Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome

Vries, Roos M. van der Vuurst de; Mescheriakova, Julia; Runia, Tessel F.; Jafari, Naghmeh; Siepman, Theodora A. M.; Hintzen, Rogier Q.

doi:10.1001/jamaneurol.2016.4997

Cited by 39 publications

(42 citation statements)

References 36 publications

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“…In order to further justify the relevance of the added proteins as potential biomarkers, we proceeded to study three secreted proteins that our model predicted to be differentially expressed in the MS dataset (Annexin A1, sCD40L and sCD27). Notably, these proteins have been associated with MS previously [22,23,25]. We analysed if cerebrospinal fluid (CSF) levels of these proteins related to clinical outcome and immunomodulatory treatment in two independent cohorts, namely newly diagnosed MS patients (clinically isolated syndrome (CIS) and relapsing/remitting MS, n=41) vs healthy controls (HC, n=23), and response to Natalizumab treatment in relapsing remitting MS patients (see supplementary notes, n=16).…”

Section: Applying the Model To Clinical Datasets Revealed Potential Bmentioning

confidence: 99%

A validated strategy to infer protein biomarkers from RNA-Seq by combining multiple mRNA splice variants and time-delay

Magnusson

Rundquist

Kim

et al. 2019

Preprint

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BackgroundProfiling of mRNA expression is an important method to identify biomarkers but complicated by limited correlations between mRNA expression and protein abundance. We hypothesised that these correlations could be improved by mathematical models based on measuring splice variants and time delay in protein translation. MethodsWe characterised time-series of primary human naïve CD4 + T cells during early T-helper type 1 differentiation with RNA-sequencing and mass-spectrometry proteomics. We then performed computational time-series analysis in this system and in two other key human and murine immune cell types. Linear mathematical mixed time-delayed splice variant models were used to predict protein abundances, and the models were validated using out-of-sample predictions. Lastly, we re-analysed RNA-Seq datasets to evaluate biomarker discovery in five T-cell associated diseases, validating the findings for multiple sclerosis (MS) and asthma. ResultsThe new models demonstrated median correlations of mRNA-to-protein abundance of 0.79-0.94, significantly out-performing models not including the usage of multiple splice variants and time-delays, as shown in cross-validation tests. Our mathematical models provided more differentially expressed proteins between patients and controls in all five diseases. Moreover, analysis of these proteins in asthma and MS supported their relevance. One marker, sCD27, was clinically validated in MS using two independent cohorts, for treatment response and prognosis. ConclusionOur splice variant and time-delay models substantially improved the prediction of protein abundance from mRNA data in three immune cell-types. The models provided valuable biomarker candidates, which were validated in clinical studies of MS and asthma. We propose that our strategy is generally applicable for biomarker discovery.MG initiated and supervised the study. RM and OR performed bioinformatics analyses, and RM performed the modelling. These analyses were led by MG, CA, JT, and DGC. OR performed experimental work on T-cell differentiation, which were supervised by CEN, MCJ, JE and MB. MJK and CHN performed the proteomics analysis, which was supervised by MSK. FP and JM recruited patients and collected clinical material, and SH performed and analysed the biomarker validation assays, which were led by IK, MCJ, and JE. All authors contributed to and approved the final draft for publication. mRNA expression levels. Mol Biosyst 2009, 5: 1512-26. 7. Vogel C, Marcotte EM: Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 2012, 13: 227-32. 8. Liu Y, Beyer A, Aebersold R: On the Dependency of Cellular Protein Levels on mRNA Abundance. Cell 2016, 165: 535-50. 9. Zhao J, Qin B, Nikolay R, Spahn CMT, Zhang G: Translatomics: The Global View of Translation. Int J Mol Sci 2019, 20. 10. Wethmar K, Smink JJ, Leutz A: Upstream open reading frames: molecular switches in (patho)physiology. Bioessays 2010, 32: 885-93. 11. Floor SN, Doudna JA: Tunable protein synthesi...

