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Frontiers | Detection of Protein Aggregates in Brain and Cerebrospinal Fluid Derived from Multiple Sclerosis Patients | Multiple Sclerosis and Neuroimmunology

Studies of the properties of soluble oligomers species of amyloidogenic proteins, derived from different proteins with little sequence homology, have indicated that they share a common structure an...
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Microglia and early brain development: An intimate journey

Microglia and early brain development: An intimate journey | NeuroImmunology | Scoop.it
Cross-talk between the nervous and immune systems has been well described in the context of adult physiology and disease. Recent advances in our understanding of immune cell ontogeny have revealed a notable interplay between neurons and microglia during the prenatal and postnatal emergence of functional circuits. This Review focuses on the brain, where the early symbiotic relationship between microglia and neuronal cells critically regulates wiring, contributes to sex-specific differences in neural circuits, and relays crucial information from the periphery, including signals derived from the microbiota. These observations underscore the importance of studying neurodevelopment as part of a broader framework that considers nervous system interactions with microglia in a whole-body context.
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Scooped by Gilbert C FAURE from Multiple sclerosis New Drugs Review
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Novartis  NDA/MAA filing and acceptance of siponimod by FDA/EMA, the first and only drug shown to meaningfully delay disability progression in typical SPMS patients

Novartis  NDA/MAA filing and acceptance of siponimod by FDA/EMA, the first and only drug shown to meaningfully delay disability progression in typical SPMS patients | NeuroImmunology | Scoop.it

Basel, October 08, 2018 Novartis today announced that both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have accepted the company's New Drug Application (NDA) and Marketing Authorization Application (MAA) respectively, for investigational oral, once-daily siponimod (BAF312) for the treatment of secondary progressive multiple sclerosis (SPMS) in adults. This phase of multiple sclerosis (MS) can substantially impact lives, due to physical and cognitive impairments[2]. To bring this treatment to the MS community as quickly as possible, Novartis used a review voucher to expedite the review of siponimod in the US. Regulatory action for siponimod is anticipated in the US in March of 2019 and in Europe in late 2019.

 

More than 80% of people with relapsing-remitting MS (RRMS) - the most common form of the condition at diagnosis - go on to develop SPMS, with or without relapses[2],[3]. SPMS is a form of MS that leads to progressive, irreversible disability, such as the need for enhanced walking aids and wheelchairs, bladder dysfunction and cognitive decline, largely independent of relapses. Following the initial RRMS course, there is a gradual increase in the number of patients transitioning to SPMS, with around 25% progressing by 10 years post-onset, 50% by 20 years and more than 75% by 30 years[2],[3].

 

The regulatory application is based on data from the EXPAND study, a randomized, double-blind, placebo-controlled Phase III study, comparing the efficacy and safety of siponimod versus placebo in people living with typical SPMS. At study initiation, more than 50% of patients in the EXPAND study relied on a walking aid[1]. Results from the pivotal study showed siponimod significantly reduced the risk of three-month confirmed disability progression versus placebo (primary endpoint; 21% versus placebo, p=0.013). Siponimod also meaningfully delayed the risk of six-month confirmed disability progression (26% vs placebo, p=0.0058) and demonstrated favorable outcomes in other relevant measures of MS disease activity and progression[1]. Further, more advanced analyses of the EXPAND study showed that siponimod reduced the risk of disability progression largely disassociated from relapses (three-month disability progression, range 14-20%; six-month disability progression 29-33%)[1].

 

  • There is a critical need for safe and effective treatments for secondary progressive multiple sclerosis (SPMS) - a highly debilitating form of MS characterized by gradual, irreversible worsening of disability, largely independent of relapses 
     
  • If approved, siponimod (BAF312) would be the first oral disease-modifying therapy with the potential to delay progression and expand possibilities for SPMS patients 
     
  • Filings are supported by Phase III EXPAND data, which showed siponimod had beneficial effects on disability, relapses and magnetic resonance imaging (MRI) disease activities in typical SPMS patients[1]
     
  • Novartis used a priority review voucher to expedite review of siponimod in the US to ensure patients could benefit from the drug as soon as possible, pending approval

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Krishan Maggon 's curator insight, October 8, 3:22 PM

About Siponimod (BAF312)
Siponimod is an investigational, selective modulator of specific subtypes of the sphingosine-1-phosphate (S1P) receptor[5]. Siponimod binds to the S1P1 sub-receptor on lymphocytes, which prevents them from entering the central nervous system (CNS) of patients with multiple sclerosis. This leads to the anti-inflammatory effects of siponimod.[1] Siponimod also enters the CNS and binds to the S1P5 sub-receptor on specific cells in the CNS (oligodendrocytes and astrocytes)[6]. By binding to these specific receptors, siponimod has the potential to modulate damaging cell activity, and preclinical studies suggest that it may prevent synaptic neurodegeneration and promote remyelination in the CNS[7].

