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Antibody-mediated biorecognition of myelin oligodendrocyte glycoprotein: computational evidence of demyelination-related epitopes

Antibody-mediated biorecognition of myelin oligodendrocyte glycoprotein: computational evidence of demyelination-related epitopes | NeuroImmunology | Scoop.it
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FASEB Journal Spotlights UC Davis Researchers’ Work on Stem Cell-Based Neurological Therapies

FASEB Journal Spotlights UC Davis Researchers’ Work on Stem Cell-Based Neurological Therapies | NeuroImmunology | Scoop.it
FASEB Journal Spotlights UC Davis Researchers’ Work on Stem Cell-Based Neurological Therapies...
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A mouse model of seizures in anti–N‐methyl‐d‐aspartate receptor encephalitis | MyNeuroNews

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Seizures develop in 80% of patients with anti–N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality.Anti‐NMDAR...
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Specific Gut Microbes Linked with Depression: Study

Specific Gut Microbes Linked with Depression: Study | NeuroImmunology | Scoop.it
The research is among the first to find the connection in humans.
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The prevalence and treatment outcomes of antineuronal antibody-positive patients admitted with first episode of psychosis. - PubMed - NCBI

The prevalence and treatment outcomes of antineuronal antibody-positive patients admitted with first episode of psychosis. - PubMed - NCBI | NeuroImmunology | Scoop.it
BJPsych Open. 2018 Mar 16;4(2):69-74. doi: 10.1192/bjo.2018.8. eCollection 2018 Mar.
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Frontiers | The Effect of Disease Modifying Therapies on Disability Progression in Multiple Sclerosis: A Systematic Overview of Meta-Analyses | Neurology

Frontiers | The Effect of Disease Modifying Therapies on Disability Progression in Multiple Sclerosis: A Systematic Overview of Meta-Analyses | Neurology | NeuroImmunology | Scoop.it
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.

Via Krishan Maggon
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Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery

Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery | NeuroImmunology | Scoop.it
In a mouse model of ischaemic stroke, regulatory T cells infiltrate the injured brain in response to the chemokines CCL1 and CCL20 and suppress excessive astrogliosis via the production of amphiregulin.
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Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities

Liu et al. employ a genetic knockin reporter system in mice to track and reciprocally
delete and/or express IL-1 receptor 1 (IL-1R1) in specific CNS cell types. They define cell-type-specific roles for IL-1 signaling, including an essential role for endothelial IL-1R1 in mediating sickness...
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Myelin oligodendrocyte glycoprotein immunoglobulin G‐associated disease: An overview - Fujihara - 2018 - Clinical and Experimental Neuroimmunology - Wiley Online Library

