45 research outputs found
Functional diversity of chemokines and chemokine receptors in response to viral infection of the central nervous system.
Encounters with neurotropic viruses result in varied outcomes ranging from encephalitis, paralytic poliomyelitis or other serious consequences to relatively benign infection. One of the principal factors that control the outcome of infection is the localized tissue response and subsequent immune response directed against the invading toxic agent. It is the role of the immune system to contain and control the spread of virus infection in the central nervous system (CNS), and paradoxically, this response may also be pathologic. Chemokines are potent proinflammatory molecules whose expression within virally infected tissues is often associated with protection and/or pathology which correlates with migration and accumulation of immune cells. Indeed, studies with a neurotropic murine coronavirus, mouse hepatitis virus (MHV), have provided important insight into the functional roles of chemokines and chemokine receptors in participating in various aspects of host defense as well as disease development within the CNS. This chapter will highlight recent discoveries that have provided insight into the diverse biologic roles of chemokines and their receptors in coordinating immune responses following viral infection of the CNS
Two-dimensional SDS-PAGE fractionation of biological samples for biomarker discovery
Two-dimensional electrophoresis is still a very valuable tool in proteomics,
due to its reproducibility and its ability to analyze complete proteins.
However, due to its sensitivity to dynamic range issues, its most suitable use
in the frame of biomarker discovery is not on very complex fluids such as
plasma, but rather on more proximal, simpler fluids such as CSF, urine, or
secretome samples. Here, we describe the complete workflow for the analysis of
such dilute samples by two-dimensional electrophoresis, starting from sample
concentration, then the two-dimensional electrophoresis step per se, ending
with the protein detection by fluorescence
S100B as a potential biomarker and therapeutic target in multiple sclerosis
Multiple sclerosis (MS) pathology is characterized by neuroinflammation and demyelination. Recently, the inflammatory molecule S100B was identified in cerebrospinal fluid (CSF) and serum of MS patients. Although seen as an astrogliosis marker, lower/physiological levels of S100B are involved in oligodendrocyte differentiation/maturation. Nevertheless, increased S100B levels released upon injury may induce glial reactivity and oligodendrocyte demise, exacerbating tissue damage during an MS episode or delaying the following remyelination. Here, we aimed to unravel the functional role of S100B in the pathogenesis of MS. Elevated S100B levels were detected in the CSF of relapsing-remitting MS patients at diagnosis. Active demyelinating MS lesions showed increased expression of S100B and its receptor, the receptor for advanced glycation end products (RAGE), in the lesion area, while chronic active lesions displayed increased S100B in demyelinated areas with lower expression of RAGE in the rim. Interestingly, reactive astrocytes were identified as the predominant cellular source of S100B, whereas RAGE was expressed by activated microglia/macrophages. Using an ex vivo demyelinating model, cerebral organotypic slice cultures treated with lysophosphatidylcholine (LPC), we observed a marked elevation of S100B upon demyelination, which co-localized mostly with astrocytes. Inhibition of S100B action using a directed antibody reduced LPC-induced demyelination, prevented astrocyte reactivity and abrogated the expression of inflammatory and inflammasome-related molecules. Overall, high S100B expression in MS patient samples suggests its usefulness as a diagnostic biomarker for MS, while the beneficial outcome of its inhibition in our demyelinating model indicates S100B as an emerging therapeutic target in MS.This work was supported by Medal of Honor L’Oréal
for Women in Science (FCT, UNESCO, L’Óreal) and innovation
grant (Ordem dos Farmacêuticos) to AF, a post-doctoral grant from
Fundação para a Ciência e Tecnologia (FCT-SFRH/BPD/96794/2013)
and a DuPré Grant from the European Committee for Treatment and
Research in Multiple Sclerosis (ECTRIMS) to AB, and by FCT-Pest-
OE/SAU/UI4013 to iMed.ULisboa.info:eu-repo/semantics/publishedVersio
Bias and Evolution of the Mutationally Accessible Phenotypic Space in a Developmental System
Genetic and developmental architecture may bias the mutationally available phenotypic spectrum. Although such asymmetries in the introduction of variation may influence possible evolutionary trajectories, we lack quantitative characterization of biases in mutationally inducible phenotypic variation, their genotype-dependence, and their underlying molecular and developmental causes. Here we quantify the mutationally accessible phenotypic spectrum of the vulval developmental system using mutation accumulation (MA) lines derived from four wild isolates of the nematodes Caenorhabditis elegans and C. briggsae. The results confirm that on average, spontaneous mutations degrade developmental precision, with MA lines showing a low, yet consistently increased, proportion of developmental defects and variants. This result indicates strong purifying selection acting to maintain an invariant vulval