Immunomodulatory Activity of Interferon-Beta

Multiple sclerosis (MS) is a complex disorder of the central nervous system that appears to be driven by a shift in immune functioning toward excess inflammation that results in demyelination and axonal loss. Beta interferons were the first class of disease-modifying therapies to be approved for patients with MS after treatment with this type I interferon improved the course of MS on both clinical and radiological measures in clinical trials. The mechanism of action of interferon-beta appears to be driven by influencing the immune system at many levels, including antigen-presenting cells, T cells, and B cells. One effect of these interactions is to shift cytokine networks in favor of an anti-inflammatory effect. The pleiotropic mechanism of action may be a critical factor in determining the efficacy of interferon-beta in MS. This review will focus on select immunological mechanisms that are influenced by this type I cytokine

Early MRI results and odds of attaining 'no evidence of disease activity' status in MS patients treated with interferon β-1a in the EVIDENCE study

Abstract Introduction 'No evidence of disease activity' (NEDA) is increasingly used as a treatment target with disease-modifying drugs for relapsing multiple sclerosis. Methods This post-hoc analysis of the randomised EVIDENCE trial compared interferon beta-1a injected subcutaneously three times weekly (IFN β-1a SC tiw) with interferon β-1a injected intramuscularly once weekly (IFN β-1a IM qw) on NEDA and clinical activity-free (CAF) status. The influence of the frequency of magnetic resonance imaging (MRI) scanning on NEDA and the effect of baseline T1 gadolinium-enhancing (Gd +) lesions on NEDA and CAF were also investigated. Results More patients in the IFN β-1a SC tiw group achieved NEDA compared with the IFN β-1a IM qw group, although rates were lower when monthly MRI scans through 24 weeks were included (35.0% vs. 21.6%, respectively; p p p = 0.022), and CAF through Week 48 in patients receiving IFN β-1a SC tiw ( p = 0.024). Conclusions IFN β-1a SC tiw was associated with significantly higher rate of NEDA status compared with IFN β-1a IM qw. Baseline Gd + lesions augured less frequent CAF or NEDA status. Inclusion of more MRI scans in the analysis reduced rates of NEDA status

The rhythms of AMBEs (arousal-related motor behavioral episodes) in Agrypnia Excitata: a video motor analysis

In patients with Agrypnia Excitata with fatal familial insomnia (AE-FFI), oscillatory EEG rhythms appear during "pseudosleep" and during atypical REM sleep.Episodes of arousal-related motor behavioral episodes (AMBEs) with and without clearly elaborated behaviors, such as REM Behavior Disorder, constitute an intriguing finding without a known mechanism.Spinal cord involvement should be added to the manifestations of thalamo-limbic-brainstem disconnection. AMBEs can be incorporated into the context of motor abnormalities observed in FFI and other prionopathies.Fil: Garay, Arturo. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Giardino, Daniela Laura. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Huck Iriart, Cristián. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Blanco, Susana Alicia Ana. Ministerio de Salud. Instituto Nacional del Cáncer; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Reder, Anthony T.. University of Chicago; Estados Unido

Interferonβ-1b Induces the Expression of RGS1 a Negative Regulator of G-Protein Signaling

We present evidence of a link between interferonβ-1b (IFN-β) and G-protein signaling by demonstrating that IFN-β can induce the expression of the negative regulator of G-protein signaling 1 (RGS1). RGS1 reduces G-protein activation and immune cell migration by interacting with heterotrimeric G-proteins and enhancing their intrinsic GTPase activity. In this study, IFN-β treatment resulted in the induction of RGS1 in peripheral blood mononuclear cells (PBMCs), monocytes, T cells, and B cells. Induction of RGS1 by IFN-β was concentration dependent and observed at both the RNA and protein level. Other members of the RGS family were not induced by IFN-β, and induction of RGS1 required the activation of the IFN receptor. In addition, RGS1 induction was observed in PBMCs obtained from IFN-β-treated multiple sclerosis patients suggesting a possible, as yet unexplored, involvement of G-protein regulation in disease treatment. The upregulation of RGS1 by IFN-β has not been previously reported

Adaptive and innate immune responses in multiple sclerosis with anti-CD20 therapy: Gene expression and protein profiles