Myelin oligodendrocyte glycoprotein immunoglobulin G‐associated disease: An overview - Fujihara - 2018 - Clinical and Experimental Neuroimmunology - Wiley Online Library | NeuroImmunology | Scoop.it
Abstract Myelin oligodendrocyte glycoprotein (MOG) is localized at the outermost layer of the myelin sheath and is accessible for autoantibodies. Although experimental autoimmune encephalitis induced with MOG immunization has been studied for 30 years, the results of previous reports on MOG immunoglobulin G (IgG) detection with enzyme‐linked immunosorbent assay and Western blot are confusing. However, after the development of human MOG‐transfected cell‐based assay to detect conformational‐sensitive MOG‐IgG, unique groups of patients have been found seropositive, and MOG‐IgG‐associated disease has become a hot topic in clinical neuroimmunology. Currently, the clinical spectrum of MOG‐IgG‐associated disease includes idiopathic optic neuritis, acute disseminated encephalomyelitis, encephalitides (brainstem and cerebral cortical), idiopathic myelitis, atypical multiple sclerosis, aquaporin‐4 IgG‐negative neuromyelitis optica spectrum disorders and others. MOG‐IgG‐associated disease occurs in both children and adults, and the female:male ratio is almost 1:1. Pleocytosis in the cerebrospinal fluids during acute exacerbation is often seen, but oligoclonal IgG bands are usually negative. T helper cell 17, B cells and neutrophil‐related cytokines appear to be upregulated intrathecally. The pathology of acute lesions is characterized by active inflammation demyelination with deposition of immunoglobulins and complements. Just like aquaporin 4 IgG‐positive neuromyelitis optica spectrum disorders, some disease‐modifying drugs for multiple sclerosis seem to be inefficacious in MOG‐IgG‐associated disease, and chronic immunosuppression is required to prevent relapse, especially in patients persistently positive for MOG‐IgG. Our understanding of this newly recognized disease remains insufficient, and the progress of research is much expected. Introduction Inflammatory diseases of the central nervous system in humans include multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), idiopathic optic neuritis and myelitis, Balo's concentric sclerosis and others.1-4 Neuromyelitis optica spectrum disorders (NMOSD) had long been considered a member of this clinical entity, but after the discovery of aquaporin‐4 (AQP4) immunoglobulin G (IgG), an NMOSD‐specific autoantibody, the pathological data on NMOSD has accumulated, and AQP4‐IgG‐seropositive NMOSD is now recognized as an astrocytopathic disease.5, 6 Myelin oligodendrocyte glycoprotein (MOG) is a myelin protein,7, 8 and MOG peptides have been used as an immunogen to induce experimental autoimmune encephalomyelitis (EAE).9 However, the results of previous studies on human disease for the presence of MOG‐IgG detected by enzyme‐linked immunosorbent assay and Western blot have been confusing. With cell‐based assay (CBA) to detect conformation‐sensitive MOG‐IgG, a unique group of patients have been found seropositive for the myelin autoantibody.10-16 In this article, we present a brief overview of the biology of MOG, MOG‐IgG assay, the clinical, neuroimaging and laboratory findings, pathology and pathomechanisms, and therapy of MOG‐IgG‐associated diseases. Biology of MOG MOG is a type I integral membrane protein, and is localized in the extracellular surface of oligodendrocytes and the outermost lamellae of myelin sheath, suggesting that MOG might be accessible for autoantibodies.7, 8, 17 The extracellular portion has an immunoglobulin‐like domain. MOG has monomeric and dimeric species. The primary transcript of the MOG gene has 15 561 nucleotides, and human MOG has 139 amino acids. Human MOG cDNA is homologous to rats, mice, and bovine, and the amino acid sequences are highly conserved among animal species (>90%). The function of MOG is not fully understood, but MOG seems to serve as a homophilic adhesion receptor, and contribute to compaction and maintenance of myelin. MOG‐EAE resembles NMO MOG is highly immunogenic, and can stimulate both T‐ and B‐cell responses. Such MOG peptides as MOG1‐22, MOG35‐55 and MOG92‐106 are encephalitogenic in EAE, and MOG35‐55 can induce various clinical phenotypes of EAE (relapsing–remitting and progressive). MOG‐EAE has been studied for 30 years, and is known to mimic human NMO to some extent.9 Of particular note is a report on spontaneous bilateral optic neuritis and lumbar myelitis closely resembling Devic's