Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Trend, Stephanie; Jones, Anderson P.; Geldenhuys, Sian; Byrne, Scott N.; Fabis-Pedrini, Marzena J.; Nolan, David; Booth, David R.; Carroll, William M.; Lucas, Robyn; Kermode, Allan G.; Hart, Prue H.

doi:10.3390/ijms18061277

Cited by 8 publications

(10 citation statements)

References 24 publications

(27 reference statements)

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Section: Resultsmentioning

confidence: 89%

“…Earlier work from this laboratory investigated differences in PBMC subsets between HC (a different cohort than those reported here) and those with CIS ( 17 , 18 ). The frequencies of transitional B cells and CD1c + B cells were increased in people with CIS compared with HC ( 18 ). Treg and Tfr cells were categorized into different fractions according to FoxP3 and CD45RA expression ( 17 ), which is a more advanced dissection of Tregs originally described by Sakaguchi and colleagues ( 23 ), as well as by their expression of Helios, a key transcription factor associated with Treg functions ( 24 ).…”

Section: Resultsmentioning

confidence: 89%

“…B cell, Treg, and Tfr subset frequencies and Treg/Tfr levels of Helios expression in the blood samples from 18 of the 20 individuals in the CIS cohort were previously reported ( 17 , 18 ). In this study, data from two additional blood donors with CIS were included and analyzed as previously described.…”

Section: Methodsmentioning

confidence: 80%

“…Peripheral venous blood was collected from individuals with CIS and extensive phenotypes of peripheral blood mononuclear cells (PBMCs) were obtained by multicolor flow cytometry as previously described ( 17 , 18 ). Blood was also collected in Vacutainer SST tubes (Becton Dickinson, North Ryde, NSW, Australia) and serum separated by centrifugation at 800 × g for 10 min, then stored at −80°C until batch analyses.…”

Section: Methodsmentioning

confidence: 99%

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Higher Serum Immunoglobulin G3 Levels May Predict the Development of Multiple Sclerosis in Individuals With Clinically Isolated Syndrome

et al. 2018

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Clinically isolated syndrome (CIS) is a first episode of neurological symptoms that may precede a diagnosis of multiple sclerosis (MS). Therefore, studying individuals with CIS may lead to breakthroughs in understanding the development and pathogenesis of MS. In this study, serum levels of immunoglobulin (Ig)G, IgA, IgM, and IgG1–4 were measured in 20 people with CIS and compared with those in 10 healthy controls (HC) and 8 people with MS. Serum Ig levels in individuals with CIS were compared with (a) the time to their conversion from CIS to MS, (b) serum levels of antibodies to Epstein–Barr virus, (c) frequencies of T regulatory (Treg), T follicular regulatory (Tfr), and B cell subsets, and (d) Treg/Tfr expression of Helios. Serum IgG, IgM, and IgG2 levels were significantly lower in people with CIS than HC, and IgG, IgM, and IgG1 levels were significantly lower in people with CIS than MS. After adjusting for age, sex, and serum 25(OH) vitamin D3 [25(OH)D] levels, CIS was associated with lower serum levels of IgG and IgG2 compared with HC (p = 0.001 and p < 0.001, respectively). People with MS had lower IgG2 levels (p < 0.001) and IgG2 proportions (%IgG; p = 0.007) compared with HC. After adjusting for age, sex, and 25(OH)D, these outcomes remained, in addition to lower serum IgA levels (p = 0.01) and increased IgG3 levels (p = 0.053) in people with MS compared with HC. Furthermore, serum from people with MS had increased proportions of IgG1 and IgG3 (p = 0.03 and p = 0.02, respectively), decreased proportions of IgG2 (p = 0.007), and greater ratios of “upstream” to “downstream” IgG subclasses (p = 0.001) compared with HC. Serum IgG3 proportions (%IgG) from people with CIS correlated with the frequency of plasmablasts in peripheral blood (p = 0.02). Expression of Helios by Treg and Tfr cell subsets from individuals with CIS correlated with levels of serum IgG2 and IgG4. IgG3 levels and proportions of IgG3 (%IgG) in serum at CIS diagnosis were inversely correlated with the time until conversion to MS (p = 0.018 and p < 0.001, respectively), suggesting they may be useful prognostic markers of individuals with CIS who rapidly convert to MS.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

