Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis

Gurevich, Michael; Miron, Gadi; Falb, Rina; Magalashvili, David; Dolev, Mark; Stern, Yael; Achiron, Anat

doi:10.1186/s12883-015-0495-x

Cited by 12 publications

(9 citation statements)

References 30 publications

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“…Of note, there is no known association between latitude and prevalence of neuromyelitis optica, an MS-related disease that worsens upon IFN-β therapy ( 48 ). In the present analysis, the type I IFN genes found to be regulated have previously been identified to be regulated upon IFN-β therapy in RRMS patients who were classified as IFN-β therapy responders ( 49 , 50 ). The down-regulation of AHR and TIPARP , known counter-actors of type I IFN-signaling, further supports a direct up-regulation of type I IFNs through phototherapy ( 51 ).…”

Section: Discussionmentioning

confidence: 77%

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Ostkamp¹,

Salmen

Görlich³

et al. 2020

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

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Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β–treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.

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Section: Discussionmentioning

confidence: 77%

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Ostkamp¹,

Salmen

Görlich³

et al. 2020

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

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“…If part of the effect of UVR is mediated directly through type I interferons, it is possible that IFN-β treatment could mask the effects of UVR / latitude. In fact, the type I interferon genes found to be regulated have previously been shown to be regulated upon IFN-β therapy in RRMS patients who were classified as IFN-β therapy responders (48, 49). The downregulation of AHR and TIPARP , known counter-actors of type I interferons-signaling, further supports a direct upregulation of type I interferons through phototherapy (50).…”

Section: Discussionmentioning

confidence: 99%

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Ostkamp¹,

Salmen

Pignolet

et al. 2020

Preprint

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Background: Multiple sclerosis (MS) disease risk is associated with reduced sun exposure. This study assessed the relationship between measures of sun-exposure (vitamin D (vitD), latitude) and MS disease severity, the mechanisms of action, and effect-modification by medication and sun-sensitivity associated MC1R variants. Methods: Two multi-center cohort studies (nNationMS=946, nBIONAT=991). Outcomes were the multiple sclerosis severity score (MSSS) and the number of Gd-enhancing lesion (GELs). RNAseq of four immune cell populations before and after UV-phototherapy of five MS patients. Results: High serum vitD was associated with reduced MSSS (PNationMS=0.021; PBIONAT=0.007) and reduced risk for disease aggravation (PNationMS=0.032). Low latitude was associated with higher vitD, lower MSSS (PNationMS=0.018), fewer GELs (PNationMS=0.030) and reduced risk for aggravation (PNationMS=0.044). The influence of latitude on disability seemed to be lacking in the subgroup of interferon-β treated patients (interaction-PBIONAT=0.042, interaction-PNationMS=0.053). In genetic analyses, carriers of MC1R:rs1805008(T), who reported increased sensitivity towards sunlight (PNationMS=0.038), the relationship between latitude und the number of GELs was inversed (PNationMS=0.001). Phototherapy induced a vitD and type I interferon signature that was most apparent in the transcriptome of monocytes (P=1x10-6). Conclusion: VitD is associated with reduced MS severity and disease aggravation. This is likely driven by sun-exposure, as latitude also correlated with disability and serum vitD. However, sun-exposure might be detrimental for sun-sensitive patients. A direct induction of type I interferons through sun-exposure could explain a reduced effect of latitude in interferon-β treated patients. This could also explain opposite effects of sun-exposure in MS and the type I interferon and sun-sensitivity-associated disease Lupus.

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“…In this study, as in most studies of this type ( 41 – 44 ), the PBMCs are considered as a valid cellular group since they are able to reflect patterns of expression characteristic of certain diseases and treatment effects. The majority of studies evaluating the transcriptomic effect of a treatment do it on whole PBMCs.…”

Section: Discussionmentioning

confidence: 99%

“…The majority of studies evaluating the transcriptomic effect of a treatment do it on whole PBMCs. In fact, the changes in expression levels on PBMCs in patients with MS treated with IFN-β are known as IFN signature and it has been proposed as a response marker ( 44 ). In addition, a recent study showed that the transcriptional change induced by fingolimod belong almost entirely to CD4 lymphocytes and based on these results, the efficiency of the sorting could be lower than the analysis of the entire population of PBMCs ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

Torres

Garcı́a²,

Marconi

et al. 2018

Front. Immunol.

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BackgroundFingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment.Materials and methodsSamples were obtained from relapsing–remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics.ResultsFingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod.ConclusionMS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker.

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Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis

Cited by 12 publications

References 30 publications

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

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