High Interferon-γ Uniquely in Vδ1 T Cells Correlates with Markers of Inflammation and Axonal Damage in Early Multiple Sclerosis

Singh, Avadhesh Kumar; Novakova, Lenka; Axelsson, Markus; Malmeström, Clas; Zetterberg, Henrik; Lycke, Jan; Cardell, Susanna

doi:10.3389/fimmu.2017.00260

Cited by 17 publications

(19 citation statements)

References 57 publications

(59 reference statements)

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“…We recently reported findings of a genome-wide copy number variation (CNV) association study where deletion-type CNVs at TCRα and γ loci greatly enhanced susceptibility to MS ( 20 ). Given that deletion-type CNV at the TCRα locus also covers TCRδ genes ( 5 ), we hypothesized that a deviation in TCR γδ gene rearrangement contributes to the pathogenesis of MS. Only two previous reports have described an increase of peripheral blood Vδ1 + γδ T cells in Caucasian MS patients ( 21 , 22 ); however, neither study directly measured Vδ2 + γδ T cells. No previous studies have reported the peripheral blood Vδ and Vγ repertoires in MS, nor their relationship with αβ T cells.…”

Section: Introductionmentioning

confidence: 86%

Association of Decreased Percentage of Vδ2+Vγ9+ γδ T Cells With Disease Severity in Multiple Sclerosis

et al. 2018

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We recently reported that deletion-type copy number variations of the T cell receptor (TCR) γ, α, and δ genes greatly enhanced susceptibility to multiple sclerosis (MS). However, the effect of abnormal TCR γδ gene rearrangement on MS pathogenesis remains unknown. In the present study, we aimed to clarify γδ TCR repertoire alterations and their relationship to clinical and immunological parameters in MS patients by comprehensive flow cytometric immunophenotyping. Peripheral blood mononuclear cells obtained from 30 untreated MS patients in remission and 23 age- and sex-matched healthy controls (HCs) were stained for surface markers and intracellular cytokines after stimulation with phorbol 12-myristate 13-acetate and ionomycin, and analyzed by flow cytometry. MS patients showed significantly decreased percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells (pcorr = 0.0297 and pcorr = 0.0288, respectively) and elevated Vδ1/Vδ2 ratios compared with HCs (p = 0.0033). The percentages of interferon (IFN)-γ+Vδ2+ and interleukin (IL)-17A+IFN-γ+Vδ2+ cells in γδ T cells, as well as IFN-γ+ cells in Vδ2+ γδ T cells, were significantly lower in MS patients than in HCs (pcorr < 0.0009, pcorr = 0.0135, and pcorr = 0.0054, respectively). The percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells were negatively correlated with both the Expanded Disability Status Scale score (r = −0.5006, p = 0.0048; and r = −0.5040, p = 0.0045, respectively) and Multiple Sclerosis Severity Score (r = –0.4682, p = 0.0091; and r = –0.4706, p = 0.0087, respectively), but not with age at disease onset, disease duration, or annualized relapse rate. In HCs, the percentages of Vδ2+ and Vδ2+Vγ9+ cells of total CD3+ T cells had strong positive correlations with the percentage of CD25+CD127low/− cells in CD4+ T cells (r = 0.7826, p < 0.0001; and r = 0.7848, p < 0.0001, respectively), whereas such correlations were totally absent in MS patients. These findings suggest that decreased Vδ2+Vγ9+ γδ T cells are associated with disability in MS. Therefore, the Vδ1/Vδ2 ratio might be a candidate biomarker for predicting disease severity in MS.

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Section: Introductionmentioning

confidence: 86%

Association of Decreased Percentage of Vδ2+Vγ9+ γδ T Cells With Disease Severity in Multiple Sclerosis

et al. 2018

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“…The prevailing hypothesis about the pathophysiology of MS contends that the myelin sheath of CNS axons is targeted, and ultimately destroyed, by a macrophage mediated, adaptive-immune cell driven autoimmune process. While the factors that initiate CNS autoimmunity are still unclear, the resulting inflammation and loss of myelin that characterize the acute MS lesion are known to occur through the operation of lymphocytes, macrophages, microglial cells and potentially astrocytes [2][3][4][5][6][7].…”