 

Investigational compounds include siponimod (BAF312, a selective modulator of the S1P receptor subtypes 1 and 5), for SPMS, and ofatumumab (OMB157), a fully human monoclonal antibody in development for relapsing MS. Ofatumumab targets CD20, and is currently being investigated in two Phase III pivotal studies.

 

Sales of Gilenya (fingolimod) were $3 billion in 2017

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Opinion | He Got Schizophrenia. He Got Cancer. And Then He Got Cured. - The New York Times

Opinion | He Got Schizophrenia. He Got Cancer. And Then He Got Cured. - The New York Times | NeuroImmunology | Scoop.it
A bone-marrow transplant treated a patient’s leukemia — and his delusions, too. Some doctors think they know why.
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Mast Cells in Neuroimmune Interactions

A major aspect of the regulatory function of mast cells appears to be their role as
intermediaries between the nervous and immune systems. Mast cells are activated by
neurotransmitters allowing neural control of innate and adaptive immunity.
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Genetically-engineered olfactory cells successfully bypass the BBB to kill brain cancer tumours.

Genetically-engineered olfactory cells successfully bypass the BBB to kill brain cancer tumours. | NeuroImmunology | Scoop.it
Olfactory neurons are cells in the nasal cavity which perceive odors, passing the information along to the brain, and have the ability to regenerate.  They project axons to the olfactory bulb within the brain itself with olfactory ensheathing cells surrounding the growing axons, assisting in their...
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Scooped by Gilbert C FAURE from Cancer Immunotherapy Review
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T cells engineered to home in on brain cancer

T cells engineered to home in on brain cancer | NeuroImmunology | Scoop.it
Immunotherapies activate T cells to destroy tumours, but the approach has failed in some brain cancers. A strategy to improve migration of T cells across the blood–brain barrier could overcome this limitation.

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JCI Insight - Single-cell RNA sequencing reveals microglia-like cells in cerebrospinal fluid during virologically suppressed HIV

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CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature

CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature | NeuroImmunology | Scoop.it
Louveau et al. demonstrate that meningeal lymphatics drain CSF-derived macromolecules and immune cells and play a key role in regulating neuroinflammation. Meningeal lymphatics may represent a new therapeutic target for multiple sclerosis.
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THUR 154 NMDAR-AB encephalitis: frequency of diagnosis and outcomes

THUR 154 NMDAR-AB encephalitis: frequency of diagnosis and outcomes | NeuroImmunology | Scoop.it
Background The association of N-methyl d-aspartate receptor-antibodies (NMDAR-Abs) and encephalitis is now well recognised.

Methods Retrospective review of frequency of diagnosis and outcomes in encephalitis with NMDAR-Abs identified at the Walton Centre between 2012–2017.
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Scooped by Gilbert C FAURE from Multiple sclerosis New Drugs Review
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The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics. - The Microbiome

The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics. - The Microbiome | NeuroImmunology | Scoop.it
PubMed ID: 29860380 Camara-Lemarroy CR, Metz L, Meddings JB, Sharkey KA, Wee Yong V Brain. Jul 2018. doi: 10.1093/brain/awy131 COMMENT: This review is focused on the role that the gut microbiome and the intestinal barrier could play in the pathophysiology of multiple sclerosis. In several works it has been reported that some gastrointestinal disorders with intestinal barrier breakdown show evidence of CNS demyelination, probably due to the impact on the functions of CNS microglia that the microbial organisms entering in the circulation provoke. The authors highlight the importance of the intestinal barrier and the mucosal immune cells in the brain-gut axis and describe this host-microbiome interface as a crucial zone of interaction between immune cells and microbial cells: In this review, we describe the intestinal barrier as the physical and functional zone of interaction between the luminal microbiome and the host. Besides its essential role in the regulation of homeostatic processes, the intestinal barrier contains the gut mucosal immune system, a guardian of the integrity of the intestinal tract and the whole organism. Barrier-stabilizing strategies of treatment for multiple esclerosis as probiotics and stabilizers of tight junctions are discussed along the review and proposed as new therapeutic possibilities for multiple esclerosis.   Contributor Raquel Tobes

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Scooped by Gilbert C FAURE from from Flow Cytometry to Cytomics
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ANGLE : Parsortix shows evidence of CTCs in glioblastoma | MarketScreener

ANGLE : Parsortix shows evidence of CTCs in glioblastoma | MarketScreener | NeuroImmunology | Scoop.it
ANGLE plc


PARSORTIX SYSTEM PROVIDES THE FIRST EVIDENCE OF CIRCULATING TUMOUR CELL CLUSTERS IN GLIOBLASTOMA


Parsortix system detects CTCs in...| août 28, 2018...
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https://angleplc.com/wp-content/uploads/British-Journal-of-Cancer-Glioblastoma-01aug18.pdf

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Cerveau et immunité : un dialogue insoupçonné | Pour la Science

