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Multiple sclerosis (MS) Is an autoimmune disease of the CNS, featuring Inflammation and demyelination with variable recovery. In this issue of the JCI, Kapell, Fazio, and authors address the potential for targeting neuron-oligodendrocyte potassium shuttling at the nodes of Ranvier as a neuroprotective strategy during inflammatory demyelination of the CNS in experimental MS. Their extensive and impressive study could serve as a template for defining the physiologic properties of a putative protective pathway. The authors examined MS features in existent disease models, investigated the impact of pharmacologic intervention, and evaluated its status in tissues from patients with MS. We await future studies that will tackle the challenge of translating these findings into a clinical therapy., Early events in multiple sclerosis drive disability Multiple sclerosis (MS) follows an unpredictable clinical disease course most frequently characterized by initial episodes of neurologic relapses with variable recovery; up to [...]

T follicular helper cells (Tfh), a subset of [CD4.sup.+] T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of [CXCR5.sup.+] and [PD-1.sup.+] cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1-bright ([CXCR5.sup.Br][PD-1.sup.Br]) Tfh population in thoracic duct lymph (TDL). These [CXCR5.sup.Br][PD-1.sup.Br] TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in [CXCR5.sup.Br][PD-1.sup.Br] TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the [CXCR5.sup.Br][PD-1.sup.Br] TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue., Introduction T follicular helper cells (Tfh) are a subset of [CD4.sup.+] T cells that provide B cell help within the follicles of secondary lymphoid tissues. Tfh promote B cell class [...]

Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by β-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non-cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders., Astrocytes are the most abundant cells in the CNS. Under normal conditions, astrocytes modulate synaptic activity and provide nutrients and support for neuronal survival (1-4). In the context of neuroinflammation, [...]

Byline: Sridar Narayanan (1), Nicola De Stefano (1), Gordon S. Francis (1), Rozie Arnaoutelis (1), Zografos Caramanos (1), D. Louis Collins (1), Daniel Pelletier (1), Barry G. W. Arnason (3), Jack P. Antel (1), Douglas L. Arnold (1) Keywords: Key words Interferon-beta; Multiple sclerosis; N-acetylaspartate; Axons; Magnetic resonance spectroscopy Abstract: Patients with multiple sclerosis (MS) can benefit from treatment with interferon [beta]--1b. However, the mechanisms of action of this drug are incompletely understood and effects of interferon [beta]--1b on axonal injury are not known. A measure of axonal injury can be obtained in vivo using magnetic resonance spectroscopy to quantify the resonance intensity of the neuronal marker, N-acetylaspartate (NAA). In a small pilot study, we performed combined magnetic resonance imaging and magnetic resonance spectroscopic imaging on 10 patients with relapsing-remitting MS before and 1 year after starting treatment with subcutaneous interferon [beta]--1b. Resonance intensities of NAA relative to creatine (Cr) were measured in a large, central brain volume. These measurements were compared with those made in a group of 6 untreated patients selected to have a similar range of scores on the Expanded Disability Status Scale and mean NAA/Cr at baseline. NAA/Cr in the treated group [2.74 (0.16), mean (SD)] showed an increase of 5.5 % 12 months after the start of therapy [2.89 (0.24), p = 0.05], while NAA/Cr in the untreated group decreased, but not significantly [2.76 (0.1) at baseline, 2.65 (0.14) at 12 months, p &gt 0.1]. NAA/Cr had become significantly higher in the treated group at 12 months than in the untreated group (p = 0.03). Our data suggest that, in addition to losing axons, patients with chronic multiple sclerosis suffer from chronic, sublethal axonal injury that is at least partially reversible with interferon [beta]--1b therapy. Author Affiliation: (1) Montreal Neurological Institute, 3801 University Street, Montreal, Quebec H3A 2B4, Canada, Tel.: (514) 398-8185, Fax: (514) 398-2975, E-mail: doug@mrs.mni.mcgill.ca, CA (2) Institute of Neurological Sciences, Neurometabolic Unit, University of Siena, Italy, IT (3) Department of Neurology, Pritzker School of Medicine, and the Brain Research Institute, University of Chicago, Chicago Illinois, USA, US Article note: Received: 2 August 2000, Received in revised form: 11 December 2000, Accepted: 26 February 2001

Members of the tumor necrosis factor/nerve growth factor receptor superfamily of cell-surface molecules can play the dual role of mediating either cytotoxicity or cell survival, both in the immune system and in the nervous system. A member of this superfamily, CD95 (also known as Apol or Fas), was initially identified in the immune system and has been shown to mediate receptor-dependent programmed cell death and to be expressed in the nervous system. In neurodegenerative disorders, CD95-CD95 ligand expression on glial cells might precede receptor-mediated apoptosis by cells of the CNS. It is now being recognized that CD95 signaling by immune cells mediates effects other than apoptosis, such as cell survival and under inflammatory conditions expression of this protein promotes neural-immune interactions. Both neuroscientists and immunologists can contribute to defining the mechanisms underlying these divergent effects and utilize such knowledge to aid understanding of cell death and survival.

Further research is needed to determine whether a blood test for antibodies to myelin could be used to diagnose patients with the early stage of multiple sclerosis (MS). A study published in 2003 found that patients in the early stages of MS who had these antibodies were more likely to develop chronic MS than patients who did not have the antibodies. The development of a blood test would make it much easier to diagnose MS early when it can be easily treated.

Author(s): Jack P. Antel [1]; Josephine Nalbantoglu [1]; Andre Olivier [1] Successful therapy OF the destructive and degenerative disorders that affect the adult human central nervous system (CNS) will require [...]