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Two-dimensional immunoblots revealed a spectrum of 200 kDa neurofilament polypeptides (Nf-H) of apparent molecular weights ranging from 200 to 170 kDa. The entire spectrum was stained immunocytochemically by three monoclonal antibodies specific for nonphosphorylated neurofilaments, while more restricted staining was revealed by four monoclonal antibodies specific for phosphorylated neurofilament epitopes. Treatment with increasing amounts of phosphatase suggested the existence of various forms of partially phosphorylated neurofilaments that possess phosphoepitopes that differ in their ease of dephosphorylation. Immunoprecipitation in low detergent concentration confirmed the existence of microheterogeneous forms of Nf-H that differed in extent of phosphorylation or in distribution of phosphorylated sites.

From an examination of electroimmunoblots and peptide maps, a mouse monoclonal antibody to human myelin basic protein MBP was shown to react with the amino acid sequence Ala-Ser-Asp-Tyr-Lys-Ser which is located in the C-terminal half of MBP. Although a completely different immunization schedule was used by Sires et al. (1981) they obtained a monoclonal antibody reacting with the same determinant. In contrast to results with other monoclonal antibodies to globular proteins (Todd et al. 1982) this monoclonal antibody seems to react with a sequential rather than a topographical determinant.

A monoclonal antibody designated III 5H8 was shown to bind both to astrocytes and to myelin sheaths as studied with immunocytochemical techniques on brain sections and cell cultures. Binding to astrocytes was confirmed by double immunofluorescent labelling of frozen sections and cell cultures with anti-GFAP, and appeared to be sensitive to formalin treatment. Binding to myelin sheaths was confirmed by comparing sections labelled with III 5H8 with sections labelled with antibodies against axons and myelin basic protein as well as by staining of sections of hypomyelinated spinal cord with III 5H8. On immunoblots of separated white matter III 5H8 revealed two bands, while on immunoblots of purified myelin only one band was seen. The findings are discussed with respect to the function of astrocytes in white matter and shared antigenic determinants between astrocytes and oligodendrocytes.

During incubation with phosphatase, the 200 kDa neurofilament protein in cytoskeletal preparations is degraded extensively. Degradation, which is divalent cation-independent, does not occur when inhibitors of phosphatase are added. The 160 kDa chymotryptic fragment of neurofilaments or affinity-purified 200 kDa protein are not degraded by phosphatase. The results suggest that phosphorylated neurofilaments are protected against proteolysis, and dephosphorylated neurofilaments are degraded by a calcium-independent, endogenous proteinase which is associated with assembled neurofilaments or with other cytoskeletal components, and not with the phosphatase used.

SUMO (small ubiquitin like modifier) conjugated proteins have emerged as an important post translational modifier of cellular function. SUMOylation modulates several cellular processes involved in transcriptional regulation of genes, protein-protein interactions and DNA damage and repair. Since abnormalities in SUMOylation has been observed in neoplastic and neurodegenerative disorders, the SUMO pathway has become an attractive site for targeting of new therapies to regulate SUMOylation and reduce disease burden. Conjugation of SUMO to their respective substrates is orchestrated by an enzymatic cascade involving three main enzymes, E1, activation enzyme, E2, conjugating enzyme and E3, a protein ligase. Each of these enzymes are therefore potential "druggable" sites for future therapeutics. SUMOylation is a well-known mechanism by which the innate immune response is regulated in response to viral infections and in the adaptive immune response to tumor immunity. We have shown that small molecules which inhibit the SUMO activation pathway are also capable of inhibiting autoimmune response. TAK981 which forms adducts with SUMO and anacardic acid which inhibits the E1 enzyme of the SUMO pathway were effective in preventing the development of experimental allergic encephalitis (EAE), a mouse model of multiple sclerosis. Anacardic acid and TAK981 inhibited activation of TH17 cells and reduced clinical and pathological injury in IL-17 mediated myelin oligodendrocyte glycoprotein (MOG) induced EAE. Ginkgolic acid, another known inhibitor of SUMO pathway, was also shown to be effective in reducing the severity of inflammatory arthropathies which is also IL-17 mediated. In addition, the increase in the transcription of myelin genes with TAK981 and anacardic acid improved remyelination in experimental models of demyelination. In the present review paper, we examine the mechanism of action of inhibitors of the SUMO pathway on regulating the immune response and the possibility of the use of these agents as therapeutics for MS. • Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. • Inhibition of SUMOylation is accomplished by inhibiting the enzymes of the SUMO pathway. • Inhibition of SUMOylation is accompanied by increase in innate immunity and increased production of beta Interferon. • Inhibition of SUMOylation increases the expression of myelin genes and inhibits TH17 expression. • The effects of SUMO inhibitors on a immune response and promoting myelination offers a novel treatment approach for multiple sclerosis [ABSTRACT FROM AUTHOR]

