Immune cell-specific transcriptional profiling highlights distinct molecular pathways controlled by Tob1 upon experimental autoimmune encephalomyelitis

Didonna, Alessandro; Cekanaviciute, Egle; Oksenberg, Jorge R.; Baranzini, Sergio E.

doi:10.1038/srep31603

Cited by 9 publications

(8 citation statements)

References 34 publications

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“…Consistent with prior MS studies, genes associated with the SMAD/TGF-β1 signaling pathway were down-regulated in CSF plasmablast/plasma cells using both single-cell and bulk analyses (74). Furthermore, TOB1, a gene involved in the SMAD/TGF-β1 signaling pathway, was down-regulated in CSF plasmablast/plasma cells (75). Low TOB1 expression, previously only reported in T cells from MS subjects and here reported in B cells, has been associated with a higher risk of MS conversion from CIS to RRMS, and its ablation worsens disease severity in EAE models (76,77).…”

Section: Discussionsupporting

confidence: 48%

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

Ramesh

Schubert

Greenfield

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood–brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein–Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.

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Section: Discussionsupporting

confidence: 48%

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

Ramesh

Schubert

Greenfield

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

143

169

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“…For immunofluorescence staining, enzyme activity assays, and serum lactate levels, a subset of mice was killed at each time point (n = 3-6 CTRL, 3-6 W4, 3-6 W6, and 3-6 W6 + W6 recovery). For EAE induction, 8-wk-old C57BL/6J female mice were injected s.c. with 100 μg of myelin oligodendrocyte glycoprotein (MOG , in complete Freund's adjuvant (Difco Laboratories) (67). After immunization and 2 d later mice received 400 ng of pertussis toxin i.p.…”

Section: Discussionmentioning

confidence: 99%

Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Guglielmetti

Najac

Didonna

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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133

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Proinflammatory mononuclear phagocytes (MPs) play a crucial role in the progression of multiple sclerosis (MS) and other neurodegenerative diseases. Despite advances in neuroimaging, there are currently limited available methods enabling noninvasive detection of MPs in vivo. Interestingly, upon activation and subsequent differentiation toward a proinflammatory phenotype MPs undergo metabolic reprogramming that results in increased glycolysis and production of lactate. Hyperpolarized (HP) 13 C magnetic resonance spectroscopic imaging (MRSI) is a clinically translatable imaging method that allows noninvasive monitoring of metabolic pathways in real time. This method has proven highly useful to monitor the Warburg effect in cancer, through MR detection of increased HP [1-13 C]pyruvate-tolactate conversion. However, to date, this method has never been applied to the study of neuroinflammation. Here, we questioned the potential of 13 C MRSI of HP [1-13 C]pyruvate to monitor the presence of neuroinflammatory lesions in vivo in the cuprizone mouse model of MS. First, we demonstrated that 13 C MRSI could detect a significant increase in HP [1-13 C]pyruvate-to-lactate conversion, which was associated with a high density of proinflammatory MPs. We further demonstrated that the increase in HP [1-13 C]lactate was likely mediated by pyruvate dehydrogenase kinase 1 up-regulation in activated MPs, resulting in regional pyruvate dehydrogenase inhibition. Altogether, our results demonstrate a potential for 13 C MRSI of HP [1-13 C]pyruvate as a neuroimaging method for assessment of inflammatory lesions. This approach could prove useful not only in MS but also in other neurological diseases presenting inflammatory components.hyperpolarized 13 C MR spectroscopy | multiple sclerosis | neuroinflammation | metabolism | macrophages M ultiple sclerosis (MS) is a multifaceted disorder of the CNS and is one of the most common causes of neurological disability in young adults (1, 2). Cortical and white-matter demyelination occurs early in MS pathogenesis and has been associated with disease progression and subsequent cognitive impairment (3). In the vast majority of cases, demyelinating lesions present a high inflammatory component, with elevated density of activated microglia/macrophages (mononuclear phagocytes, MPs) (4-6). Importantly, evidence suggests that proinflammatory MPs are one of the most abundant sources of reactive oxygen species (7), which mediate demyelination and axonal injury (8). Due to their central role in MS pathogenesis, noninvasive imaging of proinflammatory MPs would be of high importance for monitoring progression and response to antiinflammatory therapeutic approaches.Several recent studies have demonstrated that, upon activation and differentiation toward a proinflammatory phenotype, MPs undergo metabolic reprogramming toward enhanced glucose uptake and increased glycolysis (9-14). As for the Warburg effect observed in cancer cells, this augmented glycolysis takes place under aerobic conditions and results in the...

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“…Increasingly more reports indicate that the TOB1 gene is associated with human immune-related disorders 33 . Low levels of TOB1 may promote an aberrant immune response and affect disease progression 34 .…”

Section: Discussionmentioning

confidence: 99%

Association between the SNPs of the TOB1 gene and gastric cancer risk in the Chinese Han population of northeast China

et al. 2018

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The TOB1 (ErbB-2,1) gene is an anti-proliferative factor that has the potential to regulate cell growth and encodes a member of the transducer of erbB-2/B-cell translocation gene protein. The association between the polymorphisms of the TOB1 gene and gastric cancer (GC) risk is still unclear. In this study, 506 GC cases and 548 healthy controls (HCs) were collected to evaluate the association between the eleven SNPs (rs35220381, rs12950561, rs7221352, rs61482741, rs9303568, rs34700818, rs12949115, rs9903822, rs12601477, rs11656976 and rs4626) of the TOB1 gene and GC risk in the population of northeast China. The results showed that there were significant associations of haplotype GCCTTGC, haplotype ATCTTGG, and haplotype GCCACGC with GC risk (P < 0.05, P < 0.001, and P <0.001, respectively). The association between rs12601477 GA+AA genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.53, 95% CI=1.05-2.22, P< 0.05). The association between rs4626 AG+GG genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.54, 95% CI = 1.03-2.28, P<0.05). The rs34700818 CT+TT genotypes were associated with a significantly increased risk of T3-T4 (CT+TT vs CC, adjusted OR=1.71, 95% CI= 1.01-2.88, P<0.05) and TNM stage II (CT+TT vs CC, adjusted OR=2.40, 95% CI =1.27-4.52, P<0.01). The rs61482741 CG+GG genotypes were also associated with a significantly increased risk of T3-T4 (CG+GG vs CC, adjusted OR=1.71, 95% CI = 1.01-2.88, P<0.05) and TNM stage II (CG+GG vs CC, adjusted OR=2.40, 95% CI=1.27-4.52, P<0.01). The results suggest that four SNPs (rs12601477, rs4626, rs34700818 and rs61482741) of the TOB1 gene play an important role in the occurrence and development of GC in the Chinese Han population of northeast China.

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Immune cell-specific transcriptional profiling highlights distinct molecular pathways controlled by Tob1 upon experimental autoimmune encephalomyelitis

Cited by 9 publications

References 34 publications

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Association between the SNPs of the TOB1 gene and gastric cancer risk in the Chinese Han population of northeast China

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Immune cell-specific transcriptional profiling highlights distinct molecular pathways controlled by Tob1 upon experimental autoimmune encephalomyelitis

Cited by 9 publications

References 34 publications

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

Association between the SNPs of the TOB1 gene and gastric cancer risk in the Chinese Han population of northeast China

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Hyperpolarized ¹³ C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model