Cerveau et immunité : un dialogue insoupçonné | Pour la Science | NeuroImmunology | Scoop.it
La relation entre le cerveau et le système immunitaire ? Inexistante, pensait-on, sauf dans des cas pathologiques. Or on découvre que les deux systèmes sont intimement liés. Une connexion qui aurait une influence sur l’apprentissage et le comportement social.
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GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis

GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis | NeuroImmunology | Scoop.it
Although it is well established that autoreactive lymphocytes induce demyelination in multiple sclerosis, the exact antigenic targets that initiate disease are undefined. Planas et al . studied CD4+ T cells from the cerebrospinal fluid of patients with multiple sclerosis. One CD4+ T cell clone was reactive to the human enzyme GDP-l-fucose synthase; T cells from other patients were then identified, as well as myelin-reactive cells. Intriguingly, some of the GDP-l-fucose synthase–reactive cells could also be stimulated by a bacterial version of the enzyme. These tantalizing results identify a new autoantigen and suggest that one possible trigger of disease could be cross-reactivity to microbiota-derived peptides.

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.
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PET scans show fibromyalgia patients have inflammation in the brain - UPI.com

PET scans show fibromyalgia patients have inflammation in the brain - UPI.com | NeuroImmunology | Scoop.it
People with fibromyalgia have widespread inflammation in their brains, new research reveals.
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Phenotypic heterogeneity of astrocytes in motor neuron disease - Trias - - Clinical and Experimental Neuroimmunology - Wiley Online Library