phenotype. Both developmental system and genotype significantly bias the spectrum of mutationally inducible phenotypic variants. First, irrespective of genotype, there is a developmental bias, such that certain phenotypic variants are commonly induced by MA, while others are very rarely or never induced. Second, we found that both the degree and spectrum of mutationally accessible phenotypic variation are genotype-dependent. Overall, C. briggsae MA lines exhibited a two-fold higher decline in precision than the C. elegans MA lines. Moreover, the propensity to generate specific developmental variants depended on the genetic background. We show that such genotype-specific developmental biases are likely due to cryptic quantitative variation in activities of underlying molecular cascades. This analysis allowed us to identify the mutationally most sensitive elements of the vulval developmental system, which may indicate axes of potential evolutionary variation. Consistent with this scenario, we found that evolutionary trends in the vulval system concern the phenotypic characters that are most easily affected by mutation. This study provides an empirical assessment of developmental bias and the evolution of mutationally accessible phenotypes and supports the notion that such bias may influence the directions of evolutionary change
A lack of association between elevated serum levels of S100B protein and autoimmunity in autistic children
<p>Abstract</p> <p>Background</p> <p>S100B is a calcium-binding protein that is produced primarily by astrocytes. Increased serum S100B protein levels reflect neurological damage. Autoimmunity may have a role in the pathogenesis of autism in some patients. Autoantibodies may cross the blood-brain barrier and combine with brain tissue antigens, forming immune complexes and resulting in neurological damage. We are the first to investigate the relationship between serum levels of S100B protein, a marker of neuronal damage, and antiribosomal P protein antibodies in autistic children.</p> <p>Methods</p> <p>Serum S100B protein and antiribosomal P antibodies were measured in 64 autistic children in comparison to 46 matched healthy children.</p> <p>Results</p> <p>Autistic children had significantly higher serum S100B protein levels than healthy controls (<it>P </it>< 0.001). Children with severe autism had significantly higher serum S100B protein than patients with mild to moderate autism (<it>P </it>= 0.01). Increased serum levels of antiribosomal P antibodies were found in 40.6% of autistic children. There were no significant correlations between serum levels of S100B protein and antiribosomal P antibodies (<it>P </it>= 0.29).</p> <p>Conclusions</p> <p>S100B protein levels were elevated in autistic children and significantly correlated to autistic severity. This may indicate the presence of an underlying neuropathological condition in autistic patients. Antiribosomal P antibodies may not be a possible contributing factor to the elevated serum levels of S100B protein in some autistic children. However, further research is warranted to investigate the possible link between serum S100B protein levels and other autoantibodies, which are possible indicators of autoimmunity to central nervous system in autism.</p
Worse Neurological State During Acute Ischemic Stroke is Associated with a Decrease in Serum Albumin Levels
Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis
International audienceMultiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients
Cladribine Exposure Results in a Sustained Modulation of the Cytokine Response in Human Peripheral Blood Mononuclear Cells
Understanding the consequences of chronic inflammatory demyelinating polyradiculoneuropathy from impairments to activity and participation restrictions and reduced quality of life: the ICE study.
A randomized trial (ICE trial) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) demonstrated significantly more improvement with intravenous immunoglobulin (Gamunex(\uae), Talecris Biotherapeutics, Inc., Research Triangle Park, NC) than placebo. To understand the relationship between CIDP impairments, activity and participation restrictions, and quality of life (QoL) in this trial, we investigated the association between scales representing these outcome levels. Gamunex or placebo was given every 3 weeks for up to 24 weeks to 117 patients in an initial treatment period after which treatment failures were crossed over (alternative treatment). We assessed impairments, activity and participation, and SF-36 component mental (MCS) and physical summaries (PCS). Regression analyses of baseline data were performed (all subjects) and change from baseline to endpoint (Gamunex-treated group only) to determine correlations between outcomes. Grip strength, medical research council (MRC) sum score, and inflammatory neuropathy cause and treatment (INCAT) sensory sum score were the strongest explanatory variables of disability (at baseline: r(2) = 0.46; change from baseline: r(2) = 0.66). Only up to half of the variance in QoL scores (PCS at baseline: r(2) = 0.30; change from baseline: r(2) = 0.41; MCS: at baseline: r(2) = 0.10; change from baseline: r(2) = 0.24) was explained by impairment and activity and participation measures. Future studies are required to elucidate the impact of CIDP on disability and QoL changes, because the obtained correlations provide only partial explanation