disease in a double‐transgenic mouse model of autoimmune T‐cell/B‐cell cooperation (recombination‐competent immune cells expressing a T‐cell receptor‐alpha/beta specific for MOG35‐55 peptide in the context of I‐Ab along with an immunoglobulin J region replaced by the recombined heavy chain of a monoclonal antibody binding to a conformational epitope on MOG).18 However, in those days, AQP4‐IgG attracted a great deal of attention as a newly‐discovered, NMO‐specific biomarker, and the MOG story was not so conspicuous in the research of the human disease. Disappointment at MOG‐IgG seropositivity A number of studies on MOG‐IgG with enzyme‐linked immunosorbent assay, Western blot or immunohistochemistry had been published, but they were not able to reveal a unique group of patients.10, 16 Later, MOG‐IgG took center stage in MS research when the patients with clinically isolated syndrome who were seropositive for both MOG‐IgG and myelin basic protein (MBP) IgG in the blood were reported to be highly likely to convert to clinically definite MS.19, 20 Unfortunately, subsequent studies did not confirm the predictive value of the myelin antibodies. CBA to detect MOG‐IgG The MOG protein does not retain the native three‐dimensional structure in enzyme‐linked immunosorbent assay or Western blot, and there are some amino acid sequence changes between humans and rodents. Recently, human MOG‐transfected CBA was developed to detect conformation‐sensitive MOG‐IgG, and the CBA was able to identify unique patient groups.10-16 Although MOG‐IgG seropositivity is greatly influenced by which transfectants and secondary antibodies are used, recent studies have shown that a combination of full‐length human MOG‐transfected cells and secondary antibody specific to Fc or IgG1 is relatively good to detect unique patient groups. However, false positive and false negative results can occur, and further studies will be required to establish a highly reliable standard assay for MOG‐IgG. As for human MOG‐IgG reactivity: (i) the CC′‐loop of MOG is most commonly recognized; (ii) no epitope spreading occurs over time, and (iii) human MOG‐IgG does not recognize rodent MOG, which is important in developing animal models of MOG‐IgG‐associated disease.21 As some patients with NMO are MOG‐IgG‐positive, it is interesting to know if there are cases doubly positive for MOG‐IgG and AQP4‐IgG. In most recent studies with MOG‐IgG‐CBA, no patients possessed both MOG‐IgG and AQP4‐IgG, but some doubly positive cases have been reported.22, 23 Clinical, magnetic resonance imaging and laboratory features The average age of onset of MOG‐IgG‐associated disease is approximately 30 years, but it ranges widely from <5 years to >70 years, and the ratio of women to men is almost 1:1. This disease seems to be distributed nationwide and worldwide, but large‐scale epidemiological surveys have not been carried out.24-29 The clinical spectrum of MOG‐IgG‐associated disease is shown in Fig. 1. MOG‐IgG assayed by CBA is detectable in some patients with idiopathic optic neuritis, idiopathic myelitis, ADEM, AQP4‐IgG‐seronegative NMOSD, atypical MS, and brainstem and cerebral cortical encephalitides. At least half of the patients have a relapsing disease (~40 relapses). Generally speaking, the frequency of MOG‐IgG‐positive cases in the clinical phenotypes appears to be higher in children than in adults. Coexisting other autoimmune disorders are less common in MOG‐IgG‐positive disease than in AQP4‐IgG‐positive NMOSD. Nevertheless, such cases are occasionally seen (we experienced a patient positive for both NMDA receptor antibody and MOG‐IgG who had recurrent central nervous system demyelinating episodes).30 In cerebrospinal fluid (CSF) examination during acute exacerbation, pleocytosis (mononuclear cells and polymorphonuclear cells) is often seen, but oligoclonal IgG bands are mostly negative and the IgG index is not high. Clinical phenotypes of MOG‐IgG‐associated disease Case examples of magnetic resonance imaging (MRI) abnormalities are shown in Fig. 2. Optic neuritis Optic neuritis is probably the most common clinical phenotype of MOG‐IgG‐associated disease. It can be unilateral or simultaneous bilateral, but in contrast to AQP4‐IgG‐positive optic neuritis, optic chiasmal involvement is rare.24, 31 In the acute phase, severe visual impairment occurs, but functional recovery is relatively good, and unlike AQP4‐IgG‐positive optic neuritis, blindness is uncommon in MOG‐IgG‐positive optic neuritis. Orbital MRI might show hyperintense lesions along