Abstract Accumulating evidence has shown that astrocytes do not just support the function of neurons, but play key roles in maintaining the brain environment in health and disease. Contrary to the traditional understanding of astrocytes as static cells, reactive astrocytes possess more diverse functions and phenotypes than previously predicted. In the present focused review, we summarize the evidence showing that astrocytes are playing profound roles in the disease process of amyotrophic lateral sclerosis. Aberrantly activated astrocytes in amyotrophic lateral sclerosis rodents express microglial molecular markers and provoke toxicities to accelerate disease progression. In addition, TIR domain–containing adapter protein–inducing interferon‐β‐dependent innate immune pathway in astrocytes also has a novel function in terminating glial activation and neuroinflammation. Furthermore, heterogeneity in phenotypes and functions of astrocytes are also observed in various disease conditions, such as other neurodegenerative diseases, ischemia, aging and acute lesions in the central nervous system. Through accumulating knowledge of the phenotypic and functional diversity of astrocytes, these cells will become more attractive therapeutic targets for neurological diseases. Introduction Neurodegenerative diseases are characterized by the selective death of certain types of neurons. In addition, activation of glial cells surrounding the degenerating neurons is also a common pathological finding in almost all neurodegenerative diseases. For a long time, glial activation has been regarded just as a consequence of neurodegeneration; however, accumulating evidence has shown the active roles of glial cells in neurodegenerative diseases, and the term “neuroinflammation” has been used to describe the key phenomenon involving the glia‐mediated pathology of these diseases.1 Among the glial cell types, such as astrocytes, oligodendrocytes, microglia and NG2 cells, astrocytes are a key component in maintaining the brain environment. Astrocytes used to be regarded as static cells, simply supporting neurons, and participating in wound healing by forming glial scars. However, recent research results have shown that astrocytes actively control synaptic functions and formation, regulate the concentration of neurotransmitters at synapses, control the vasculature to increase the blood flow, and are involved in a wide range of homeostatic functions, including sleep.2 In the lesions of neurodegenerative diseases, astrocytes robustly change their morphology and the expression of molecules, and are referred to as reactive or activated astrocytes.3-6 Furthermore, several lines of evidence show that the activation phenotypes of astrocytes are more complex and heterogenous than previously predicted. The present focused review summarizes the accumulating evidence showing that astrocytes are playing critical roles in the disease process of amyotrophic lateral sclerosis (ALS). Furthermore, we discuss the phenotypic heterogeneity of activated astrocytes mainly in ALS, and also in other neurological diseases based on studies using rodent models. Non‐cell autonomous neurodegeneration in ALS Patients with ALS develop progressive paralysis of skeletal muscles and respiratory failure within 2–5 years of disease onset as a result of selective degeneration of both the upper and lower motor neurons. Most ALS cases develop disease sporadically; however, approximately 10% of them are familial cases, and >20 causative genes have been identified to date. Dominant mutations in the gene for copper/zinc superoxide dismutase 1 (SOD1) are the second most frequent cause of inherited ALS after the C9orf72 gene.7 Ubiquitous overexpression of the mutant human SOD1 gene in mice leads to progressive motor neuron degeneration accompanied by extensive gliosis. It is now generally recognized that all SOD1 mutant proteins uniformly provoke unidentified toxicities in degenerating neurons, and that toxicities are not mediated by changes in the enzymatic activity.7, 8 To date, many hypotheses have been proposed to explain the mutant SOD1‐mediated toxicity in SOD1‐linked ALS, including damage to mitochondria, endoplasmic reticulum stress, defects in protein degradation machinery, axonal transport dysfunction, excitotoxicity from excess glutamate at synapse and overproduction of neurotoxic molecules through neuroinflammation.9-11 It is likely that the combination of the aforementioned mechanisms, rather than a single one, contributes to neurodegeneration in ALS. Although pathologies within motor neurons are a key determinant of triggering disease, several studies including ours showed that a non‐cell autonomous mechanism also plays an important role in motor neuron degeneration.12, 13 Studies using chimeric mice derived from wild‐type and mutant SOD1 mice,12 as well as those derived from mutant SOD1 and Olig−/− mice,13 showed that wild‐type non‐neuronal cells are capable of protecting mutant SOD1‐expressing motor neurons, supporting the concept of non‐cell autonomous neurodegeneration in ALS. Astrocytes in ALS To identify the non‐neuronal cell types crucial for non‐cell autonomous neurodegeneration in ALS, we and others have created mouse models of ALS in which the mutant SOD1 transgene can be eliminated in a cell type‐specific manner using the Cre‐loxP system.14, 15 Ablation of the mutant SOD1 transgene in either astrocytes, microglia, or oligodendrocytes from floxed SOD1G37R or SOD1G85R mice using Cre recombinase significantly slowed the disease progression and extended survival times of mice.14-18 Mutant SOD1‐ablated astrocytes delayed the degree of microglial activation and conferred neuroprotection, suggesting that an interaction between astrocytes and microglia modifies neuroinflammation and disease progression in ALS. An interplay between astrocytes and motor neurons has also been examined using in vitro co‐culture experiments. Co‐culture studies using embryonic stem cell‐ or induced pluripotent stem cells‐derived motor neurons and mutant SOD1‐expressing astrocytes have shown that mutant SOD1 astrocytes selectively provoke toxicity to motor neurons, providing additional support for the role of astrocytes in non‐cell autonomous neurodegeneration in ALS.19-22 The adverse role of ALS astrocytes has also been shown in sporadic and non‐SOD1 inherited ALS. Astrocytes derived from post‐mortem ALS spinal cord or differentiated directly from the fibroblasts of sporadic and C9orf72‐linked ALS patients appear to be harmful to motor neurons in vitro.23-25 Astrocyte‐mediated toxicity to motor neurons is associated with profound changes of astrocytic phenotype A noteworthy question in ALS pathogenesis is, why the degenerating spinal cord in both sporadic and familial ALS cases does generate glial cells capable