NeuroImmunology

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Multiple sclerosis (MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified. Epstein-Barr virus (EBV), vitamin D, and smoking are among the most well-established environmental risk factors in MS. Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. This review examines the role of EBV in MS pathophysiology and summarizes the recent clinical and radiological findings, with a focus on B-cells and in vivo imaging. Addressing the potential link between EBV and MS allows the better understanding of MS pathogenesis and helps to identify additional disease biomarkers that may be responsive to B-cell depleting intervention.

Keywords: Epstein-Barr virus; multiple sclerosis; meningeal inflammation; magnetic resonance imaging; leptomeningeal contrast enhancement; mononucleosis; human endogeneous retrovirus-W; B-cells

Autoreactive T cells are suspected to destroy hypocretin-producing neurons in narcolepsy. Here the authors detect CD8 T cells recognizing narcolepsy-related proteins in healthy individuals and in patients with narcolepsy, and show that the frequency of self-reactive CD8 T cells differs between...

A team of researchers under the direction of the Medical Center—University of Freiburg has created an entirely new map of the brain's own immune system in humans and mice. The scientists demonstrated for the first time ...

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FASEB Journal Spotlights UC Davis Researchers’ Work on Stem Cell-Based Neurological Therapies...

BJPsych Open. 2018 Mar 16;4(2):69-74. doi: 10.1192/bjo.2018.8. eCollection 2018 Mar.

Background: Disease modifying therapy (DMT) efficacy trials make an essential contribution to the development of evidence-based clinical treatments and practices for people with multiple sclerosis (MS). Meta-analysis is a critical part of this process and provides a powerful tool to assess the effects of DMT on MS progression. However, although there have been several meta-analyses on the effect of DMT on MS disease progression, they often do not reach the same conclusions.

Objective: Our aim was to better understand and contextualize the results of meta-analyses evaluating DMT, identify differences in methodology that might explain their differing conclusions, and highlight areas for future research that will improve our ability to develop clinical recommendations.

Methods: We conducted an overview of systematic reviews with meta-analyses assessing the efficacy of DMT on disability progression in people with MS in PubMed (Medline) and the Cochrane Database of Systematic Reviews.

Results: We included 22 meta-analyses in this overview: eight general (on >3 DMT), 11 specific (on ≤3 DMT), 2 that evaluated subsets, and 1 that evaluated long-term effects. We found that there is good evidence that DMT improve short-term (≤2–3 years) disability progression outcomes relative to placebo in people with relapsing-remitting MS. However, results varied substantially between meta-analyses, and there is little evidence of their efficacy in other populations or over longer periods. The relative effects of individual DMT also remain unclear. The variance in results between meta-analyses may be related to the substantial differences in inclusion criteria, which was reflected in the limited overlap in included studies, as well as the year of meta-analysis publication. Of the 123 total unique studies included in the general meta-analyses, 77 (62.6%) were included in only one meta-analysis. This incongruence was also evident in the included DMT. Six of the 16 (37.5%) DMT evaluated in the general meta-analyses were only included in one meta-analysis.

Conclusions: Translating DMT efficacy studies into evidence-based clinical practice requires greater methodological consistency in meta-analyses, more data on the relative effects of DMT through head-to-head clinical trials, and better reporting of adverse events.

Federal health regulators on Tuesday warned consumers against controversial "young blood" treatments - plasma infusions from young donors marketed for conditions such as Parkinson's, Alzheimer's, multiple sclerosis and post-traumatic stress disorde...

