Biomarkers for Multiple Sclerosis

Tomioka, Ryo; Matsui, Makoto

doi:10.2169/internalmedicine.53.1246

Cited by 39 publications

(32 citation statements)

References 33 publications

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“…In clinical practice, a severe immune inhibition is not very common in patients. On the contrary, the immune system of patients with autoimmune diseases is sometimes in an active state, such as an increase in Th1, CD4 + , and CD25 + T cells [42]. Increased numbers and activation of microglia/macrophages have been also reported [43].…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of interleukin 7 receptor (IL-7R) contributes to central nervous system demyelination

et al. 2017

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Interleukin 7 receptor (IL-7R) has been associated with the pathogenesis of multiple sclerosis (MS), though the mechanisms are not clear. Because myelin expression is highly conserved between zebrafish and mammals, zebrafish have become an ideal model for studying demyelination. We used a transgenic (Tg; mbp:nfsB-egfp) zebrafish line in which oligodendrocytes expressed green fluorescent protein (GFP) from the larval stage to adulthood. Exposing adult transgenic zebrafish to metronidazole induced demyelination that resembled the morphological changes associated with the early stages of MS. The metronidazole-induced demyelination was confirmed by magnetic resonance imaging (MRI) for the first time. Microarray analysis revealed down-regulation of IL-7R during demyelination. Targeted knockdown of IL-7R demonstrated that IL-7R is essential for myelination in embryonic and larval zebrafish. Moreover, IL-7R down-regulation induced signaling via the JAK/STAT pathway leading to apoptosis in oligodendrocytes. These findings contribute to our understanding of the role of IL-7R in demyelination, and provide a rationale for the development of IL-7R-based therapies for MS and other demyelinating diseases.

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Section: Discussionmentioning

confidence: 99%

Down-regulation of interleukin 7 receptor (IL-7R) contributes to central nervous system demyelination

et al. 2017

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“…Non-invasive specific monitoring of demyelination and remyelination could provide clinically-important information on disease progression and treatment efficacy. Although the development of such biomarkers has come a long way (Galvin et al, 1976), it is still a vast area of research (Filippi et al, 2014; Tomioka and Matsui, 2014). …”

Section: Introductionmentioning

confidence: 99%

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy

et al. 2016

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There is a need for accurate quantitative non-invasive biomarkers to monitor myelin pathology in vivo and distinguish myelin changes from other pathological features including inflammation and axonal loss. Conventional MRI metrics such as T2, magnetization transfer ratio and radial diffusivity have proven sensitivity but not specificity. In highly coherent white matter bundles, compartment-specific white matter tract integrity (WMTI) metrics can be directly derived from the diffusion and kurtosis tensors: axonal water fraction, intra-axonal diffusivity, and extra-axonal radial and axial diffusivities. We evaluate the potential of WMTI to quantify demyelination by monitoring the effects of both acute (6 weeks) and chronic (12 weeks) cuprizone intoxication and subsequent recovery in the mouse corpus callosum, and compare its performance with that of conventional metrics (T2, magnetization transfer, and DTI parameters). The changes observed in vivo correlated with those obtained from quantitative electron microscopy image analysis. A 6-week intoxication produced a significant decrease in axonal water fraction (p < 0.001), with only mild changes in extra-axonal radial diffusivity, consistent with patchy demyelination, while a 12-week intoxication caused a more marked decrease in extra-axonal radial diffusivity (p = 0.0135), consistent with more severe demyelination and clearance of the extra-axonal space. Results thus revealed increased specificity of the axonal water fraction and extra-axonal radial diffusivity parameters to different degrees and patterns of demyelination. The specificities of these parameters were corroborated by their respective correlations with microstructural features: the axonal water fraction correlated significantly with the electron microscopy derived total axonal water fraction (ρ = 0.66; p = 0.0014) but not with the g-ratio, while the extra-axonal radial diffusivity correlated with the g-ratio (ρ = 0.48; p = 0.0342) but not with the electron microscopy derived axonal water fraction. These parameters represent promising candidates as clinically feasible biomarkers of demyelination and remyelination in the white matter.

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“…Among them, CCL2 and CCL5 are produced by various cell types in the brain, such as neurons, astrocytes, and microglia (15,20), and are suggested to be involved in viral and autoimmune inflammatory neurological disorders (1,13). Previous infection with Epstein-Bar virus may contribute to the development of multiple sclerosis (17), and elevated levels of CCL2 and CCL5 are associated with the activity of this disease (3,29).…”

Section: Discussionmentioning

confidence: 99%

<b>Gnetin C suppresses double-stranded RNA-induced C-C motif chemokine ligand 2 (CCL2) and CCL5 production by inhibiting Toll-like receptor 3 signaling </b><b>pathway </b>

et al. 2018

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The innate immune system is a prerequisite for biophylactic ability, but its dysregulation can cause inflammatory and autoimmune diseases. To determine a safe method of controlling inflammatory reactions in the brain, we examined the effects of gnetin C, a natural resveratrol dimer, on CC motif chemokine ligand 2 (CCL2) and CCL5 (pro-inflammatory chemokines) production observed after treatment with polyinosinic-polycytidylic acid [poly IC; a synthetic analog of dsRNA as a Toll-like receptor 3 (TRL3) ligand, 30 μg/mL] in cultured human astrocytoma U373MG and neuroblastoma SH-SY5Y cells. The addition of gnetin C (10 μM) to the media moderately reduced the CCL2 production and markedly suppressed CCL5 production in both cells. In the TLR3-interferon (IFN)-β-phosphorylated-STAT1 (signal transducer and activator of transcription protein 1)-RIG-I (retinoic acid-inducible gene-I) pathway that mediates CCL2 and CCL5 production, gnetin C first inhibits IFN-β expression in SH-SY5Y cells and primarily inhibits STAT1 phosphorylation in U373MG cells. In any case, gnetin C attenuated the dsRNA-activated TLR3 signaling resulting in CCL2 and CCL5 production, thus, may be useful for controlling TLR3-mediated inflammation in the brain.

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Biomarkers for Multiple Sclerosis

Cited by 39 publications

References 33 publications

Down-regulation of interleukin 7 receptor (IL-7R) contributes to central nervous system demyelination

Down-regulation of interleukin 7 receptor (IL-7R) contributes to central nervous system demyelination

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy

<b>Gnetin C suppresses double-stranded RNA-induced C-C motif chemokine ligand 2 (CCL2) and CCL5 production by inhibiting Toll-like receptor 3 signaling </b><b>pathway </b>

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