the optic nerve with gadolinium enhancement, and the optic nerve is often tortuous as a result of severe swelling. The perineural tissue is often gadolinium enhanced as well. In the chronic phase, the retinal nerve fiber layer thickness measured in optical coherence tomography is thicker in MOG‐IgG‐associated disease than in AQP4‐IgG‐seropositive NMOSD, suggesting milder neuronal damage in MOG‐IgG‐positive optic neuritis.32 Myelitis MOG‐IgG‐positive myelitis can be transverse, and approximately half of them are longitudinally extensive (longer than three vertebral segments) on MRI.24, 33 The cervical and thoracic cord are commonly involved, but as compared with AQP4‐IgG‐positive myelitis, the lumbosacral region is relatively commonly involved. Sensory disturbance and dysuria are common, and some patients might not have leg weakness. ADEM Most patients with ADEM are children, and generally speaking, MOG‐IgG‐positive ADEM is characterized by large, widespread brain MRI lesions, longitudinally extensive transverse myelitis and favorable outcome.34 AQP4‐IgG‐seronegative NMOSD In adults, patients with definite NMO (optic neuritis + longitudinally extensive transverse myelitis) are mostly AQP4‐IgG‐positive (~80%), and MOG‐IgG‐positive definite NMO is a minor population (~3%). Meanwhile, in pediatric patients with definite NMO, MOG‐IgG might be positive in approximately 40% of the total cases. MOG‐IgG‐positive NMO is generally milder than AQP4‐IgG‐positive NMO.24 Interestingly, among the 17 cases compiled by Gault and Devic in Gault's thesis in 1894, the average onset age was 31 years (range 12~52 years), there were more men than women, optic neuritis was bilateral in 15 patients and the course was monophasic in 14 patients. They are features of MOG‐IgG‐positive cases rather than AQP4‐IgG‐positive NMO. Some of the case series might have been MOG‐IgG‐positive. Atypical MS Typical MS cases are largely MOG‐IgG‐negative. In a study of 50 Japanese cases with AQP4‐IgG‐negative opticospinal MS, just two were MOG‐IgG‐positive, but they had some features atypical for MS, such as bilateral optic neuritis, longitudinally extensive transverse myelitis or moderate pleocytosis.35 In a German study, 5% of MS with severe involvement of the spinal cord, optic nerve or brainstem were MOG‐IgG‐positive and showed poor responses to multiple disease‐modifying drug therapies, although they were oligoclonal band‐positive and had typical brain MRI lesions.36 Approximately 10% of pediatric MS cases have been reported to develop longitudinally extensive transverse myelitis, and AQP4‐IgG‐seropositivity in those cases is low relative to adult patients with such long spinal cord lesions. At least a certain percentage of pediatric MS patients might be MOG‐IgG‐positive. The brain lesions of relapsing–remitting (RR) MS fulfill the MRI criteria of: (i) at least one lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; (ii) the presence of a subcortical U‐fiber lesion; or (iii) a Dawson's finger‐type lesion, with high sensitivity and specificity, and the criteria is useful to distinguish relapsing–remitting MS from MOG‐IgG‐associated disease, and AQP4‐IgG‐positive NMOSD with brain lesions.37 MOG‐IgG‐associated disease frequently develops fluffy brainstem lesions, often located in the pons and/or adjacent to the fourth ventricle.38 Brainstem and cerebral cortical encephalitides Various brain stem lesions can develop, but area‐postrema syndrome manifesting intractable hiccups, nausea and vomiting is less common in MOG‐IgG‐positive disease than in AQP4‐IgG‐positive NMOSD. Recently, we reported MOG‐IgG‐positive unilateral cerebral cortical encephalitis with epilepsy in adults that is distinct from other known autoimmune encephalitis.39 The cortical lesions were best shown by fluid‐attenuated inversion recovery images. Some of the patients developed optic neuritis as well. Epileptic seizures in those patients were often resistant to anti‐epilepsy drug therapy alone, but responded swiftly to high‐dose intravenous methylprednisolone. The fluid‐attenuated inversion recovery‐hyperintense cortical lesions disappeared after several months. We also reported a MOG‐IgG‐positive patient who initially presented with paraparesis as a result of bilateral medial frontal cortex encephalitis.40 Pathology and pathomechanisms A small number of brain‐biopsied cases with MOG‐IgG‐positive tumefactive brain lesions have been reported, and the pathological findings are characterized by so‐called MS type II pathology (active inflammatory