15 Feb 2019 One of the characteristic features of Alzheimer’s disease is reduced blood flow in the brain. What brings it down? A paper in the February 11 Nature Neuroscience suggests that white blood cells can clog up the works. Scientists led by Chris Schaffer, Cornell University, New York, discovered that neutrophils—leukocytes that are some of the first responders in the innate immune system—get stuck to vessel walls on their way through capillaries in mouse models of AD. Since cells have to squeeze through, single-file, in these tiny blood vessels, this completely blocks blood flow until the cells work their way free. Even though less than 2 percent of capillaries are affected, their interconnectedness with other vessels means blockages can reduce overall blood flow in the brain by 30 percent. However, antibodies that interfere with the binding of neutrophils to vessel walls restored blood flow and memory quickly, even at advanced stages of disease. The results suggest a possible contributing mechanism to Alzheimer’s. Cortical blood flow stalls in AD mouse models. Neutrophils wedge themselves in brain capillaries, clogging them up. Blocking neutrophil receptors or depleting the cells restores blood flow and memory. “The small vessels in the brain are often overlooked in the context of AD,” said Susanne van Veluw, Massachusetts General Hospital, Boston. She emphasized how even the smallest changes in capillaries had a significant impact on cerebral blood flow in the mouse brains. “The authors point to a potentially relevant and overlooked mechanism that could contribute to this well-known phenomenon of reduced cerebral blood flow in Alzheimer’s disease.” Schaffer’s group wanted to study the effects of microvascular injuries on AD pathology. They used transcranial imaging to visualize the vasculature of the mouse brain. They injected fluorescent dye that labeled just the plasma (not red blood cells) of the mice and allowed them to track blood flow after they induced injuries. However, in the process of studying AD mouse controls, they noticed that about 2 percent of capillaries were already blocked, four times more than in wild-type mice. This same obstructed capillary flow has recently been reported in a tau mouse model (Bennett et al., 2018). What was causing this? No Flow. In a mouse model of AD, red blood cells moving through capillaries in the brain occlude fluorescence from the plasma (red), appearing as dark spots that move over time (top). In a few percent of vessels, the dark spots hold their position, indicating that blood flow is at a standstill (bottom). [Courtesy of Hernández et al., 2019. Nat Neurosci.] To examine the phenomenon more closely, first author Jean Cruz Hernández and colleagues first confirmed it happened in several different mouse models of AD. About 1.8 percent of capillaries stalled in APP/PS1 mice as young as 12 weeks old, before plaques had developed. These tiny vessels also clogged in five- to six-month-old 5xFAD mice, and in 10- to 13-month-old TgCRND8 mice. Most plugs lasted less than five minutes, but a third held out for more than 15. The same small subset of capillaries stalled again and again. To identify what caused the obstructions, Hernández tested a series of antibodies to different blood cells and proteins. An antibody to Ly6G, a neutrophil cell-surface marker, labelled almost all the stalled capillaries. To the authors’ surprise, high doses of the anti-Ly6G label abolished plugs completely within minutes. For both seven- to nine-month-old APP/PS1 animals and five- to six-month-old 5xFAD mice, this boosted blood flow by 30 percent and overall brain perfusion by 20 percent, about two-thirds of the way to wild-type levels. Three hours after treatment, transgenic mice were better able to recognize the location of a new object and remember which arm of a Y-maze they had last explored, demonstrating improvements in spatial and working memory. Though the effects only lasted a couple of days due to neutrophil turnover, repeated doses of anti-Ly6G carried the benefits on for a month. Schaffer has unpublished data suggesting the strategy works for 15- to 16-month-old mice, though not 17- to 20-month-old animals, implying that even at relatively advanced disease stages, improvements in blood flow can improve learning and memory. What caused the neutrophils to lodge themselves in capillaries? The data aren’t conclusive, but Schaffer strongly suspects that inflammation in the brain and its vasculature driven by Aβ aggregates increases the expression of ICAM1 and VCAM1 on vessel walls (Park et al., 2008). These proteins bind integrin receptors on neutrophils to help them adhere. Basically, the blood vessels become stickier. A previous study reported that anti-Ly6G, through an unknown mechanism, alters the shape of integrins on neutrophils and interferes with adhesion to vessel walls, making the cells themselves less likely to stick (Wang et al., 2012). That may enable them to slide right through the vessel as usual, Schaffer said. The ties between AD and vascular disease run deep, with countless studies linking poor cardiovascular and cerebrovascular health with greater risk for the disease, and marking it as one of the earliest features of Alzheimer’s (Jun 2014 news; Feb 2012 news; Jul 2016 