A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis

Comabella, Manuel; Lünemann, JD; Río, Jordi; Sánchez, Àlex; López, Cristina; Julià, Eva; Fernández, Marta; Nonell, Lara; Camiña-Tato, M.; Deisenhammer, Florian; Caballero, E. Jiménez; Tórtola, María Teresa; Prinz, Marco; Montalbán, Xavier; Martin, Roland

doi:10.1093/brain/awp228

Cited by 186 publications

(161 citation statements)

References 43 publications

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“…[1,2]). However, a poor response to this treatment may also reflect the heterogeneity of the disease and individual genetic or metabolic differences not associated with the presence of NAbs [12,16]. Our cohorts of NAbspositive and -negative patients did not present significant differences in their clinical characteristics at baseline and at the moment of NAbs analysis.…”

Section: Discussionmentioning

confidence: 89%

Influence of apolipoprotein E plasma levels and tobacco smoking on the induction of neutralising antibodies to interferon-beta

et al. 2010

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Interferon-beta (IFN-beta) therapy for multiple sclerosis (MS) is associated with a potential for induction of neutralizing antibodies (NAbs). Because immune reactivity depends on changes in lipoprotein metabolism, we investigated whether plasma lipoprotein profiles could be associated with the development of NAbs. Thirty-one female MS patients treated with subcutaneously administered IFN-beta were included. Demographic and clinical characteristics were compared between NAbs response groups using t tests for continuous and logistic regression analysis and Fisher's exact tests for categorical data, respectively. Multivariate logistic regression was used to evaluate the effect of potential confounders. Patients who developed NAbs had lower apoE levels before treatment, 67 (47-74) mg/L median (interquartile range), and at the moment of NAb analysis, 53 (50-84) mg/L, in comparison to those who remained NAb-negative, 83 (68-107) mg/L, P = 0.03, and 76 (66-87) mg/L, P = 0.04, respectively. When adjusting for age and smoking for a onestandard deviation decrease in apoE levels, a 5.6-fold increase in the odds of becoming NAb-positive was detected: odds ratios (OR) 0.18 (95% CI 0.04-0.77), P = 0.04. When adjusting for apoE, smoking habit became associated with NAb induction: OR 5.6 (95% CI 1.3-87), P = 0.03. These results suggest that apoE-containing lipoprotein metabolism and, possibly, tobacco smoking may be associated with risk of NAb production in female MS patients treated with IFN-beta.

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Section: Discussionmentioning

confidence: 89%

Influence of apolipoprotein E plasma levels and tobacco smoking on the induction of neutralising antibodies to interferon-beta

et al. 2010

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“…The reason that nonresponders do not express TRAIL on monocytes might be a result of failure to activate p38 or p65 (as shown here in MS patient 4; Fig. 4), or much lower activation of STAT1 (35). ISG15 is expressed only in Kupffer cells of responders to pegylated IFN-α2 therapy in patients with chronic hepatitis C (32).…”

Section: Cell Type-specific Activation Of Stats Plus Other Tfs As a Mmentioning

confidence: 80%

The role of cell type-specific responses in IFN-β therapy of multiple sclerosis

Zula

Green

Ransohoff

et al. 2011

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

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The mechanism of IFN-β therapy in relapsing-remitting multiple sclerosis (RRMS) is not well understood, but induction of apoptosis in specific leukocyte subsets is likely to be important. Enhanced expression of TNFSF10 or TNF-related apoptosis-inducing ligand (TRAIL) mRNA in unseparated leukocytes has been put forward as a therapeutic response marker, but it is unclear which leukocyte subsets express TRAIL. We investigated the basis of TRAIL expression in response to IFN-β by studying activation of STATs 1, 3, and 5, p38 MAPK, and NF-κB in different leukocyte subsets of patients with RRMS. Monocytes, B cells, and T cells showed substantial differences in the activation of p38 and the STATs in response to i.m. injection of IFN-β1a or stimulation in vitro. Induction of cellsurface TRAIL, analyzed in nine leukocyte subsets, was observed only on monocytes and granulocytes and correlated with the activation of p38 and/or NF-κB in these subsets only, in agreement with previous work in fibroblasts showing that the induction of TRAIL in response to IFN-β depends on the activation of p38 and NF-κB as well as STATs 1 and 2. We propose that, in myeloid cells, the differential activation of p38 and NF-κB and induction of TRAIL, which sensitizes cells to apoptosis, can help to explain differences in responsiveness to IFN-β therapy among patients with RRMS and, furthermore, that such differential patterns of activation and expression may also be important in understanding the therapeutic responses to IFN-α/β in hepatitis and cancer.humans | phosphoproteins | signal transduction | flow cytometry

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“…These studies are complicated by the influences of potential confounders and by modification of the effect of OC use from differential treatment effects ("interaction bias"). Most patients with RR-MS are now treated very early with immunomodulatory agents, which could alter the natural history of the disease, though some may not respond or have poor responses to these treatments [10]. In order to investigate a potential association between OC use and the clinical course of the disease it would be important to avoid interaction bias that heterogeneous responses to current therapies could create.…”

Section: Introductionmentioning

confidence: 99%

Oral contraceptive use and clinical outcomes in patients with multiple sclerosis

Sena¹,

Couderc²,

Vasconcelos³

et al. 2012

Journal of the Neurological Sciences

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Experimental and clinical data suggest a role of sex steroids in the pathogenesis of multiple sclerosis (MS). Scant information is available about the potential effect of oral contraceptive (OC) use on the prognosis of the disease. We aimed to evaluate this. The study population consisted of 132 women with relapsing-remitting MS before receiving disease modifying treatment and a mean disease duration 6.2 (SD 5.1) years. Three groups of patients were distinguished according to their OC behavior: [1] never-users, patients who never used OC [2] past-users, patients who stopped OC use before disease onset, and [3] after-users, those who used these drugs after disease onset. Multiple linear and logistic regression models were used to analyze the association between oral contraceptive use and annualized relapse rates, disability accumulation and severity of the disease. After-user patients had lower Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) values than never users (p b 0.001 and p = 0.002, respectively) and past users (p = 0.010 and p = 0.002, respectively). These patients were also more likely to have a benign disease course (MSSS b 2.5) than never and past users together (OR: 4.52, 95%CI: 2.13-9.56, p b 0.001). This effect remained significant after adjustment for confounders, including smoking and childbirths (OR: 2.97, 95%CI: 1.24, 6.54, p = 0.011 and for MSSS β: − 1.04; 95% C.I. − 1.78, − 0.30, p = 0.006). These results suggest that OC use in women with relapsing-remitting MS is possible associated with a milder disabling disease course.

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A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis

Cited by 186 publications

References 43 publications

Influence of apolipoprotein E plasma levels and tobacco smoking on the induction of neutralising antibodies to interferon-beta

Influence of apolipoprotein E plasma levels and tobacco smoking on the induction of neutralising antibodies to interferon-beta

The role of cell type-specific responses in IFN-β therapy of multiple sclerosis

Oral contraceptive use and clinical outcomes in patients with multiple sclerosis

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