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Section: Applying the Model To Clinical Datasets Revealed Potential Bmentioning

confidence: 99%

A validated strategy to infer protein biomarkers from RNA-Seq by combining multiple mRNA splice variants and time-delay

Magnusson

Rundquist

Kim

et al. 2019

Preprint

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“… 14 In a recent study, high sCD27 levels in CSF associate with MS diagnosis and disease course in adult patients with clinically isolated syndromes (CISs). 15 …”

Section: Introductionmentioning

confidence: 99%

T-cell activation marker sCD27 is associated with clinically definite multiple sclerosis in childhood-acquired demyelinating syndromes

et al. 2018

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Background:Cerebrospinal fluid (CSF) levels of T-cell activation marker soluble CD27 (sCD27) are associated with subsequent disease activity after a first attack of suspected MS in adults. The predictive value for disease course in children with acquired demyelinating syndromes (ADS) is unknown.Objectives:To assess the predictive value of sCD27 levels for clinically definite multiple sclerosis (CDMS) diagnosis in childhood ADS.Methods:Children <18 years with a first demyelinating event were prospectively included and followed. Soluble CD27 was determined in CSF using an enzyme-linked immunosorbent assay (ELISA). Cox regression analyses were used to calculate hazard ratios (HRs) for CDMS.Results:A total of 94 ADS children were included (ADS with encephalopathy (ADS+) n = 33 and ADS without encephalopathy (ADS–) n = 61). Of the 61 ADS– children, 21 (48%) were diagnosed with CDMS during follow-up. At baseline, sCD27 levels were higher in patients with a future CDMS diagnosis (n = 29) than in monophasic ADS+ (n = 30), monophasic ADS– (n = 28) and relapsing non-MS patients (n = 7; p < 0.001). In ADS– patients, sCD27 was associated with CDMS (HR = 1.8 per 100 U/mL increase in sCD27 levels, p = 0.031), after adjustments for age, oligoclonal bands and the presence of dissemination in space on baseline magnetic resonance imaging (MRI).Conclusion:CSF sCD27 levels at first attack of demyelination were associated with CDMS diagnosis in children. This makes sCD27 a potential clinically relevant quantitative marker when performing routine CSF diagnostics.

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“…CSF sCD27 of patients with a clinically isolated syndrome is associated with MS diagnosis and a high relapse rate [16]. MS patients with more active disease have significantly higher levels of CSF sCD27 than subjects with quiescent disease, and patients with a higher EDSS score show an increased CSF sCD27 concentration [11, 12].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Level of Soluble CD27 Is Associated with Disease Severity in Neuromyelitis Optica Spectrum Disorder

Liu¹,

Zhong²,

Liu³

et al. 2018

Neuroimmunomodulation

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Object: CD27 belongs to the tumor necrosis factor receptor family and is constitutively expressed on T cells. The concentration of cerebrospinal fluid (CSF) soluble (s)CD27 is elevated in patients with multiple sclerosis (MS). However, whether the level of CSF sCD27 is elevated in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. The aim of this study was to measure the CSF concentration of sCD27 and to determine its relationship with NMOSD disease activity. Methods: CSF CXCL13 was measured by ELISA in neuromyelitis optica (NMO) (n = 31) and MS (n = 23) patients and in controls (CTLs) (n = 22). Results: The concentration of sCD27 was higher in the NMO group than in the MS (p = 0.082) and CTL (p = 0.002) groups, and there was a positive correlation with CSF IL-6 (p = 0.000) and a negative correlation with IL-10 (p = 0.073). In the NMO group, patients with higher sCD27 concentrations exhibited worse disease disability in their CSF (p = 0.006). Moreover, the sCD27 concentrations had a significantly positive correlation with the level of CSF total protein (p = 0.030). Furthermore, the patients positive for AQP4-IgG (n = 26) seemed to have higher levels of sCD27 in their CSF (p = 0.069) than those negative for AQP4-IgG (n = 5). Conclusions: We revealed that the level of CSF sCD27 was elevated in NMOSD and correlated with NMOSD disease activity.

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Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome

Cited by 39 publications

References 36 publications

A validated strategy to infer protein biomarkers from RNA-Seq by combining multiple mRNA splice variants and time-delay

A validated strategy to infer protein biomarkers from RNA-Seq by combining multiple mRNA splice variants and time-delay

T-cell activation marker sCD27 is associated with clinically definite multiple sclerosis in childhood-acquired demyelinating syndromes

Cerebrospinal Fluid Level of Soluble CD27 Is Associated with Disease Severity in Neuromyelitis Optica Spectrum Disorder

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