of killing motor neurons. Astrocytes and microglia in ALS do not seem to be constitutively toxic for motor neurons, as the entire motor system develops normally in ALS rodents and patients carrying ALS genes until adulthood. However, it appears that glial cells in ALS show a predisposition to become neurotoxic when subjected to cellular stress, such as the expression of mutant ALS‐linked genes or the cell culture condition. Such glial vulnerability might be associated with permanent epigenetic changes, prompting an activated glial phenotype. After activation, the neurotoxic astrocyte phenotype seems to be maintained by mitochondria dysfunction, oxidative stress, disrupted inflammatory signaling, endoplasmic reticulum stress and so on.26-29 In addition, activation of astrocytes in ALS is associated with increased proliferation and their inability to reach final differentiation,30, 31 a condition involving decrease in the expression of glutamate transporters,32-34 elevated levels of nicotinamide adenine dinucleotide phosphate oxidase, reactive oxygen species and inducible nitric oxide synthase,22, 26 and increased productions of pro‐inflammatory cytokines/mediators, such as interferon‐γ,35 prostaglandin D2,21 and transforming growth factor‐β.36 Even wild‐type cultured rat neonatal astrocytes can be induced to develop a permanent neurotoxic phenotype when subjected to different acute and sublethal stressful conditions, such as exposure to lipopolysaccharide or peroxynitrite.37-39 A strikingly similar switch to a neurotoxic phenotype has been reported in cultured microglia obtained from murine models of ALS or when activated by means of inflammatory or toxic stimuli.40-43 This evidence further shows that glial cells are prone to switch to a neurotoxic phenotype in response to sublethal cytotoxic damage, and that this phenotype can be perpetuated by autocrine or epigenetic mechanisms. Long‐lasting activation of glial cells in the ventral horn is likely triggered by factors released by damaged motor neurons. After peripheral nerve lesions or spinal cord injury, as well as ALS, motor neurons upregulate several inflammatory mediators and growth factors that induce microglia activation including CSF1,44, 45 CX3CL1 (fractalkine),46 fibroblast growth factors,47, 48 HBMG149 and major histocompatibility complex encoded antigens.50, 51 From activated glial cells to the emergence of aberrant phenotypes Aberrant glial cells drive neurodegeneration in ALS Motor neuron death in the spinal cord of symptomatic ALS rodents is closely associated with local microglia activation, immune cell infiltration and astrocytosis, the latter involving major changes in cell morphology and proliferation rate. This observation led to the prediction that motor neuron pathology in ALS could be initiated by the emergence of phenotypically “aberrant” astrocytes playing an active pathogenic role during disease progression.47, 48 Subsequent reports have established that astrocytes and microglia cells expressing mutant SOD1 are directly toxic to motor neurons in rodent models, as well as in ALS patients.19, 20, 23, 26, 52, 53 Furthermore, the discovery by Diaz‐Amarilla et al. of a cell type different from reactive astrocytes or microglia and directly associated with rapid disease progression in SOD1G93A rats provided a new avenue to study and understand ALS pathogenesis.54 In the degenerating spinal cord of SOD1G93A rats, aberrant glial cells are characterized by the simultaneous expression of microglia and astrocytic markers.54, 55 These cells can typically be localized in areas surrounding the dying motor neurons in the ventral horn of the spinal cord, and can be identified by immunostaining for astrocytic markers, such as GFAP, S100β and Cx43, as well as microglia markers, such as Iba1 and CD163.55 These aberrant features have not been previously described in other neurodegenerative diseases, but are commonly observed in glioblastoma multiforme, an aggressive type of human astroglial tumor undergoing intense inflammation.56, 57 Notably, the emergence of aberrant glia directly correlates with disease onset and progression, suggesting that they might mediate the rapid course of disease characteristics of the SOD1G93A rat model.54 Aberrant glia seem to actively proliferate, as estimated by the high proportion of cells labeled with BrdU or the proliferation marker Ki67.40 Thus, the potential pathogenic role of aberrant glia in mediating motor neuron damage and neuroinflammation is evidenced not only by observational analysis in ALS rats, but also by cell transplant23, 58, 59 and pharmacological experiments.60 As described below, aberrant glia likely originate from overactivated and inflammatory microglia undergoing a phenotypic transition to astrocyte‐like cells. Microglia in ALS rats show exceptional overactivation and atypical behaviors, such as microglia clusters32, 61 and multinucleated giant cells,62 further indicating major phenotypic instability. Aberrant features would denote chronic inflammatory overactivation, dedifferentiation and epigenetic changes, resulting in a loss or gain of function, finally leading to neuronal toxicity. One feature of aberrant glia cells is that they can be easily cultured and expanded from the spinal cord of symptomatic adult transgenic SOD1G93A rats, as compared with cultures from non‐transgenic rat cords yielding only a few or no cells.54, 55 When first established, cell morphology is that of hypertrophic and rapidly dividing phagocytic microglia. After a few days in culture, the cells transition to clusters of proliferating flat cells resembling astrocytic monolayers, which can be further propagated for months. Such cells were named AbAs (aberrant astrocytes), and are characterized by the simultaneous expression of astrocyte and microglial markers (GFAP, S100β, vimentin, connexin 43, Glutamine synthase, Iba1, CD11b, CD206; Fig. 1a).54, 55 These atypical features define the “aberrant” immunophenotype. Aberrant glia show a robust proliferating capacity and a lack of replicative senescence after several passages in cell culture. Cultured aberrant glia appear to be the most toxic cells yet identified for embryonic motor neurons, as compared with mutant SOD1‐bearing astrocytes or microglia.54 When seeded on confluent monolayers of aberrant glia, motor neuron survival was <10%, suggesting a non‐permissive environment for motor neuron growth and differentiation. The conditioned medium from aberrant glia also showed a potent toxicity, producing significant motor neuron loss at 1:1000‐fold dilutions, more than 10‐fold higher than that of SOD1G93A‐expressing neonatal astrocytes.54 Thus, AbAs potentially play an important role in mediating motor neuron damage through various complex molecular mechanisms. Although it remains unknown whether