Section: Pathophysiology Of Msmentioning

confidence: 99%

Temperature sensitivity in multiple sclerosis: An overview of its impact on sensory and cognitive symptoms

et al. 2018

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Multiple sclerosis (MS) is an autoimmune neurodegenerative disease characterized by demyelination of the central nervous system (CNS). The exact cause of MS is still unknown; yet its incidence and prevalence rates are growing worldwide, making MS a significant public health challenge. The heterogeneous distribution of demyelination within and between MS patients translates in a complex and varied array of autonomic, motor, sensory and cognitive symptoms. Yet a unique aspect of MS is the highly prevalent (60-80%) temperature sensitivity of its sufferers, where neurological symptoms are temporarily exacerbated by environmental-or exercise-induced increases (or decreases) in body temperature. MS temperature sensitivity is primarily driven by temperature-dependent slowing or blocking of neural conduction within the CNS due to changes in internal (core) temperature; yet changes in skin temperature could also contribute to symptom exacerbation (e.g. during sunlight and warm ambient exposure). The impact of temperature sensitivity, and particularly of increases in core temperature, on autonomic (e.g. thermoregulatory/cardiovascular function) and motor symptoms (e.g. fatigue) is well described. However, less attention has been given to how increases (and decreases) in core and skin temperature affect sensory and cognitive symptoms. Furthermore, it remains uncertain whether changes in skin temperature alone could also trigger worsening of symptoms. Here we review the impact of temperature sensitivity on MS sensory and cognitive function and discuss additional factors (e.g. changes in skin temperature) that potentially contribute to temperature-induced worsening of symptoms in the absence of alteration in core temperature.

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“…) and may be involved in the early phase of the immunopathogenesis of RRMS (Singh et al . ). Furthermore, the CSF carries antigens that activate immune cells.…”

Section: Resultsmentioning

confidence: 97%

“…To stain for the intracellular cytokine IFN‐γ, PBMC were stimulated with phorbol 12‐myristate 13‐acetate (50 ng/mL) and ionomycin (500 ng/mL) (Sigma‐Aldrich, Saint Louis, MO, USA) in the presence of Brefeldin A (Cat# 00‐4506‐51; eBioscience, San Diego, CA, USA) for 4 h at 37°C, as described before (Singh et al . ). Stimulated cells were first incubated with Fc receptor binding inhibitor (Cat# 14‐9161‐73, RRID: AB_468582; eBioscience, San Diego, CA, USA), and then stained with surface monoclonal antibodies (mAbs) for 30 min at 4°C using the following fluorochrome‐conjugated anti‐human mAbs: anti‐CD3ε (Cat# 317330, RRID: AB_2563507), anti‐CD19 (Cat# 302218, RRID: AB_314248), anti‐TCRγδ (Cat# 331212, RRID: AB_1089214) (all from BioLegend, San Diego, CA, USA), and anti‐TCR Vδ1 (Cat# TCR2730, RRID: AB_223624; Thermo Fisher Scientific, Rockford, IL, USA).…”

Section: Methodsmentioning

confidence: 97%

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Sulfatide isoform pattern in cerebrospinal fluid discriminates progressive MS from relapsing‐remitting MS

Novakova

Singh

Axelsson

et al. 2018

Journal of Neurochemistry

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Several biomarkers including proteins and lipids have been reported in MS cerebrospinal fluid (CSF), reflecting different aspects of the pathophysiology particularly of relapsing-remitting MS (RRMS). Sulfatide, abundant in the myelin sheath and a proposed target for autoimmune attack in MS, has been reported altered in MS CSF. Here, we investigated the potential of CSF sulfatide and its isoforms as biomarkers in MS. A highly sensitive and quantitative mass spectrometry method was employed to determine levels of sulfatide isoforms in CSF from RRMS and progressive MS (PMS) patients, and healthy donors (HD). We demonstrate that levels of total CSF sulfatide and C24:1, C26:1, and C26:1-OH isoforms were significantly increased in PMS compared with RRMS patients and HD, while C23:0-OH was significantly decreased in CSF from PMS patients compared to the other two groups. Multivariate discriminant analysis showed that CSF sulfatide isoform pattern in PMS patients was distinct and non-overlapping with that of RRMS patients and HD. Sulfatide levels did not correlate with tested biomarkers or clinical parameters. The results suggest that CSF sulfatide isoform levels may be used to discriminate the phenotype of MS and might play a role in the progression of the disease.

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High Interferon-γ Uniquely in Vδ1 T Cells Correlates with Markers of Inflammation and Axonal Damage in Early Multiple Sclerosis

Cited by 17 publications

References 57 publications

Association of Decreased Percentage of Vδ2+Vγ9+ γδ T Cells With Disease Severity in Multiple Sclerosis

Association of Decreased Percentage of Vδ2+Vγ9+ γδ T Cells With Disease Severity in Multiple Sclerosis

Temperature sensitivity in multiple sclerosis: An overview of its impact on sensory and cognitive symptoms

Sulfatide isoform pattern in cerebrospinal fluid discriminates progressive MS from relapsing‐remitting MS

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