demyelination with deposition of immunoglobulins and complements).41, 42 Our studies on cell damage markers in the CSF during acute exacerbations showed that regardless of the clinical phenotypes, the CSF MBP level was high, whereas the CSF‐glial fibrillary acidic protein level was not elevated at all, clearly showing that MOG‐IgG‐positive disease is an inflammatory demyelinating disease, even if the clinical phenotype is NMO.43, 44 Data on immunological abnormalities in MOG‐IgG‐positive disease are insufficient, but T helper cell 17, B cells and neutrophil‐related cytokines seem to be upregulated in the CSF during the acute phase of the disease.45 Although pathogenicity of MOG‐IgG has not been clarified, there have been some reports supporting it. An Australian group showed that MOG‐IgG affected oligodendrocyte cytoskeleton.46 MOG‐IgG derived from an NMO patient caused reversible lesions in the mouse brain (independent of complement).47 More recently, a study from Denmark showed that MOG‐IgG and complement was sufficient to induce central nervous system demyelination, and was dependent on type I interferon signaling.48 In fact, the major IgG subclass of MOG‐IgG is IgG1, and thus MOG‐IgG can efficiently activate complements. Treatment Therapy for MOG‐IgG‐positive disease has not been established and existing evidence is very limited. However, in the acute phase, as with MS and NMOSD, the first‐line therapy is intravenous methylprednisolone and most patients respond well, but if refractory to intravenous methylprednisolone, plasma exchange should be started as a rescue therapy.14, 25, 49 Immunosuppression (corticosteroid, mycophenolate mofetil, methotrexate etc.) is the mainstay for treatment to prevent relapse.25, 46 In common with AQP4‐IgG‐positive NMOSD, disease‐modifying drugs for MS, such as like interferon‐beta and fingolimod, might not be efficacious in MOG‐IgG‐positive patients.50, 51 The persistence of MOG‐IgG might be crucial for relapse of MOG‐IgG‐associated disease, and useful in considering relapse prevention. Meanwhile, MOG‐IgG is only transiently positive in some patients, and the disease in those patients tends to be monophasic. Curiously, a fraction of patients persistently positive for MOG‐IgG might also be relapse‐free without chronic immunosuppression for over a long period of time. Long‐term follow‐up data should be accumulated to address the issue. Conflict of interest Professor Kazuo Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma, Takeda Pharmaceutical Company Limited, Asahi Kasei Medical, Daiichi Sankyo and Nihon Pharmaceutical; serves as an editorial board member for Clinical and Experimental Neuroimmunology (2009 to present), and is an advisory board member of Sri Lanka Journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo‐Sero‐Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical and Genzyme Japan; is funded by Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (#22229008, 2010‐2015; #26293205, 2014–2016), and by Grants‐in‐Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010 to present). Dr Douglas Kazutoshi Sato has received a scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; Grants‐in‐Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI 15K19472); research support from CAPES/Brasil (CSF‐PAJT—88887.091277/2014‐00); and speaker honoraria from Novartis. Dr Ichiro Nakashima has received funding for travel and received speaker honoraria from Tanabe Mitsubishi Pharma Corporation; has received research funding from LSI Medience Corporation; and Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Dr Yoshiki Takai has received research support from Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Dr Shuhei Nishiyama has received research support from Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Dr Hiroshi Kuroda has received research support from Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Professor Masashi Aoki has received research support from Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. Dr Tatsuro Misu has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical and Astellas Pharma, and has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical, The Chemo‐Sero‐Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma Corporation and Teijin Pharma; and Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. The other authors report no conflict of interest. References
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Immunogenetics of glioblastoma: the future of personalized patient management