aberrant glial cells emerge in patients with sporadic or familial ALS, few studies have reported increased levels of aberrant cell markers. A subset of hypertrophic astrocytes expressing S100β were identified close or in indirect contact to motor neurons in the spinal cord of ALS patients,63 such proximity being strongly evocative of aberrant glial cells found in the ALS rat model.54 Also, the motor cortex and spinal cord from ALS patients showed increased levels of connexin 43, a protein highly expressed in aberrant glial cells.64 Connexin 43 was also increased in astrocytes obtained from human‐induced pluripotent stem cells, further suggesting an association of this protein with ALS pathology.64 Pro‐inflammatory effects of aberrant glia after transplantation into the spinal cord While aberrant glia appear as a distinct but relevant glial cell type associated with rapid disease progression in ALS rats, Ibarburu et al. analyzed the neurotoxic and inflammatory potential of aberrant glia isolated from SOD1G93A rats at 7 days after the focal transplantation into the spinal cord of wild‐type syngeneic rats.59 Although transplanted glia survived and proliferated within the site of injection, they strongly activated endogenous astrocytes and microglia that appeared to isolate the exogenous cells, restricting the migration and neurotoxicity on host motor neurons. Neuroinflammation induced by transplanted aberrant glia propagated well beyond the lumbar injection site, extending to the cervical spinal cord, and was associated with incipient motor neuron damage assessed by ubiquitin aggregation. These results suggest that the emergence of aberrant glial cells could be sufficient to initiate ALS‐like pathology, even in wild‐type rats. Results are also in agreement with a previous study showing neuroinflammation and motor neuron death induced by transplantation of glial‐restricted precursors bearing SOD1G93A into the wild‐type rat spinal cord.58 Aberrant glia could release colony‐stimulating factor 1 or interleukin‐34 to potently induce microgliosis and inflammation in the neuroaxis. Astrocytes are a major source of colony‐stimulating factor 1 and interleukin‐34, both factors being potent agonists of the colony‐stimulating factor 1 receptor promoting proliferation and activation of microglia and aberrant glia.45, 60 Interestingly, transplanted aberrant cells expressed misfolded SOD1G93A species, which might have a relevant pathogenic role in ALS pathology, both in familial and sporadic cases.65, 66 Ultrastructural features of aberrant glial cells Further evidence for the aberrant nature of cultured aberrant glial cells isolated from SOD1G93A symptomatic rats has been obtained from ultrastructural analysis.67 Cells show an absence of intermediate filaments, an abundance of microtubules together with an important production of extracellular matrix components, suggesting a pro‐fibrotic activity. In addition, cells showed exacerbated endoplasmic reticulum stress together with a significant abundance of lipid droplets, autophagy images and many heterogeneous formations including vesicles, suggesting a role in secretion. Cells express markers of secretory granules, such as chromogranin A and secretogranin II (chromogranin C),68, 69 which might interact with mutant SOD1 to promote inflammation and neuronal death.70 Thus, considering that aberrant glia proliferate and migrate actively, the ultrastructural features are indicative of a profound cellular pathology only comparable with tumor cells. Phenotypic changes and elimination of activated astrocytes A previous study reported that astrocytes of symptomatic SOD1G85R mice were immunopositive for ubiquitinated‐SOD1 aggregates, suggesting that they are defective in proteostasis.71 A subsequent study showed that activated astrocytes in SOD1 mice had an atypical shape, and were co‐labeled with ubiquitin and cleaved caspase‐3, concluding that they were degenerating astrocytes.72 This phenotype is similar to that of aberrant astrocytes isolated from SOD1G93A rats, discussed previously.54 A recent study also showed that aberrantly activated astrocytes are accumulated in the spinal cord of several lines of SOD1‐ALS mice, and are immunopositive for GFAP, ALDH1L1 and S100β, and surprisingly expressing Mac‐2 (galectin‐3), an activation marker for microglia. However, they are negative for CD68 and Iba‐1, typical microglial markers, concluding that these cells are aberrantly activated astrocytes (Fig. 1b).73 As these cells do not express typical microglial markers, CD68 and Iba‐1, the origin and identity of these cells might be different from aberrant glia discussed in the prior section. Although the phenotypic changes of reactive astrocytes and their characteristics were described, the fate of those activated astrocytes has not been shown. The authors recently uncovered the mechanism for eliminating overactivated astrocytes in SOD1‐ALS models.73 When TIR domain–containing adapter protein–inducing interferon‐β (TRIF), an innate immune adaptor protein essential for the Toll‐like receptor (TLR) 3/4 was deleted, disease progression was substantially accelerated, thereby shortening the survival time of SOD1 mice. In contrast, gene ablation of MyD88, which is crucial for all TLR signaling except TLR3, had a marginal impact on the survival time of SOD1 mice. Aberrantly activated Mac‐2+ astrocytes often express cleaved caspase‐3, showing that they undergo apoptosis. In TRIF‐deficient ALS mice, the number of Mac‐2+ astrocytes increased through insufficient apoptosis of those cells. The TRIF‐dependent TLR pathway is known to induce apoptosis in multiple cell types, such as microglia and macrophages, for eliminating those cells after infection by pathogens. The cited study uncovers the novel role of TRIF signaling in eliminating aberrantly activated astrocytes. In Mac‐2+ astrocytes, accumulation of p62 and ubiquitin, as well as elevated expression of nicotinamide adenine dinucleotide phosphate oxidase, suggests that they are neurotoxic by overproducing reactive oxygen species. Correlation analysis in SOD1‐ALS mice showed that greater numbers of Mac‐2+ astrocytes predicted shorter survival times of ALS mice, suggesting that they are harmful to motor neurons.73 It is possible that the pathways other than TRIF signaling might participate in eliminating abnormal reactive astrocytes. Therefore, further studies are required to provide a complete picture of the mechanisms for eliminating activated glial cells and terminating neuroinflammation. Phenotypic heterogeneity of astrocytes in ALS and other neurological diseases Phenotypic heterogeneity of astrocytes is not restricted to the context of ALS. A study showed that toxic reactive astrocytes, referred to as A1 astrocytes, were induced by three cytokines released from