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Higher Serum Immunoglobulin G3 Levels May Predict the Development of Multiple Sclerosis in Individuals With Clinically Isolated Syndrome

et al. 2018

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“…Until today, there is very little known about how responsiveness to treatment can be predicted. One small current study aimed to identify the blood signature of CIS patients to provide clues for potential immunomodulatory therapies; increased levels of transitional B cells were found in CIS patients compared to healthy donors [ 2 ]. This small study emphasizes the possible important role of B cells not only for individuals suffering from CIS, but also from MS.…”

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confidence: 99%

Advances in Multiple Sclerosis 2017

Göbel

Kleinschnitz

Meuth

2018

IJMS

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Multiple sclerosis (MS) is one of the most emerging fields in neurology. Recent pathophysiological insights have cleared the way for novel therapeutic strategies to combat disease aggravation. For instance, the B-cell depleting antibody ocrelizumab was recently approved for the treatment of relapsing-remitting (RRMS) and early primary progressive MS (PPMS). However, despite this progress, unmet medical necessities remain, especially for pediatric MS. Both new and more sophisticated therapeutic strategies and improved markers for predicting disease progression and/or treatment responses are still in demand.In the special issue "Advances in Multiple Sclerosis 2017", promising findings of this most prevalent neuroimmunological disease are depicted, covering different aspects of disease development and prediction, treatment options, and pathophysiological insights derived from both animal models and clinical studies.For instance, the search for (novel) biomarkers predicting disease progression and/or conversion from clinically isolated syndrome (CIS) to MS is still ongoing. Schwenkenbecher et al. recently described the critical role of intrathecal IgG synthesis and visual evoked potentials (VEPs) in this context [1]. If CIS patients presented unique oligoclonal bands in the cerebrospinal fluid (CSF), conversion to MS was more than twice as likely. While pathologic VEPs did not add further information to the conversion rate by patients with oligoclonal bands, they helped to predict the conversion rate in patients with optic neuritis and absent oligoclonal bands. To avoid or at least delay conversion from CIS to MS, an appropriate therapy must be chosen. Until today, there is very little known about how responsiveness to treatment can be predicted. One small current study aimed to identify the blood signature of CIS patients to provide clues for potential immunomodulatory therapies; increased levels of transitional B cells were found in CIS patients compared to healthy donors [2]. This small study emphasizes the possible important role of B cells not only for individuals suffering from CIS, but also from MS.Lehmann-Horn et al. recently reviewed the current knowledge of B cells in MS, including also their regulatory functions [3]. Nonetheless, further studies are needed to harness the evolving knowledge to improve the future efficacy and even safety of B cell-directed treatments. While the relevance of B cell-directed therapies in MS has to be seen in the next years, a clear strategy to increase the safety of highly effective therapy with natalizumab is still under development. There is growing concern regarding the risk of progressive multifocal leukoencephalopathy (PML), particularly after 24 doses and in patients that have previously received immunosuppressive drugs [4]. Nonetheless, clinical experiences are not homogenous, and there are no generally established guidelines so far. The same thing is true for the treatment of relapses following therapeutic plasma exchange as a second-line after a glucosteroid-unrespon...

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Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

et al. 2018

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ObjectivesClinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS.MethodsAs immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l‐tryptophan‐ and l‐arginine‐catabolising enzymes, indoleamine 2,3‐dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS. As one measure of cell function, cytokine mRNA levels were analysed directly ex vivo and in cells after culture for 4 h in the absence of regulatory factors in autologous serum.ResultsWhen measured directly ex vivo, the expression of IDO and ARG was greater in cells from patients with CIS and MS than cells from healthy controls. Although not linked to IDO and ARG expression, PBMCs from the CIS patients were characterised by low IL‐10 and TGFB mRNA levels and not by greater expression of proinflammatory cytokines. When the cells were cultured for 4 h without autologous serum, pro‐ and anti‐inflammatory cytokine mRNA levels positively correlated with IDO1 expression, and TGFB mRNA levels correlated with ARG1 expression.ConclusionHigher IDO and ARG expression in CIS and MS provides one sustained homeostatic mechanism to control MS‐associated inflammation. However, potent extrinsic mediators in serum may regulate immune cell function in CIS and associations between IDO, ARG and cytokine expression.

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Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI

Cited by 8 publications

References 24 publications

Higher Serum Immunoglobulin G3 Levels May Predict the Development of Multiple Sclerosis in Individuals With Clinically Isolated Syndrome

Higher Serum Immunoglobulin G3 Levels May Predict the Development of Multiple Sclerosis in Individuals With Clinically Isolated Syndrome

Advances in Multiple Sclerosis 2017

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

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