneg/CD25dim) cells. Our data demonstrate a significant decrease in the total and Resting Tregs in AD patients when compared to healthy subjects. The percentage of the results of the Resting Tregs were also reduced in MS patients together with a parallel frequency increase of Activated Tregs. Our data suggest that altered Treg phenotypes observed in both diseases could play a role in the impairment of the Treg-mediated immunological tolerance, recalling a possible link between the two pathologies. Given that this study was conducted on a restricted population, if confirmed by a further and enlarged study, the implications of the autoimmune mechanisms in AD pathophysiology could open new immunotherapeutic perspectives based on Treg modulation.
Background: Previous studies evidenced a link between metabolic dysregulation, inflammation, and neurodegeneration in multiple sclerosis (MS). Objectives: To explore whether increased adipocyte mass expressed as body mass index (BMI) and increased serum lipids influence cerebrospinal fluid (CSF) inflammation and disease severity. Methods: In this cross-sectional study, 140 consecutive relapsing-remitting (RR)-MS patients underwent clinical assessment, BMI evaluation, magnetic resonance imaging scan, and blood and CSF collection before any specific drug treatment. The CSF levels of the following cytokines, adipocytokines, and inflammatory factors were measured: interleukin (IL)-6, IL-13, granulocyte macrophage colony-stimulating factor, leptin, ghrelin, osteoprotegerin, osteopontin, plasminogen activator inhibitor-1, resistin, and Annexin A1. Serum levels of triglycerides, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) were assessed. Results: A positive correlation emerged between BMI and Expanded Disability Status Scale score. Obese RR-MS patients showed higher clinical disability, increased CSF levels of the proinflammatory molecules IL-6 and leptin, and reduced concentrations of the anti-inflammatory cytokine IL-13. Moreover, both the serum levels of triglycerides and TC/HDL-C ratio showed a positive correlation with IL-6 CSF concentrations. Conclusion: Obesity and altered lipid profile are associated with exacerbated central inflammation and higher clinical disability in RR-MS at the time of diagnosis. Increased adipocytokines and lipids can mediate the negative impact of high adiposity on RR-MS course.
The aim of this study was to assess the frequency of organ- and nonorgan-specific autoantibodies in MS patients and evaluate whether the presence of autoantibodies is an indicator of disease activity and/or a prognosis factor. One hundred and five definite MS patients in different stages and with different course and 75 blood donors were tested for the autoantibodies TgA, TMA/TPO-A, PCA, ANA, aCl, SMA, AMA and ANCA. All patients were screened for the LAC. Autoantibodies to at least one autoantigen were found in 66.6% MS patients and in 13.3% controls (P < 0.001). The frequency of TgA, TMA/TPO-A, ANA, aCl and SMA was statistically higher in patients than in controls. Circulating ANCAs were found in seven MS, a never reported finding. An early onset of MS (< 20 years) was associated with a lower autoantibody frequency (P < 0.01) Primary and secondary progressive MS had a higher antibody frequency than relapsing-remitting (P < 0.05) or benign (P < 0.001) MS. Up to 86% of patients were autoantibody-positive during the acute stage, but only 30% of them remained positive during the remission stage (P < 0.001). A generalised immune dysregulation occurs in MS patients, mostly during the acute stages and in the progressive courses, involving activation of both autoreactive Th1-cells (mainly linked to CNS lesions) and B-cells via Th2 cells.
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