Bioenergetics profile of CD4 + T cells in relapsing remitting multiple sclerosis subjects

Riccardis, Lidia De; Rizzello, Antonia; Ferramosca, Alessandra; Urso, Emanuela; Robertis, Francesca De; Danieli, Antonio; Giudetti, Anna Maria; Trianni, Giorgio; Zara, Vincenzo; Maffia, Michele

doi:10.1016/j.jbiotec.2015.02.015

Cited by 44 publications

(42 citation statements)

References 84 publications

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“…A recent study carried out by our group showed a significant reduction of SOD activity in CD4 + T cells of MS patients [7]. In the present study we found that GA treatment was able to increase SOD activity, which was significantly reduced in MS baseline.…”

Section: Discussionsupporting

confidence: 76%

“…Metabolic changes in T cells influence immune functions in human diseases: in HIV patients, it was shown that high levels of immune activation and markers of inflammation, correlated with Glut-1 overexpression and the increased glycolytic metabolism in CD4 + T cells [48]. In the same cells of Multiple Sclerosis first diagnosis patients, we found an increase in glycolytic pathway associated with a decrease in OXPHOS activity: in particular, we found a decrease in the activities of mitochondrial complex I and IV and a parallel increase in the activity of complex III, suggesting a defect in mitochondrial function [7]. The impairment of mitochondrial respiration efficiency resulted also in decreased RCR values, which are a measure of the tightness of coupling between electron transport and oxidative phosphorylation.…”

Section: Discussionmentioning

confidence: 58%

“…In particular, previous studies carried out by our group demonstrated that CD4 + T cells of MS patients have a reduction in oxygen consumption in association with an increase in the activity of glycolytic enzymes respect to the cells of control ones [7]. These findings lead us to propose CD4 + T cell bio-energetic status as a marker for diagnosis and follow up for MS [7]. During the last decade, new therapies have been shown to significantly improve MS disease course.…”

Section: Introductionmentioning

confidence: 76%

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Metabolic response to glatiramer acetate therapy in multiple sclerosis patients

et al. 2016

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Glatiramer acetate (GA; Copaxone) is a random copolymer of glutamic acid, lysine, alanine, and tyrosine used for the treatment of patients with multiple sclerosis (MS). Its mechanism of action has not been already fully elucidated, but it seems that GA has an immune-modulatory effect and neuro-protective properties. Lymphocyte mitochondrial dysfunction underlines the onset of several autoimmune disorders. In MS first diagnosis patients, CD4+, the main T cell subset involved in the pathogenesis of MS, undergo a metabolic reprogramming that consist in the up-regulation of glycolysis and in the down-regulation of oxidative phosphorylation. Currently, no works exist about CD4+ T cell metabolism in response to GA treatment. In order to provide novel insight into the potential use of GA in MS treatment, blood samples were collected from 20 healthy controls (HCs) and from 20 RR MS patients prior and every 6 months during the 12 months of GA administration. GA treated patients' CD4+ T cells were compared with those from HCs analysing their mitochondrial activity through polarographic and enzymatic methods in association with their antioxidant status, through the analysis of SOD, GPx and CAT activities. Altogether, our findings suggest that GA is able to reduce CD4+ T lymphocytes' dysfunctions by increasing mitochondrial activity and their response to oxidative stress.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 76%

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Metabolic response to glatiramer acetate therapy in multiple sclerosis patients

et al. 2016

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“…To date, studies concerning T cell metabolism in MS have been carried out only on Treg cell proliferative potential , or on a heterogeneous T cell population, i.e. CD4+ T cells as a whole, giving unreliable results, which do not allow to understand if the differences observed are due to an intrinsic alteration of T cell activation pathways, or to a difference in the relative distribution of CD4+ T cell subsets between MS patients and CTR .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial functionality and metabolism in T cells from progressive multiple sclerosis patients

et al. 2019

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Patients with primary progressive (PP) and secondary progressive (SP) forms of multiple sclerosis (MS) exhibit a sustained increase in the number of Th1, T cytotoxic type-1 and Th17 cells in peripheral blood, suggesting that the progressive phase is characterized by a permanent peripheral immune activation. As T cell functionality and activation are strictly connected to their metabolic profile, we investigated the mitochondrial functionality and metabolic changes of T cell subpopulations in a cohort of progressive MS patients. T cells from progressive patients were characterized by low proliferation and increase of terminally differentiated/exhausted cells. T cells from PP patients showed lower Oxygen Consumption Rate and Extracellular Acidification Rate, lower mitochondrial mass, membrane potential and respiration than those of SP patients, a downregulation of transcription factors supporting respiration and higher tendency to shift towards glycolysis upon stimulation. Furthermore, PP effector memory T cells were characterized by higherGlucose transporter -1 levels and a higher expression of glycolytic-supporting genes if compared to SP patients. Overall, our data suggest that profound differences exist in the phenotypic and metabolic features of T cells from PP and SP patients, even though the two clinical phenotypes are considered part of the same disease spectrum.Keywords: flow cytometry r metabolism r mitochondria r multiple sclerosis r T cells Additional supporting information may be found online in the Supporting Information section at the end of the article.

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“…The deletion of autoreactive lymphocytes is normally mediated by apoptosis, however, an escape from mitochondria-mediated apoptosis has been reported in lymphocytes of MS patients [12]. Mitochondria from MS lymphocytes also show a decrease of mitochondrial respiration [13] associated with a specific decrease of complex I and complex IV activities [28], and, of note, mitochondria have been found to range in shape and size and showed thickened cristae [29]. Mitochondrial dependent apoptosis is also depending on mitochondrial respiration, shape and structure.…”

Section: Discussionmentioning

confidence: 99%

PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels

et al. 2020

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Multiple sclerosis (MS) is an autoimmune disease in which activated lymphocytes affect the central nervous system. Increase of reactive oxygen species (ROS), impairment of mitochondria-mediated apoptosis and mitochondrial alterations have been reported in peripheral lymphocytes of MS patients. Mitochondria-mediated apoptosis is regulated by several mechanisms and proteins. Among others, optic atrophy 1 (OPA1) protein plays a key role in the regulating mitochondrial dynamics, cristae architecture and release of pro-apoptotic factors. Very interesting, mutations in OPA1 gene, have been associated with multiple sclerosis-like disorder. We have analyzed OPA1 and some factors involved in its regulation. Fifteen patients with MS and fifteen healthy control subjects (HC) were enrolled into the study and peripheral blood mononuclear cells (PBMCs) were isolated. H2O2 level was measured spectrofluorimetrically, OPA1, PHB2, SIRT3, and OMA1 were analyzed by western blotting. Statistical analysis was performed using Student’s t-test. The results showed that PBMC of MS patients were characterized by a deregulation of OPA1 processing associated with increased H2O2 production, inactivation of OMA1 and increase of PHB2 protein level. The presented data suggest that the alteration of PHB2, OMA1, and OPA1 processing could be involved in resistance towards apoptosis. These molecular parameters could also be useful to assess disease activity.

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Bioenergetics profile of CD4 + T cells in relapsing remitting multiple sclerosis subjects

Cited by 44 publications

References 84 publications

Metabolic response to glatiramer acetate therapy in multiple sclerosis patients

Metabolic response to glatiramer acetate therapy in multiple sclerosis patients

Mitochondrial functionality and metabolism in T cells from progressive multiple sclerosis patients

PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels

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