MiR-126: a novel route for natalizumab action?

Meira, Maria; Sievers, Claudia; Hoffmann, Francine; Derfuss, Tobias; Kühle, Jens; Kappos, Ludwig; Lindberg, Raija L. P.

doi:10.1177/1352458514524998

Cited by 38 publications

(39 citation statements)

References 35 publications

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“…Previously miR-27a levels were shown to increase significantly in the plasma of stroke patients, and bioinformatics analysis linked the expression with inflammation-related events (Guo et al 2013). miR-126 is increased in MS patients during relapse and patients on interferon beta (IFN-β) therapy have reduced plasma levels of miR-126 (Meira et al 2014). Also miR-126 is implicated in Parkinson's pathology by dysregulating IGF/ PI3K signaling (Kim et al 2014).…”

Section: Discussionmentioning

confidence: 96%

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Targeted Stage-Specific Inflammatory microRNA Profiling in Urine During Disease Progression in Experimental Autoimmune Encephalomyelitis: Markers of Disease Progression and Drug Response

Singh

Deshpande

Salehiniya

et al. 2015

J Neuroimmune Pharmacol

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Recently, microRNAs (miRNAs) have been implicated in regulating neuroinflammatory and demyelinative responses in multiple sclerosis (MS) and its mouse model of experimental autoimmune encephalomyelitis (EAE). miRNAs have also been studied as biomarkers of disease pathology and drug-response in MS. However, no complete miRNA profiling at various stages of EAE disease has been examined, especially in the urine. We carried out a systematic analysis of miRNAs in the urine exosomes as well as in the plasma and spinal cord at pre-onset, onset and peak stages of EAE established in the chronic B6 mice model. For the first time, we provide evidence that urine exosomes can be a specific and sensitive source of miRNA biomarkers for all 3 stages of EAE disease. In a significant observation, we observed that miR-155-5p expression increased in urine exosomes, plasma and spinal cord 6 days before the onset of disease, suggesting its early involvement in the pathology of EAE disease. We also analyzed the effect of Glatiramer acetate (GA; copaxone) treatment, an approved treatment for MS patients, in modulating miRNA expression at the peak of EAE disease. We identified miR-155-5p, miR-27a-3p, miR-9-5p and miR-350-5p as putative GA-treatment responsive miRNA biomarkers. Since, EAE is a mainly CD4 cells mediated disease, we also examined the above set of miRNAs and found to be significantly altered in T cells polarized to Th1 and Th17 phenotype, similar to urine exosomes. Thus, urine exosome miRNAs hold the potential to be defined as novel accessible stage-specific biomarkers of EAE (MS) disease as well as treatment response.

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Section: Discussionmentioning

confidence: 96%

“…Of the selected miRNAs at the peak of the disease, miR-155-5p, miR27a-3p, miR-126a-5p and miR-350-3p were significantly downregulated by GA therapy. In fact, miR-126 is predicted to be the target of IFNβ therapy in MS patients (Meira et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Targeted Stage-Specific Inflammatory microRNA Profiling in Urine During Disease Progression in Experimental Autoimmune Encephalomyelitis: Markers of Disease Progression and Drug Response

Singh

Deshpande

Salehiniya

et al. 2015

J Neuroimmune Pharmacol

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“…However, miR-146a negatively regulates IL-6 [38]. Other studies have demonstrated modulation of miRNAs by MS therapies such as IFN-β and Natilizumab [39, 40]. …”

Section: Cytokine Regulation By Genetic Elementsmentioning

confidence: 99%

Seeking balance: Potentiation and inhibition of multiple sclerosis autoimmune responses by IL-6 and IL-10

2015

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The cytokines IL-6 and IL-10 are produced by cells of the adaptive and innate arms of the immune system and they appear to play key roles in genetically diverse autoimmune diseases such as relapsing remitting multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Whereas previous intense investigations focused on the generation of autoantibodies and their contribution to immune-mediated pathogenesis in these diseases more recent attention has focused on the roles of cytokines such as IL-6 and IL-10. In response to pathogens, antigen presenting cells (APC), including B cells, produce IL-6 and IL-10 in order to up- or down-regulate immune cell activation and effector responses. Evidence of elevated levels of the proinflammatory cytokine IL-6 has been routinely observed during inflammatory responses and in a number of autoimmune diseases. Our recent studies suggest that MS peripheral blood B cells secrete higher quantities of IL-6 and less IL-10 than B cells from healthy controls. Persistent production of IL-6, in turn, contributes to T cell expansion and the functional hyperactivity of APC such as MS B cells. Altered B cell activity can have a profound impact on resultant T cell effector functions. Enhanced signaling through the IL-6 receptor can effectively inhibit cytolytic activity, induce T cell resistance to IL-10-mediated immunosuppression and increase skewing of autoreactive T cells to a pathogenic Th17 phenotype. Our recent findings and studies by others support a role for the indirect attenuation of B cell responses by Glatiramer acetate (GA) therapy. Our studies suggest that GA therapy temporarily permits homeostatic regulatory mechanisms to be reinstated. Future studies of mechanisms underlying dysregulated B cell cytokine production could lead to the identification of novel targets for improved immunoregulatory therapies for autoimmune diseases.