Immunogenetics of glioblastoma: the future of personalized patient management | NeuroImmunology | Scoop.it
The prognosis of glioblastoma has changed little over the past two decades, with only minor improvements in length of overall survival through the addition of temozolomide (temodal) to standard of care and the recommended use of alternating electric field ...
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Dynamics of oligodendrocyte generation in multiple sclerosis

Dynamics of oligodendrocyte generation in multiple sclerosis | NeuroImmunology | Scoop.it
There are no new oligodendrocytes in potentially remyelinated multiple sclerosis shadow plaques, although oligodendrocyte generation is increased in the normal appearing white matter of patients with aggressive disease, informing the development of new therapies.

Via Krishan Maggon
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Rituximab in neurological disease: principles, evidence and practice

Rituximab in neurological disease: principles, evidence and practice | NeuroImmunology | Scoop.it
Rituximab is a widely used B-cell-depleting monoclonal antibody. It is unlicensed for use in neurological disorders and there are no treatment guidelines. However, as a rapidly acting, targeted therapy with growing evidence of efficacy and tolerability in several neuroinflammatory disorders, it is...
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Immune Cells Clog Capillaries in Mice, Disrupt Memory | ALZFORUM

Immune Cells Clog Capillaries in Mice, Disrupt Memory | ALZFORUM | NeuroImmunology | Scoop.it
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
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Challenges to curing primary brain tumours

Challenges to curing primary brain tumours | NeuroImmunology | Scoop.it
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...
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Frontiers | Application of plasma exchange in steroid-responsive encephalopathy. | Immunology

Plasma exchange has been widely used in autoimmune neurological diseases and is the standard treatment for myasthenia gravis crisis and Guillain-Barre syndrome. A growing body of research suggests that, in the clinical application of steroid-responsive encephalopathy, such as for Hashimoto’s...
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New Map Shows Brain Changes Associated with Alzheimer's

New Map Shows Brain Changes Associated with Alzheimer's | NeuroImmunology | Scoop.it
The protein expression data, which are freely available online, could help identify new drug targets for the disease.
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Defining distinct features of anti-MOG antibody associated central nervous system demyelination

Defining distinct features of anti-MOG antibody associated central nervous system demyelination | NeuroImmunology | Scoop.it
Extensive research over the last decades basically failed to identify a common cause of noninfectious inflammatory central nervous system (CNS) demyelinating disease. To a great extent, this may reflect that the group of inflammatory CNS demyelinating ...
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Approved Beta Interferons in Relapsing-Remitting Multiple Sclerosis: Is there an odd one Out? - Alexis Clapin, 2012

Approved Beta Interferons in Relapsing-Remitting Multiple Sclerosis: Is there an odd one Out? - Alexis Clapin, 2012 | NeuroImmunology | Scoop.it
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

Via Krishan Maggon
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Système lymphatique et cerveau | médecine/sciences

Système lymphatique et cerveau | médecine/sciences | NeuroImmunology | Scoop.it
médecine/sciences (M/S), revue internationale dans le domaine de la recherche biologique, médicale et en santé
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sujet abordé sur https://www.scoop.it/t/neuroimmunology?q=lymphatics

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Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation

Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation | NeuroImmunology | Scoop.it
Multiple distinct populations of potential antigen-presenting cells (APCs) are interspersed among the different anatomical components of the brain, including microglia, B lymphocytes, macrophages, and dendritic cells (DCs). Mundt et al. investigated which steady-state APC types are responsible for displaying peptide fragments of myelin proteins to pathogenic CD4+ T cells with the capacity to initiate neuroinflammatory disorders such as human multiple sclerosis. Adoptive transfer of myelin-reactive CD4+ T cells to mice with conditional deletion of MHC class II molecules in specific brain APC subsets identified conventional DCs as the essential APCs enabling initiation of T cell–mediated immunopathology. The results of this study will assist in the precision targeting of immunotherapies aimed at restraining rogue T cells responsible for human neuroinflammatory diseases.

