Increased Spontaneous Ex Vivo Apoptosis and Subset Alterations in Peripheral Blood T Cells from Patients with Multiple Sclerosis

Prieto, Alfredo; Díaz, David; Barcenilla, Hugo; Castrillo, Carmen; Monserrat, Jorge; Merino, Antonio García; Álvarez‐Mon, Melchor; II-group, Genio

doi:10.1007/s10875-006-9007-5

Cited by 19 publications

(11 citation statements)

References 46 publications

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“…In contrast, the presence of anti-TIM-3 mAb enhanced IFN-␥ secretion in treated MS patients (glatiramer acetate, n ϭ 2; IFN-␤, n ϭ 5). These observations confirm results from a recent study that similarly evaluated spontaneous ex vivo apoptosis of T cells present in patients with MS (28).…”

Section: Reduced Tim-3 Expression Can Explain Lack Of Tim-3 Immunoregsupporting

confidence: 90%

Lack of TIM-3 Immunoregulation in Multiple Sclerosis

Yang

Anderson

Kuchroo

et al. 2008

The Journal of Immunology

114

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Multiple sclerosis (MS) is an inflammatory disease of the CNS white matter associated with T cell infiltrates and alterations of immune functions that can be measured in the peripheral immune system. TIM-3 has been identified as a central regulator of IFN-γ-secreting type 1 Th (Th1) cells and immune tolerance. In this study, using a newly generated mAb against human TIM-3, we examined TIM-3 function on ex vivo CD4+ T cells isolated from the circulation of healthy subjects and patients with MS. Blocking TIM-3 during T cell stimulation significantly enhanced IFN-γ secretion in control subjects but had no effect in untreated patients with MS, demonstrating a defect in TIM-3 immunoregulation. Treatment with glatiramer acetate or IFN-β reversed this functional defect. Reduced levels and altered kinetics of T cell TIM-3 expression, which was restored in treated patients, is one mechanism that can explain the loss of TIM-3 regulation of T cell function in untreated patients with MS. These data provide functional, mechanistic data for dysregulated TIM-3 immunoregulation in a human autoimmune disease and suggest that approved therapies for the treatment of MS may function in part by restoring TIM-3 immunoregulation of T cell function.

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Section: Reduced Tim-3 Expression Can Explain Lack Of Tim-3 Immunoregsupporting

confidence: 90%

Lack of TIM-3 Immunoregulation in Multiple Sclerosis

Yang

Anderson

Kuchroo

et al. 2008

The Journal of Immunology

114

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“…Organ-specific or systemic immune system-mediated diseases are characterized by the involvement of circulating lymphocytes [14,15,16]. These findings would support the hypothesis of alterations in circulating T cells from nonallergic asthmatic patients.…”

Section: Introductionmentioning

confidence: 56%

“…PB mononuclear cells (PBMC) were recovered via Ficoll-Hypaque density gradient centrifugation (Lymphoprep™; Axis-Shield, Oslo, Norway) using the Boyüm method [19]. PBMC were resuspended in RPMI 1640 medium (BioWhittaker Products, Verviers, Belgium) and added to 10% heat-activated fetal calf serum, 25 m M Hepes, and a 1% antibiotic mix (penicillin-streptomycin) (both from BioWhittaker Products) [14]. …”

Section: Methodsmentioning

confidence: 99%

Abnormal Chemokine Receptor Profile on Circulating T Lymphocytes from Nonallergic Asthma Patients

Barbarroja-Escudero

Prieto-Martín

Monserrat-Sanz

et al. 2014

Int Arch Allergy Immunol

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Background: T lymphocytes are involved in the pathogenesis of nonallergic asthma. The objective of this study was to characterize the subset distribution and pattern of chemokine receptor expression in circulating T lymphocyte subsets from nonallergic asthma patients. Methods: Forty stable nonallergic asthma patients and 16 sex- and age-matched healthy donors were studied. Twelve patients did not receive inhaled steroids (untreated patients), 16 received 50-500 μg b.i.d. of inhaled fluticasone propionate (FP) (standard-dose patients), and 12 received over 500 μg b.i.d. of inhaled FP (high-dose patients) for at least 12 months prior to the beginning of this study and were clinically well controlled. Flow cytometry was performed using a panel of monoclonal antibodies (4 colors). Results: Nonallergic asthma patients treated with high doses of inhaled FP showed a significant reduction in the percentages of CD3+ T lymphocytes compared to healthy controls. Untreated patients showed a significant increase in CCR6 expression in CD8+CD25+ and CD8+CD25+bright T cells compared to healthy controls. The results were similar for CXCR3 and CCR5 expression. In patients treated with standard doses of FP, CCR5 expression was significantly increased in CD3+ T lymphocytes relative to healthy controls. Conclusions: The different groups of clinically stable nonallergic asthmatic patients showed distinct patterns of alterations in subset distribution as well as CCR6, CXCR3, and CCR5 expression on circulating T lymphocytes.

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“…However, similar effects may act at the inflammatory effector ( i.e. lymphocyte) level, affecting the control of apoptosis, which has been also involved in MS pathogenesis [5].…”

Section: Introductionmentioning

confidence: 99%

Search for Cellular Stress Biomarkers in Lymphocytes from Patients with Multiple Sclerosis: A Pilot Study

Mazzini

Lisa

et al. 2012

PLoS ONE

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Multiple Sclerosis (MS) is a chronic disease of the central nervous system, the etiology of which, although not completely known, involves inflammation and autoimmunity. In the present study we aimed at identifying molecular markers of apoptosis, cellular stress and DNA damage in isolated peripheral blood mononuclear cells (PBMCs) of MS patients. The analysis was carried on 19 relapsing-remitting untreated MS patients and 13 healthy individuals. We investigated the emergency-driven synthesis of poly(ADP-ribose) (PAR), the expression level of the constitutive enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and the DNA damage-induced phosphorylation of histone H2AX. PAR accumulation, PARP-1 and phosphorylated H2AX (γH2AX) were detected by immunofluorescence experiments on PBMCs isolated from 19 patients and 13 healthy volunteers. Our results show for the first time a net increased amount in PAR and γH2AX in MS patients compared to healthy individuals. Patients were further subdivided in three groups, according to the neuroimaging (MRI)-based classification of disease phase. Remarkably, we found a positive correlation between the level of γH2AX and MS aggressiveness. In addition, apoptosis in PBMCs was monitored by flow cytometry of both phosphatidylserine exposure (revealed by Annexin V-FITC labeling) and membrane permeability to propidium iodide. Our observations provide the evidence that the number of apoptotic cells was significantly higher in patients compared to healthy individuals, thus suggesting that apoptosis could affect MS lymphocyte function.

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Increased Spontaneous Ex Vivo Apoptosis and Subset Alterations in Peripheral Blood T Cells from Patients with Multiple Sclerosis

Cited by 19 publications

References 46 publications

Lack of TIM-3 Immunoregulation in Multiple Sclerosis

Lack of TIM-3 Immunoregulation in Multiple Sclerosis

Abnormal Chemokine Receptor Profile on Circulating T Lymphocytes from Nonallergic Asthma Patients

Search for Cellular Stress Biomarkers in Lymphocytes from Patients with Multiple Sclerosis: A Pilot Study

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