activated microglia in vitro. These astrocytes were also observed in the lesions of neurodegenerative diseases, including sporadic ALS, Alzheimer's disease, Parkinson's disease and Huntington's disease.74 A1 astrocytes lose their ability to support neuronal survival and phagocytosis, and induce cell death in cultured neurons. Questions remain about the detailed molecular basis of astrocyte‐mediated toxicities of A1 astrocytes, and whether the mechanism of A1 astrocytes‐mediated toxicities is common to the above‐mentioned neurodegenerative diseases. Table 1 shows some features of aberrant glial cells, including astrocytes or microglia, abnormally‐expressing markers from different cell lineages have been also reported in Alzheimer's disease,75 Huntington's disease,76 central nervous system acute lesions77-79 and aging,74, 80 as well as glioma,56, 57, 81 brain ischemia and trauma,78, 79, 82 further suggesting the phenotypic switch is strongly associated with inflammation and tissue remodeling after damage. Disease Cell type Model/human Markers Features Function References Amyotrophic lateral sclerosis Aberrant glial cells SOD1G93A rats and mice. S100β/GFAP/Cx43 coexpressing Iba1 and CD163. GFAP/S100β co‐expression with Mac2. Elevated levels of p62 and ubiquitin. Abnormally activated astrocytes. High proliferation rate, no replicative senescence when isolated. Defects in autophagy‐lysosome and ubiquitin‐proteasomal degradation Pathways. SOD1 inclusions. Toxic to motor neurons. Secrete neurotoxic factors. Induce oxidative stress. 54, 55, 72, 73 Huntington's disease Aberrant astrocytes R6/2 HD mice models and human patients Increased VEGF‐A levels. Through VEGF‐A release, mediate neurovascular abnormalities Reduced pericyte survival. 76 Alzheimer's disease Aberrant astrocytes Alzheimer's disease patients – iPSC‐derived astrocytes Nuclear S100β, lower nuclear EAAT1 and GS levels. Reduced morphological heterogeneity, atrophy Altered release of soluble inflammatory mediators 75 Alexander disease Neurotoxic reactive astrocytes AxD mice model carrying hGFAP (R239H mutation) Increase GFAP expression, vimentin, lipocalin 2, SerpinA3N Downregulation of Ca2+ homeostasis molecules Produce aberrant extra‐large Ca2+ signals 88 Neuroinflammation/aging A1 astrocytes Microglia activation induce A1 astrocytes Complement component 3 (C3). Co‐expression of C3 with GFAP and S100β Do not promote synapse formation or function. Reduced phagocytic capacity. Could constitute part of toxic astrocytes present in neurodegenerative conditions Highly neurotoxic, Impair oligodendrocytes differentiation and division. Release neurotoxic factors. 74, 80 CNS acute lesion Cells expressing astrocyte/microglia markers Cortex and spinal cord injury/Chronic neurodegeneration Co‐expression of GFAP/Tmem119/Aldh1. GFAP/Cx3Cr1/Iba1/CD68 co‐expression A subpopulation of cells expressing both markers might be a fusion of astrocytes with monocytes. ‐ 77 Neurotoxic Microglia expressing astrocyte markers Mouse spinal cord injury A subpopulation of Iba1+ microglia expressing GFAP, vimentin, serpina3n and Aldh1 l1. Up‐regulation of Brca1 Proliferation and DNA damage. Dual phenotype with an acute increase in anti‐inflammatory factors followed by later upregulation of pro‐ and anti‐inflammatory factors. Upregulation of anti‐ and pro‐inflammatory transcripts being neuroprotective but also neurotoxic. Activation of DNA damage pathway 78 IDAs: ischemia‐derived astrocytes Rat brain focal ischemic lesion Nestin. GFAP overexpression. Isolated cells express Iba1 and S100β Show reduced replicative senescence, increased cell division and spontaneous migration. Contribute to glial scar formation. Potentiate death of oxygen‐glucose deprived cortical neurons. Propagate reactive gliosis on quiescent astrocytes in vitro and in vivo. 79 CNS tumor Human gliomas Astrocytoma/GBM GFAP/CD68/HLA‐class II/MAC 387 Potential fusion of both linages in the tumor microenvironment. Functional behavior as mesenchymal cells with phagocytic activities. Astrocytes with phagocytic‐like properties. 56, 57, 81 The lists of diseases, glial cell types and names, model animals/human, molecular markers, features, and functions are summarized with references. CNS, central nervous system; iPSC, induced pluripotent stems cells; SOD1, superoxide dismutase 1. Compared with microglia/macrophages, astrocytes have been regarded to retain fewer phagocytic abilities. However, recent studies uncovered the phagocytic function of astrocytes under the various settings; synaptic elimination,83 clearance of dead cells,84 brain ischemia82 and glaucoma.85 For example, Mac2+ astrocytes are also observed in the specific subpopulation in the myelination transition zone of the optic nerve head, indicating that those astrocytes are phagocytic and contribute to neurodegeneration in glaucoma.85 In a brain ischemia lesion, Mac2+ reactive astrocytes can function as phagocytes through inducing ABCA1, a molecule required for the engulfment and phagocytosis of debris and dead cells.82 An apolipoprotein E4 variant is known as the most prominent genetic risk factor in Alzheimer's disease. In apolipoprotein E4 knock‐in mice, apolipoprotein E‐4‐producing astrocytes are defective in phagocytic activity and failed to eliminate synapses in a complement‐dependent manner.86 Phagocytosis of astrocytes is also promoted by sleep deprivation.87 In this context, enhanced phagocytic activity of astrocytes seems to be protective to the brain by cleaning worn components of heavily used synapses on prolonged wakefulness. Conclusion In the present review, we provided evidence supporting that the activation phenotypes of astrocytes are more heterogeneous mainly from the research for ALS. Contrary to the traditional understanding of astrocytes as static cells, reactive astrocytes possess more diverse functions than previously thought. Through achieving more knowledge of the phenotypic and functional diversity of astrocytes, astrocytes will become more attractive therapeutic targets for neurodegenerative diseases. Acknowledgements This work was supported by Institut Pasteur de Montevideo – FOCEM Mercosur (COF 03/11), Agencia Nacional de Investigación e Innovación (ANII), Programa de Desarrollo de las Ciencias Básicas (PEDECIBA) and Sistema Nacional de Investigadores (SNI, Uruguay) (to L.B.). This work was also supported by Grants‐in‐Aid for Scientific Research 26293208, 16H01336 and 18H02740 (to K.Y.) from the Ministry for Education, Culture and Sports, Science and Technology of Japan, and by the grant from Takeda Science Foundation (to K.Y.). All authors are in agreement with the content of the manuscript. Conflicts of interest None declared. References
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Relapsing–Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment

Relapsing–Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment | NeuroImmunology | Scoop.it
Multiple sclerosis (MS) is considered a T cell-mediated autoimmune disease, although several evidences also demonstrate a B cell involvement in its etiology. Follicular T helper (Tfh) cells, a CXCR5-expressing CD4+ T cell subpopulation, are essential ...
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Current state of immunotherapy for glioblastoma

Current state of immunotherapy for glioblastoma | NeuroImmunology | Scoop.it
the unique immune environment of the central nervous system needs to be considered when pursuing immune-based therapeutic approaches for glioblastoma. Nevertheless, a range of different immunotherapies are currently being actively investigated in patients with this disease, spurred on by advances in immuno-oncology for other tumour types. Herein, we examine the current state of immunotherapy for gliomas, notably glioblastoma, the implications for combining the current standard-of-care treatment modalities with immunotherapies, potential biomarkers of response, and future directions for glioblastoma immuno-oncology.

Via Krishan Maggon
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Multiple origins and modularity in the spatiotemporal emergence of cerebellar astrocyte heterogeneity

Multiple origins and modularity in the spatiotemporal emergence of cerebellar astrocyte heterogeneity | NeuroImmunology | Scoop.it
Author summary Astrocytes are abundant cells of the brain essential to support and shape neuronal activity. They can be grouped in different subclasses based on their remarkable variety of morphologies, molecular profiles, and specialized functions.
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Neuroinflammation in Alzheimer's disease

Neuroinflammation in Alzheimer's disease | NeuroImmunology | Scoop.it
Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted
to the neuronal compartment, but includes strong interactions with immunological mechanisms
in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and...
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The irresistible CCL17: New role for the allergy driver: It influences signal transmission in the brain

The irresistible CCL17: New role for the allergy driver: It influences signal transmission in the brain | NeuroImmunology | Scoop.it
Doctors have long known that a high level of the protein CCL17 in the body indicates an allergic reaction. Now scientists have discovered a completely new function: CCL17 also influences signal transmission in the brain.
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Microglial signatures and their role in health and disease

Microglial signatures and their role in health and disease | NeuroImmunology | Scoop.it
Microglia are the primary innate immune cells in the CNS. In the healthy brain, they exhibit a unique molecular homeostatic ‘signature’, consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages. In recent years, there have been a number of important advances in our understanding of the molecular signatures of homeostatic microglia and disease-associated microglia that have provided insight into how these cells are regulated in health and disease and how they contribute to the maintenance of the neural environment.

Via Krishan Maggon
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Neuro-Compass.education | A Multiple Sclerosis Online Resource

Neuro-Compass.education | A Multiple Sclerosis Online Resource | NeuroImmunology | Scoop.it
Neuro-Compass.education is a free, comprehensive, practical medical resource developed by healthcare professionals for healthcare professionals involved in the care of multiple sclerosis.

Via Krishan Maggon
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A homing system targets therapeutic T cells to brain cancer

A homing system targets therapeutic T cells to brain cancer | NeuroImmunology | Scoop.it
Therapeutic T cells bearing ligands engineered to optimize adhesion and transmigration through the blood–brain barrier can be targeted to brain tumours.
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