BackgroundAnti-CD20 is a highly effective therapy for multiple sclerosis (MS), a disease with multiple abnormalities in function of B and T cells and innate immune cells. Anti-CD20 therapy depletes B cells, which alters antibody production and has diverse effects on B cell immunity. These changes potentially affect immunity beyond B cells in MS.ObjectiveDetermine if anti-CD20 therapy effects non-B cell, as well as B cell, gene expression, and serum protein levels.MethodsSamples were collected from 10 healthy controls and from clinically stable relapsing–remitting MS – 10 untreated, 9 interferon-β-treated, and 15 ocrelizumab-treated patients were studied before, and 2  weeks and 6  months after, the first anti-CD20 infusion. Peripheral blood mononuclear cells (PBMC) were analyzed with sensitive, 135,000-transcript RNA expression microarrays, using stringent criteria. Gene expression was compared to 43 MS-relevant serum immune and neurotrophic proteins, using multiplex protein assays.ResultsAnti-CD20 therapy reduced expression of 413 total genes and 185 B-cell-regulated genes at 2  weeks vs. pre-therapy. Expression of 19 (15%) of these B cell genes returned toward baseline by 6  months, including genes for the B cell activation protein, CD79A, and for immunoglobulin A, D, and G heavy chains. Expression pathways for Th17 and CD4 regulatory T-cell (Treg) development, differentiation, and proliferation also quieted. In contrast, expression increased in Th1 and myeloid cell antiviral, pro-inflammatory, and toll-like receptor (TLR) gene pathways.ConclusionThese findings have clinical implications. B cell gene expression diminishes 2  weeks after anti-CD20 antibody infusion, but begins to rebound by 6  months. This suggests that the optimum time for vaccination is soon before reinfusion of anti-CD20 therapy. In addition, at 6  months, there is enhanced Th1 cell gene expression and induction of innate immune response genes and TLR expression, which can enhance anti-viral and anti-tumor immunity. This may compensate for diminished B cell gene expression after therapy. These data suggest that anti-CD20 therapy has dynamic effect on B cells and causes a compensatory rise in Th1 and myeloid immunity

Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)

Background: Cognitive impairment in MS impacts negatively on many patients at all disease stages and in all subtypes. Full clinical cognitive assessment is expensive, requiring expert staff and special equipment. Test versions and normative data are not available for all languages and cultures. Objective: To recommend a brief cognitive assessment for multiple sclerosis (MS) that is optimized for small centers, with one or few staff members, who may not have neuropsychological training and constructed to maximize international use. Methods: An expert committee of twelve members representing the main cultural groups that have so far contributed considerable data about MS cognitive dysfunction was convened. Following exhaustive literature review, peer-reviewed articles were selected to cover a broad spectrum of cultures and scales that targeted cognitive domains vulnerable to MS. Each was rated by two committee members and candidates scales were rated on psychometric qualities (reliability, validity, and sensitivity), international application, ease of administration, feasibility in the specified context, and acceptability to patients. Results: The committee recommended the Symbol Digit Modalities Test, if only 5 minutes was available, with the addition of the California Verbal Learning Test – Second Edition and the Brief Visuospatial Memory Test – Revised learning trials if a further 10 minutes could be allocated for testing. Conclusions: A brief cognitive assessment for MS has been recommended. A validation protocol has been prepared for language groups and validation studies have commenced

Gray matter atrophy in multiple sclerosis despite clinical and lesion stability during natalizumab treatment

Background: Brain volume loss is an important surrogate marker for assessing disability in MS; however, contribution of gray and white matter to the whole brain volume loss needs further examination in the context of specific MS treatment.Objectives: To examine whole and segmented gray, white, thalamic, and corpus callosum volume loss in stable patients receiving natalizumab for 2-5 years.Methods: This was a retrospective study of 20 patients undergoing treatment with natalizumab for 24-68 months. Whole brain volume loss was determined with SIENA. Gray and white matter segmentation was done using FAST. Thalamic and corpus callosum volumes were determined using Freesurfer. T1 relaxation values of chronic hypointense lesions (black holes) were determined using a quantitative, in-house developed method to assess lesion evolution.Results: Over a mean of 36.6 months, median percent brain volume change (PBVC) was -2.0% (IQR 0.99-2.99). There was decline in gray (p = 0.001) but not white matter (p = 0.6), and thalamic (p = 0.01) but not corpus callosum volume (p = 0.09). Gray matter loss correlated with PBVC (Spearman's r = 0.64, p = 0.003) but not white matter (Spearman's r = 0.42, p = 0.07). Age significantly influenced whole brain volume loss (p = 0.010, multivariate regression), but disease duration and baseline T2 lesion volume did not. There was no change in T1 relaxation values of lesions or T2 lesion volume over time. All patients remained clinically stable.Conclusions: These results demonstrate that brain volume loss in MS is primarily driven by gray matter changes and may be independent of clinically effective treatment.</div

Aberrant Type I Interferon Regulation in Autoimmunity: Opposite directions in MS and SLE, shaped by Evolution and Body Ecology

Studying the action of mechanisms of type I IFN provides the insight to elucidate the cause and therapy for autoimmune diseases. There are high IFN responses in some diseases such as connective tissue diseases, but low responses in multiple sclerosis. Distinct IFN features lead us to understand pathology of a spectrum of autoimmune diseases and help us to search genetic changes, gene expression, and biomarkers for diagnosis, disease progression, and treatment response