Validation of tag SNPs for multiple sclerosis HLA risk alleles across the 1000 genomes panel.

Currently, the genetic variants strongly associated with risk for Multiple Sclerosis (MS) are located in the Major Histocompatibility Complex. This includes DRB1*15:01 and DRB1*15:03 alleles at the HLA-DRB1 locus, the latter restricted to African populations; the DQB1*06:02 allele at the HLA-DQB1 locus which is in high linkage disequilibrium (LD) with DRB1*15:01; and protective allele A*02:01 at the HLA-A locus. HLA allele identification is facilitated by co-inherited ('tag') single nucleotide polymorphisms (SNPs); however, SNP validation is not typically done outside of the discovery population.

Cut-off evaluation of intrathecal oligoclonal bands of IgM in relapsing-remitting multiple sclerosis; a retrospective study.

Background: Multiple sclerosis (MS) is the most common demyelinating disease and characterized by immunological changes. Oligoclonal bands of IgG in CSF not seen in corresponding serum have been used for many years as part of the diagnostic criteria. However, considerably less is known about the role of IgM, despite several studies showing marked changes to IgM metabolism in MS.

Lanthionine Ketimine Ethyl Ester Accelerates Remyelination in a Mouse Model of Multiple Sclerosis.

Although over 20 disease modifying therapies are approved to treat Multiple Sclerosis (MS), these do not increase remyelination of demyelinated axons or mitigate axon damage. Previous studies showed that lanthionine ketenamine ethyl ester (LKE) reduces clinical signs in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and increased maturation of oligodendrocyte (OL) progenitor cells (OPCs) . In the current study, we used the cuprizone (CPZ) demyelination model of MS to test if LKE could increase remyelination.

Serum levels of lipocalin-2 are elevated at early times in African American relapsing remitting multiple sclerosis patients.

Previous studies showed that depleting Liver Kinase-B1 (LKB1) from astrocytes increased inflammatory factors lipocalin-2 (LCN2) and osteopontin (OPN) in EAE. A single nucleotide polymorphism (SNP) in STK11 (encoding LKB1) is a risk factor for MS, suggesting increased LCN2 or OPN contributes to risk. Serum LCN2 and OPN levels in African American female MS patients were higher than healthy controls, and while levels increased with disease duration in cases without the SNP, levels decreased with duration in cases with the SNP.

Liver kinase B1 rs9282860 polymorphism and risk for multiple sclerosis in White and Black Americans.

Background: We previously reported that the single nucleotide polymorphism (SNP) rs9282860 in serine threonine kinase 11 (STK11) gene which codes for liver kinase B1 (LKB1) has higher prevalence in White relapsing-remitting multiple sclerosis (RRMS) patients than controls. However it is not known if this SNP is a risk factor for MS in other populations.

Methods: We assessed the prevalence of the STK11 SNP in samples collected from African American (AA) persons with MS (PwMS) and controls at multiple Veterans Affairs (VA) Medical Centers and from a network of academic MS centers.

Deep DNA metagenomic sequencing reveals oral microbiome divergence between monozygotic twins discordant for multiple sclerosis severity.

In contrast to gut, the oral microbiome of MS patients has not been characterized. Deep sequencing of saliva DNA from a pair of monozygotic twins (MSF1 with relapsing remitting MS; MSF2 with clinically isolated syndrome) identified 2036 bacterial species. Relative abundances of 3 phyla were higher, and 3 lower in MSF1 versus MSF2.

Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis.

Liver kinase B1 (LKB1) is a ubiquitously expressed kinase involved in the regulation of cell metabolism, growth, and inflammatory activation. We previously reported that a single nucleotide polymorphism in the gene encoding LKB1 is a risk factor for multiple sclerosis (MS). Since astrocyte activation and metabolic function have important roles in regulating neuroinflammation and neuropathology, we examined the serine/threonine kinase LKB1 in astrocytes in a chronic experimental autoimmune encephalomyelitis mouse model of MS.

The origins and early history of neurochemistry and its societies.

At the 2017 joint meeting of the International Society for Neurochemistry (ISN) and the European Society for Neurochemistry, 150 years of neurochemistry - the 50th anniversary of ISN, 40 years of European Society for Neurochemistry, and 60 years of the Journal of Neurochemistry (JNC) - was celebrated with a historical symposium that explored the foundations of neurochemical societies, key international figures in the discipline of neurochemistry, and the pre-eminent role of the JNC. The foundations of neurochemistry were laid in Europe, notably France and Germany, in the late 18th and early 19th centuries. Neurochemists in the United Kingdom made globally relevant contributions before and after the Second World War, and Swedish contributions were especially prominent in the 1950s and 1960s.

Effects of the CRMP2 activator lanthionine ketimine ethyl ester on oligodendrocyte progenitor cells.

We previously showed LKE (lanthionine ketimine ester) reduces disease in the EAE model of multiple sclerosis, however whether LKE affects oligodendrocytes (OLGs) was not tested. In OLG progenitor cells (OPCs), LKE increased process number and area, but not PDGF-receptor-alpha expressing cells. In contrast, PDGF increased OPC numbers, but reduced process number and area.

Sulfatides in extracellular vesicles isolated from plasma of multiple sclerosis patients.