news). Several reasons have been proposed for the reduced blood flow in the Alzheimer’s brain, including vasoconstriction and loss of vascular density, but scientists don’t fully understand why it occurs (Niwa et al., 2001; Farkas et al., 2001). Could neutrophil stalling be involved? Some drugs that reduce the activation, migration, and adhesion of neutrophils and that are FDA-approved or in clinical trials for autoimmune diseases could help answer this question. However, Schaffer said interfering with neutrophils in Alzheimer’s disease may be unwise because it could compromise the immune system. That said, he is screening some of these drugs to see if they decrease capillary blockages in mice. If one works, a brief clinical trial could help test whether neutrophils reduce cortical blood flow in people. If so, a longer-term strategy might be to target some upstream molecular pathways that lead to the increased adhesion, he speculated. The study of neutrophils in AD has gained momentum in recent years, noted Gabriela Constantin, University of Verona, Italy. She previously reported that depleting neutrophils improves memory in mouse models of AD (Aug 2015 news). A different study found that fast-declining AD patients have more activated neutrophils than slow decliners or controls (Dong et al., 2018). “This new paper connects neutrophils to capillary stalling, adding a new mechanism by which neutrophils could be involved in disease,” she told Alzforum. Van Veluw noted that this phenomenon crops up in mice before amyloid pathology appears. “If this is something that happens early in disease and it translates to humans, it could be an interesting target for early intervention,” she said.—Gwyneth Dickey Zakaib REFERENCES News Citations Brain Injury Boosts Dementia Risk 27 Jun 2014 Silent Vascular Disease May Hasten Dementia Progression 10 Feb 2012 LOAD of Data Place Vascular Malfunction as Earliest Event in Alzheimer’s 8 Jul 2016 Could Neutrophils Be the Newest Players in Neurodegenerative Disease? 1 Aug 2015 Paper Citations Bennett RE, Robbins AB, Hu M, Cao X, Betensky RA, Clark T, Das S, Hyman BT. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease. Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1289-E1298. Epub 2018 Jan 22 PubMed. Park L, Zhou P, Pitstick R, Capone C, Anrather J, Norris EH, Younkin L, Younkin S, Carlson G, McEwen BS, Iadecola C. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1347-52. PubMed. Wang JX, Bair AM, King SL, Shnayder R, Huang YF, Shieh CC, Soberman RJ, Fuhlbrigge RC, Nigrovic PA. Ly6G ligation blocks recruitment of neutrophils via a β2-integrin-dependent mechanism. Blood. 2012 Aug 16;120(7):1489-98. Epub 2012 Jun 1 PubMed. Niwa K, Porter VA, Kazama K, Cornfield D, Carlson GA, Iadecola C. A beta-peptides enhance vasoconstriction in cerebral circulation. Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2417-24. PubMed. Farkas E, Luiten PG. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog Neurobiol. 2001 Aug;64(6):575-611. PubMed. Dong Y, Lagarde J, Xicota L, Corne H, Chantran Y, Chaigneau T, Crestani B, Bottlaender M, Potier MC, Aucouturier P, Dorothée G, Sarazin M, Elbim C. Neutrophil hyperactivation correlates with Alzheimer's disease progression. Ann Neurol. 2018 Feb;83(2):387-405. PubMed. FURTHER READING Papers Stock AJ, Kasus-Jacobi A, Pereira HA. The role of neutrophil granule proteins in neuroinflammation and Alzheimer's disease. J Neuroinflammation. 2018 Aug 27;15(1):240. PubMed. Wolters FJ, Zonneveld HI, Hofman A, van der Lugt A, Koudstaal PJ, Vernooij MW, Ikram MA, Heart-Brain Connection Collaborative Research Group. Cerebral Perfusion and the Risk of Dementia: A Population-Based Study. Circulation. 2017 Aug 22;136(8):719-728. Epub 2017 Jun 6 PubMed. News Absent Aβ, Blood-Brain Barrier Breakdown Predicts Cognitive Impairment 17 Jan 2019 Brain Damage from Cardiovascular Disease Starts Earlier Than You Think 24 Aug 2018 Could Better Blood Pressure Management Preserve Cognition? 3 Aug 2018 Lymphatic Brain Drain Withers in Aging, Worsens Disease 27 Jul 2018

Brain cancer encompasses a diverse range of complex malignancies, many of which are associated with a poor prognosis and require more effective treatments. In this Position Paper, an international panel of clinicians and laboratory-based scientists convened by Cancer Research UK identify and...

Abstract
Three interferons are marketed for the treatment of relapsing-remitting multiple sclerosis. In its pivotal trial, one of them demonstrated impressive efficacy as a once-weekly regimen, but later head-to-head studies and reviews questioned its superiority. Analysis of this pivotal trial in publications and health authority reviews has shown that its early termination might have caused attrition bias. Censored patients were different from those completing the study on magnetic resonance imaging parameters and benefited from placebo in terms of relapse rate. Early progression of disability and differences in follow-up duration could have favored the benefit observed for the progression of disability outcome. Only the raw data could be of help to confirm or refute doubts about this trial. Raw data should be made available to the scientific community.

Keywords interferons, relapsing-remitting multiple sclerosis, efficacy