The central nervous system (CNS) is under close surveillance by immune cells, which mediate tissue homeostasis, protection, and repair. Conversely, in neuroinflammation, dysregulated leukocyte invasion into the CNS leads to immunopathology and neurological disability. To invade the brain parenchyma, autoimmune encephalitogenic T helper (TH) cells must encounter their cognate antigens (Ags) presented via local Ag-presenting cells (APCs). The precise identity of the APC that samples, processes, and presents CNS-derived Ags to autoaggressive T cells is unknown. Here, we used a combination of high-dimensional single-cell mapping and conditional MHC class II ablation across all CNS APCs to systematically interrogate each population for its ability to reactivate encephalitogenic TH cells in vivo. We found a population of conventional dendritic cells, but not border-associated macrophages or microglia, to be essential for licensing T cells to initiate neuroinflammation.
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Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid

Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid | NeuroImmunology | Scoop.it
Identification and sequencing of circulating tumour DNA in the cerebrospinal fluid of patients with glioma.
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Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation

Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation | NeuroImmunology | Scoop.it
Myeloid cells, such as dendritic cells and macrophages, in the central nervous system (CNS) play critical roles in the initiation and exacerbation of multiple sclerosis (MS). Jordão et al. combined high-throughput single-cell RNA sequencing and intravital microscopy to compile a transcriptional atlas of myeloid subsets in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Microglia and other CNS-associated macrophages expanded and transformed into various context-dependent subtypes during EAE. Furthermore, dendritic cells and monocyte-derived cells, but not resident macrophages, played a critical role by presenting antigen to pathogenic T cells. This exhaustive characterization may inform future therapeutic targeting strategies in MS.

Science , this issue p. [eaat7554][1]

### INTRODUCTION

Under homeostasis, the central nervous system (CNS) hosts microglia (MG) and CNS-associated macrophages (CAMs). During experimental autoimmune encephalomyelitis (EAE), myeloid complexity drastically increases, with dendritic cells (DCs) and monocytes seeding the CNS. However, which disease-specific populations can be found during neuroinflammation remains largely unknown.

### RATIONALE

An important step for the initiation of EAE and multiple sclerosis (MS) is the infiltration of the CNS by encephalitogenic T cells, which potentially become reactivated by encountering their self-cognate antigens presented at the brain interfaces. Myeloid cells have been shown to play a critical role in antigen presentation. Consequently, their transcriptomic profile and dynamics during neuroinflammation are crucial for understanding neuroinflammatory pathology.

### RESULTS

High-throughput single-cell sequencing (scRNA-seq) of CD45+ cells isolated from several CNS compartments (including leptomeninges, perivascular space and parenchyma, and choroid plexus) allowed us to assemble a transcriptional atlas comprising 3461 immune cells, identified as homeostatic (“h”) or disease-associated (“da”) myeloid subsets. Profiling of all CAMs unraveled a core signature that consists of Mrc1 , Pf4 , Ms4a7 , Stab1 , and Cbr2 . During disease, only Ms4a7 remained stably expressed, and a strong increase of antigen-presentation molecules (such as Cd74 ) was observed. Microglia expressed genes that included P2ry12 , Tmem119 , Sparc , and Olfml3 . Although most of the core genes were down-regulated during disease, Sparc and Olfml3 expression remained unaltered and were accompanied by an up-regulation of Ly86 . Several monocyte populations were observed during EAE, including monocyte-derived cells expressing Mertk and Mrc1 or expressing Zbtb46 and Cd209a . Although DCs were scarce in the homeostatic CNS, their density highly increased during disease, and diverse disease-associated DCs could be identified.

We next established the spatiotemporal relationship between infiltrating monocytes and resident macrophages using the Cx3cr1CreERT2 system. Local proliferation of resident macrophages occurred alongside continuous monocytic infiltration up to the peak of disease. Monocytes were transiently integrated into the CNS, and resident macrophages underwent apoptosis during the chronic phase. An evaluation of microglial expansion by using Cx3cr1CreER:R26Confetti mice revealed their clonal expansion during neuroinflammation.

We then investigated the capacity of resident and hematopoietic stem cell–derived myeloid cells for antigen presentation. Time-lapse imaging of Cx3cr1CreERT2:R26tdTomato : Cd2GFP and Ccr2RFP : Cd2GFP mice showed prolonged T cell interactions with circulating myeloid cells rather than tissue-resident macrophages during neuroinflammation. Accordingly, MOG35-55 immunization of Cx3cr1CreERT2:H2-Ab1flox mice showed no overt changes in disease development, indicating that resident macrophages are redundant for antigen presentation. By contrast, Cd11cCre:H2-Ab1flox mice were highly resistant to EAE, pointing to the potential role of DCs and monocyte-derived cells in EAE onset.