Extracellular vesicles (EVs) are membrane nanovesicles of diverse sizes secreted by different cell types and are involved in intercellular communication. EVs shuttle proteins, nucleic acids, and lipids that reflect their cellular origin and could mediate their biological function in recipient cells. EVs circulate in biological fluids and are considered as potential biomarkers that could be used to analyze and characterize disease development, course and response to treatment.

The history of myelin.

Andreas Vesalius is attributed the discovery of white matter in the 16th century but van Leeuwenhoek is arguably the first to have observed myelinated fibers in 1717. A globular myelin theory followed, claiming all elements of the nervous system except for Fontana's primitive cylinder with outer sheath in 1781. Remak's axon revolution in 1836 relegated myelin to the unknown.

The emerging threat of superwarfarins: history, detection, mechanisms, and countermeasures.

Superwarfarins were developed following the emergence of warfarin resistance in rodents. Compared to warfarin, superwarfarins have much longer half-lives and stronger affinity to vitamin K epoxide reductase and therefore can cause death in warfarin-resistant rodents. By the mid-1970s, the superwarfarins brodifacoum and difenacoum were the most widely used rodenticides throughout the world.

A single-nucleotide polymorphism in serine-threonine kinase 11, the gene encoding liver kinase B1, is a risk factor for multiple sclerosis.

We identified a family in which five siblings were diagnosed with multiple sclerosis (MS) or clinically isolated syndrome. Several women in the maternal lineage have comorbidities typically associated with Peutz Jeghers Syndrome, a rare autosomal-dominant disease caused by mutations in the serine-threonine-kinase 11 (STK11) gene, which encodes liver kinase B1. Sequence analysis of DNA from one sibling identified a single-nucleotide polymorphism (SNP) within STK11 intron 5.

Effects of peptide fraction and counter ion on the development of clinical signs in experimental autoimmune encephalomyelitis.

The most commonly used immunogen to induce experimental autoimmune encephalomyelitis is MOG35-55 , a 21-residue peptide derived from myelin oligodendrocyte glycoprotein (MOG). In most studies, mice exhibit a chronic disease; however, in some studies mice show a transient disease. One variable that is not often controlled for is the peptide fraction of the purified MOG material, which can vary from less than 50% to over 90%, with the remainder of mass primarily comprised of the counter ion used for peptide purification.

IgM to S-nitrosylated protein is found intrathecally in relapsing-remitting multiple sclerosis.

This study has established the presence of IgM against S-nitrosylated proteins in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients using S-nitrosocysteine epitope (anti-SNOcys) as previously shown in serum. Anti-SNOcys IgM increased significantly in CSF during relapsing-remitting MS compared to milder neurological conditions. Evidence from albumin, IgG and IgM suggest that the production of anti-SNOcys IgM is intrathecal rather than the result of ingress from serum.

Olig1 is expressed in human oligodendrocytes during maturation and regeneration.

Myelin repair is inhibited in multiple sclerosis (MS), ultimately leading to axonal damage and disability. We aimed to understand the transcriptional mechanisms of regeneration in primary human oligodendrocyte cultures isolated from white matter of medically intractable epilepsy patients. Cultures at isolation contained 84% mature oligodendrocytes and 16% oligodendrocyte progenitor cells (OPC).

Glial cell lines: an overview.

The importance and essential functions of glial cells in the nervous system are now beginning to be understood and appreciated. Glial cell lines have been instrumental in the elucidation of many of these properties. In this Overview, the origin and properties of most of the existing cell lines for the major glial types: oligodendroglia, astroglia, microglia and Schwann cells, are documented.

Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins.

In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage. In contrast with PPARγ, agonists of PPARδ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation. In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins).

Nitric oxide synthase expression and nitric oxide toxicity in oligodendrocytes.

Oligodendrocytes (OLG) have more complex interactions with nitric oxide (NO) than initially suspected. Historically, OLG were seen only as targets of high NO levels released from other cells. Expression of nitric oxide synthase type II (NOS-2) in primary cultures of OLGs stimulated by cytokines led to controversy due to the presence of small numbers of microglia, cells also inducible for NOS-2 expression.

Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1beta production.

BACKGROUND: Under pathological conditions, microglia produce proinflammatory mediators which contribute to neurologic damage, and whose levels can be modulated by endogenous factors including neurotransmitters such as norepinephrine (NE). We investigated the ability of NE to suppress microglial activation, in particular its effects on induction and activity of the inducible form of nitric oxide synthase (NOS2) and the possible role that IL-1beta plays in that response. METHODS: Rat cortical microglia were stimulated with bacterial lipopolysaccharide (LPS) to induce NOS2 expression (assessed by nitrite and nitrate accumulation, NO production, and NOS2 mRNA levels) and IL-1beta release (assessed by ELISA).

Anti-S-nitrosocysteine antibodies are a predictive marker for demyelination in experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

Multiple sclerosis (MS) is characterized by inflammation within the CNS. This inflammatory response is associated with production of nitric oxide (NO) and NO-related species that nitrosylate thiols. We postulated that MS patients would exhibit an antibody (Ab) response directed against proteins containing S-nitrosocysteine (SNO-cysteine) and showed that anti-NO-cysteine Abs of the IgM isotype are in fact present in the sera of some MS patients (Boullerne et al.