CD40-CD40 Ligand Interactions in Experimental Allergic Encephalomyelitis and Multiple Sclerosis.

We investigated the role of CD40-CD40 ligand (CD40L) interactions in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). Activated helper T cells expressing CD40L (gp39) surface protein were found in MS patient brain sections, but not in brain tissue sections of normal controls or patients with other neurological disease. CD40L-positive cells were co-localized with CD40-bearing cells in active lesions (perivascular infiltrates). Most of these CD40-bearing cells proved to be of the monocytic lineage (macrophages or microglial cells), and relatively few were B cells. To functionally evaluate CD40-CD40L interactions, EAE was elicited in mice by means of proteolipid-peptide immunization. Treatment with anti-CD40L monoclonal antibody completely prevented the development of disease. Furthermore, administration of anti-CD40L monoclonal antibody, even after disease onset, shortly before maximum disability score was reached led to dramatic disease reduction. The presence of helper T cells expressing CD40L in brain tissue of MS patients and EAE animals, together with the functional evidence provided by successful experimental prevention and therapy in an animal model, indicates that blockade of CD40-CD40L-mediated cellular interactions may be a method for interference in active MS

Modulation of Multiple Sclerosis and its Animal Model experimental Autoimmune encephalomyelitis by Food and Gut Microbiota

Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination, axonal damage, and symptoms such as fatigue and disability. Although the cause of MS is not known, the infiltration of peripherally activated immune cells into the CNS has a key pathogenic role. Accumulating evidence supports an important role of diet and gut microbiota in immune-mediated diseases. Preclinical as well as clinical studies suggest a role for gut microbiota and dietary components in MS. Here, we review these recent studies on gut microbiota and dietary interventions in MS and its animal model experimental autoimmune encephalomyelitis. We also propose directions for future research

Exploring the VISTA of microglia:immune checkpoints in CNS inflammation

Negative checkpoint regulators (NCR) are intensely pursued as targets to modulate the immune response in cancer and autoimmunity. A large variety of NCR is expressed by central nervous system (CNS)-resident cell types and is associated with CNS homeostasis, interactions with peripheral immunity and CNS inflammation and disease. Immunotherapy blocking NCR affects the CNS as patients can develop neurological issues including encephalitis and multiple sclerosis (MS). How these treatments affect the CNS is incompletely understood, since expression and function of NCR in the CNS are only beginning to be unravelled. V-type immunoglobulin-like suppressor of T cell activation (VISTA) is an NCR that is expressed primarily in the haematopoietic system by myeloid and T cells. VISTA regulates T cell quiescence and activation and has a variety of functions in myeloid cells including efferocytosis, cytokine response and chemotaxis. In the CNS, VISTA is predominantly expressed by microglia and macrophages of the CNS. In this review, we summarize the role of NCR in the CNS during health and disease. We highlight expression of VISTA across cell types and CNS diseases and discuss the function of VISTA in microglia and during CNS ageing, inflammation and neurodegeneration. Understanding the role of VISTA and other NCR in the CNS is important considering the adverse effects of immunotherapy on the CNS, and in view of their therapeutic potential in CNS disease

Multiple sclerosis is linked to MAPK(ERK) overactivity in microglia

Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPKERK). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPKERK. This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPKERK negative feedback phosphatases that normally regulate MAPKERK activity. Consequently, these factors may contribute to inappropriate MAPKERK overactivity, and thereby to neurodegeneration. Also, MAPKERK overactivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPKERK in microglia merits further investigation as this phenomenon may imply a novel treatment approach

High-Q terahertz Bragg resonances within a metal parallel plate waveguide

One-dimensional (1D) Bragg waveguides are demonstrated at terahertz (THz) frequencies. Lithographically made 1D symmetric and asymmetric dielectric gratings on metallized high conductivity Si chips are incorporated within metal parallel plate waveguides to form Bragg waveguides. These waveguides have high throughput and have Bragg resonances with linewidths approaching 6 GHz and Q as high as 430. These high-Q resonant Bragg waveguides are excellent structures for applications in THz sensing.Peer reviewedElectrical and Computer Engineerin

Nutritional and ecological perspectives of the interrelationships between diet and the gut microbiome in multiple sclerosis:Insights from marmosets

Studies in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, have shown potential links between diet components, microbiome composition, and modulation of immune responses. In this review, we reanalyze and discuss findings in an outbred marmoset EAE model in which a yogurt-based dietary supplement decreased disease frequency and severity. We show that although diet has detectable effects on the fecal microbiome, microbiome changes are more strongly associated with the EAE development. Using an ecological framework, we further show that the dominant factors influencing the gut microbiota were marmoset sibling pair and experimental time point. These findings emphasize challenges in assigning cause-and-effect relationships in studies of diet-microbiome-host interactions and differentiating the diet effects from other environmental, stochastic, and host-related factors. We advocate for animal experiments to be designed to allow causal inferences of the microbiota's role in pathology while considering the complex ecological processes that shape microbial communities

Combinatorial models of rigidity and renormalization

We first introduce the percolation problems associated with the graph theoretical concepts of $(k,l)$-sparsity, and make contact with the physical concepts of ordinary and rigidity percolation. We then devise a renormalization transformation for $(k,l)$-percolation problems, and investigate its domain of validity. In particular, we show that it allows an exact solution of $(k,l)$-percolation problems on hierarchical graphs, for $k\leq l<2k$. We introduce and solve by renormalization such a model, which has the interesting feature of showing both ordinary percolation and rigidity percolation phase transitions, depending on the values of the parameters.Comment: 22 pages, 6 figure

Stressed backbone and elasticity of random central-force systems

We use a new algorithm to find the stress-carrying backbone of ``generic'' site-diluted triangular lattices of up to 10^6 sites. Generic lattices can be made by randomly displacing the sites of a regular lattice. The percolation threshold is Pc=0.6975 +/- 0.0003, the correlation length exponent \nu =1.16 +/- 0.03 and the fractal dimension of the backbone Db=1.78 +/- 0.02. The number of ``critical bonds'' (if you remove them rigidity is lost) on the backbone scales as L^{x}, with x=0.85 +/- 0.05. The Young's modulus is also calculated.Comment: 5 pages, 5 figures, uses epsfi

Regionally diverse astrocyte subtypes and their heterogeneous response to EAE

Astrocytes fulfil many functions in the central nervous system (CNS), including contribution to the blood brain barrier, synapse formation, and trophic support. In addition, they can mount an inflammatory response and are heterogeneous in morphology and function. To extensively characterize astrocyte subtypes, we FACS-isolated and gene expression profiled distinct astrocyte subtypes from three central nervous system regions; forebrain, hindbrain and spinal cord. Astrocyte subpopulations were separated based on GLAST/SLC1A3 and ACSA-2/ATP1B2 cell surface expression. The local brain environment proved key in establishing different transcriptional programs in astrocyte subtypes. Transcriptional differences between subtypes were also apparent in experimental autoimmune encephalomyelitis (EAE) mice, where these astrocyte subtypes showed distinct responses. While gene expression signatures associated with blood-brain barrier maintenance were lost, signatures involved in neuroinflammation and neurotoxicity were increased in spinal cord astrocytes, especially during acute disease stages. In chronic stages of EAE, this reactive astrocyte signature was slightly decreased, while obtaining a more proliferative profile, which might be relevant for glia scar formation and tissue regeneration. Morphological heterogeneity of astrocytes previously indicated the presence of astrocyte subtypes, and here we show diversity based on transcriptome variation associated with brain regions and differential responsiveness to a neuroinflammatory insult (EAE)