### CONCLUSION

In this study, we unraveled the complexity of the CNS myeloid landscape and the dynamics of several myeloid populations during neuroinflammation. Although CNS-resident macrophages quickly generated context-dependent subsets during disease, their role as APCs was irrelevant for the initiation of pathology. DCs and monocyte-derived cells, highly diverse during EAE, remain the major players in antigen presentation. The comprehensive characterization presented here will provide a strong basis for their future targeting.

![Figure][2]

Myeloid cell diversity during neuroinflammation.
The homeostatic CNS includes microglia and different CAMs. During disease, microglia clonally expand, and the transcriptomic profile of microglia and CAMs drastically change. Diverse DC and monocyte subsets simultaneously populate the CNS. The role of resident macrophages for antigen presentation is redundant, whereas DCs and/or monocyte-derived populations show high antigen-presentation capacity, pointing to their crucial role in experimental autoimmune encephalomyelitis.



The innate immune cell compartment is highly diverse in the healthy central nervous system (CNS), including parenchymal and non-parenchymal macrophages. However, this complexity is increased in inflammatory settings by the recruitment of circulating myeloid cells. It is unclear which disease-specific myeloid subsets exist and what their transcriptional profiles and dynamics during CNS pathology are. Combining deep single-cell transcriptome analysis, fate mapping, in vivo imaging, clonal analysis, and transgenic mouse lines, we comprehensively characterized unappreciated myeloid subsets in several CNS compartments during neuroinflammation. During inflammation, CNS macrophage subsets undergo self-renewal, and random proliferation shifts toward clonal expansion. Last, functional studies demonstrated that endogenous CNS tissue macrophages are redundant for antigen presentation. Our results highlight myeloid cell diversity and provide insights into the brain’s innate immune system.

[1]: /lookup/doi/10.1126/science.aat7554
[2]: pending:yes
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Novel small molecule IL‐6 inhibitor suppresses autoreactive Th17 development and promotes Treg development - Aqel - - Clinical & Experimental Immunology - Wiley Online Library

Multiple sclerosis (MS) is the leading cause of non‐traumatic neurological disability in the United States in young adults, but current treatments are only partially effective, making it necessary to develop new, innovative therapeutic strategies. Myelin‐specific interleukin (IL)‐17‐producing T helper type 17 (Th17) cells are a major subset of CD4 T effector cells (Teff) that play a critical role in mediating the development and progression of MS and its mouse model, experimental autoimmune encephalomyelitis (EAE), while regulatory T cells (Treg) CD4 T cells are beneficial for suppressing disease. The IL‐6/signal transducer and activator of transcription 3 (STAT‐3) signaling pathway is a key regulator of Th17 and Treg cells by promoting Th17 development and suppressing Treg development. Here we show that three novel small molecule IL‐6 inhibitors, madindoline‐5 (MDL‐5), MDL‐16 and MDL‐101, significantly suppress IL‐17 production in myelin‐specific CD4 T cells in a dose‐dependent manner in vitro. MDL‐101 showed superior potency in suppressing IL‐17 production compared to MDL‐5 and MDL‐16. Treatment of myelin‐specific CD4 T cells with MDL‐101 in vitro reduced their encephalitogenic potential following their subsequent adoptive transfer. Furthermore, MDL‐101 significantly suppressed proliferation and IL‐17 production of anti‐CD3‐activated effector/memory CD45RO+CD4+ human CD4 T cells and promoted human Treg development. Together, these data demonstrate that these novel small molecule IL‐6 inhibitors have the potential to shift the Teff : Treg balance, which may provide a novel therapeutic strategy for ameliorating disease progression in MS.
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Neuro–Immune Cell Units: A New Paradigm in Physiology | Annual Review of Immunology

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