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“…Dans l'optique du développement d'une médecine personnalisée et de traitements qui soient adaptés à chaque patient, une découverte intéressante a été que l'expression de miARN dérégulés dans la SEP peut être normalisée par la prise de certains médicaments. Des traitements (acétate de glatiramère, natalizumab, IFN-) modifient en effet les niveaux d'expression de diffé-rents miARN (miR-146a [54], miR-142-3p [54], miR-126 [55] et miR-17 [56]). Chaque patient pourrait être ainsi suivi en fonction du profil de miARN préalablement prédéfinis pour différents compartiments et, selon ce profil ou son évolution, l'utilisation d'une combinaison de traitements, déjà existants, pourrait être proposée.…”

Section: Th17unclassified

Les microARN

Jagot

Davoust

2017

Med Sci (Paris)

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> La sclérose en plaques (SEP) est une maladie auto-immune inflammatoire et démyélinisante dont l'étiologie reste mal connue. L'étude des microARN (miARN) apporte un éclairage nouveau sur les mécanismes physiopathologiques mis en jeu dans la SEP. Une signature miARN spéci-fique est observée tant au niveau cellulaire que dans les compartiments extracellulaires, chez les patients atteints de SEP, et dans le modèle de SEP développé chez l'animal, l'encéphalomyé-lite auto-immune expérimentale (EAE). Dans ce modèle, une association étroite a pu être mise en évidence entre la dérégulation des miARN et une modulation de la réponse immunitaire à l'origine d'un phénotype neuro-inflammatoire. La détec-tion quantitative des miARN circulants a-t-elle une valeur diagnostique ? Les miARN serontils les nouveaux biomarqueurs de la maladie ? C'est à ces questions que cette revue tente de répondre. < rait l'inflammation. De nombreuses études suggèrent en effet que la maturation et la fonction des lymphocytes Treg périphériques sont diminuées au cours de la SEP [2]. Il est probable que les lymphocytes B jouent également un rôle important dans la SEP, comme en témoigne la présence de bandes oligoclonales d'anticorps dans le liquide céphalo-rachidien (LCR) détectées par iso-électrofocalisation 1 chez plus de 95 % des patients atteints de SEP [3]. Les lymphocytes B infiltrent le SNC dès l'apparition d'un syndrome cliniquement isolé (symptômes présentés par les patients ayant leur première poussée inflammatoire de type SEP -myélite, névrite optique, etc.-, que celle-ci donne lieu à un diagnostic SEP -nécessitant une deuxième poussée de même type -ou non) [3]. Les cellules résidentes du SNC, dont les cellules microgliales (les macrophages résidents du SNC), participent également aux processus inflammatoires en lien avec la progression des lésions du tissu nerveux. Du point de vue clinique, la SEP est associée à des perturbations motrices, sensitives et cognitives qui aboutissent à un handicap plus ou moins sévère selon les profils évolutifs. Classiquement, on distingue deux formes de la maladie : celle où alternent des périodes de rechutes et de rémissions (forme rémittente ou RRMS pour relapsing remitting multiple sclerosis) et celle dite progressive (PPMS pour primary progressive multiple sclerosis), qui suit parfois une forme rémittente (SPMS pour secondary progressive multiple sclerosis), et au cours de laquelle les patients acquièrent progressivement un handicap irréversible sans phase de rémission. Malgré des différences phénoty-piques cliniques, la période qui s'écoule avant l'atteinte de certains niveaux d'incapacité et l'âge auquel ces niveaux sont atteints, sont similaires pour les patients présentant une PPMS ou une SPMS. En 1 La présence d'immunoglobulines d'isotype G (IgG) dans le LCR, due à un excès de production d'IgG dans le système nerveux central, peut être révélée par la technique d'iso-électrofocalisation.

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MiR-126: a novel route for natalizumab action?

Abstract: Our findings provided deeper insight into the mode of action of natalizumab, with possible implications for understanding both the effects of natalizumab on MS activity and its specific adverse event profile.

Cited by 38 publications

References 35 publications

Targeted Stage-Specific Inflammatory microRNA Profiling in Urine During Disease Progression in Experimental Autoimmune Encephalomyelitis: Markers of Disease Progression and Drug Response

Targeted Stage-Specific Inflammatory microRNA Profiling in Urine During Disease Progression in Experimental Autoimmune Encephalomyelitis: Markers of Disease Progression and Drug Response

Seeking balance: Potentiation and inhibition of multiple sclerosis autoimmune responses by IL-6 and IL-10

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