A demographic shift in multiple sclerosis (MS) is leading to an increased number of elderly people with MS (pwMS) and a rise in late-onset MS (LOMS) cases. This shift adds complexity to the treatment management of these patients, due to enhanced treatment-associated risks and the possible interplay between immunosenescence and disease-modifying therapies (DMTs). In the present paper, we performed a systematic review of the current evidence concerning the relationship between aging and treatment management in elderly pwMS. Our literature search identified 35 original studies relevant to this topic. The gathered evidence consistently indicates a diminished efficacy of DMTs in older pwMS, particularly in preventing disability accrual. Against this background, high-efficacy therapies (HETs) appear to show less benefit over moderate-low-efficacy DMTs in older patients. These data mainly derive from observational retrospective studies or meta-analyses conducted on randomized clinical trials (RCTs). RCTs, however, exclude pwMS older than 55 years, limiting our ability to acquire robust evidence regarding this patient group. Regarding treatment discontinuation in elderly pwMS with stable disease, the available data, which mainly focuses on older injectable DMTs, suggests that their suspension appears to be relatively safe in terms of disease activity. Nevertheless, the first RCT specifically targeting treatment discontinuation recently failed to demonstrate the non-inferiority of treatment discontinuation over continuation, in terms of MRI activity. On the other hand, the evidence on the impact of discontinuation on disease progression is more conflicting and less robust. Furthermore, there is an important lack of studies concerning sequestering DMTs and virtually no data on the discontinuation of anti-CD20 monoclonal antibodies. De-escalation strategy is gaining attention as a de-risking approach alternative to complete treatment discontinuation. It may be defined as the decision to shift from HETs to less potent DMTs in elderly pwMS who have a stable disease. This strategy could reduce treatment-related risks, while minimizing the risk of disease activity and progression potentially associated with treatment discontinuation. This approach, however, remains unexplored due to a lack of studies. Given these findings, the present scenario underlines the urgent need for more comprehensive and robust studies to develop optimized, data-driven treatment strategies for elderly pwMS and LOMS, addressing the unique challenges of MS treatment and aging. • Prevalence of elderly people with MS (pwMS) and late-onset MS cases is increasing. • Elderly pwMS treatment present challenges with risk-benefit balance concerns. • Reduced DMT efficacy in elderly pwMS: especially HETs show lesser benefits. • DMTs discontinuation: safe regarding disease activity, data on progression lacking. • De-escalation strategy may balance risks and control disease effectively. [ABSTRACT FROM AUTHOR]

Inflammation is not the only cause of depression and cannot explain its entire pathophysiology, but it is an important pathogenic factor that explains one possible mechanism of depression, with the kynurenine (KYN) pathway of tryptophan at its center. In particular, greater impairment seems to exist in the KYN pathway in inflammation-induced depression related to immunotherapy, autoimmune disease, and infection. In patients with these conditions, immunopharmacology is likely to be an important therapy. To develop this therapy, clear evidence of the immune-KYN pathway must be established via multiple types of experiments. This paper reviews the body of evidence, not only for the action of tryptophan (TRY) and consequent serotonin depletion, but also for the detrimental effects of TRY catabolites and the key enzymes in the KYN pathway that play important roles in the pathophysiology of inflammation-induced depression. In addition, this paper explores a potential treatment strategy for inflammation-induced depression using KYN metabolism. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is commonly associated with bladder dysfunction resulting in a progressive loss of voluntary control for urination over time. Here, we used the voided stain on paper (VSOP) method to investigate bladder function in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Using the VSOP test, we show that bladder dysfunction reflects pro-inflammatory processes of EAE and severity of clinical EAE symptoms, as characterized by increased urine voided volume per micturition (UVVM) on post-induction day 7 and decreased UVVM on post-induction day 14. The UVVM was closely related to a clinical disease index of EAE symptoms and plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine levels. UVVM was also sensitive to early life stress caused by animal transportation, which diminished UVVM at the peak of symptoms on post-induction day 14 in EAE mice. The results indicate that symptoms and progression of EAE can be reliably measured by VSOP as a non-motor function assessment. • Early life stress does not affect the severity of bladder dysfunction in EAE mice. • EAE severity is associated with an inflammatory response by GM-CSF cytokine. • Bladder dysfunction in terms of impaired micturition can be detectable in the EAE model. • EAE severity can be predicted by loss of bladder control in mice. • Progression of EAE can be reliably measured by VSOP. [ABSTRACT FROM AUTHOR]

In this paper the authors provide evidence that hydroxyurea (hydroxycarbamide) interacts with α7 nicotinic acetylcholine receptor, exerts anti-inflammatory and pro-survival effect, prevents α7 nicotinic receptor interaction with angiotensin-converting enzyme-2 and stimulates IgM to IgG class switch upon immunization with SARS spike protein fragment 674–685. Hydroxyurea shifts immunoglobulin glycosylation profile to anti-inflammatory phenotype and prevents the appearance of anti-idiotypic α7(179–190)-specific antibodies, as well as memory impairment. According to these results, interaction with α7 nicotinic acetylcholine receptor may underlie positive therapeutic effects of hydroxyurea upon SARS-Cov-2 infection by interfering with virus penetration into the cell and providing anti-inflammatory and immunomodulatory effects. [Display omitted] • HU interacts with α7 nAChR resulting in anti-inflammatory and pro-survival effect. • HU treatment prevents α7 nAChR – ACE-2 interaction in the brain of mice. • HU treatment stimulates IgM to IgG class switch in mice immunized with SARS(674–685). • HU affects immunoglobulin glycosylation resulting in anti-inflammatory phenotype. • HU treatment prevents memory impairment in mice immunized with SARS(674–685). [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is a leading cause of morbidity and mortality worldwide. Immunity and inflammation are key factors in the pathophysiology of IS. The inflammatory response is involved in all stages of stroke, and microglia are the predominant cells involved in the post-stroke inflammatory response. Resident microglia are the main immune cells of the brain and the first line of defense of the nervous system. After IS, activated microglia can be both advantageous and detrimental to surrounding tissue; they can be divided into the harmful M1 types or the neuro-protective M2 type. Currently, with the latest progress of transcriptomics analysis, different and more complex phenotypes of microglia activation have been described, such as disease-related microglia (DAM) associated with Alzheimer's disease (AD), white matter associated microglia (WAMs) in aging, and stroke-related microglia (SAM) etc. The triggering receptor expressed on myeloid cell 2 (TREM2) is an immune-related receptor on the surface of microglia. Its expression increases after IS, which is related to microglial inflammation and phagocytosis, however, its relationship with the microglia phenotype is not clear. This paper reviews the following: 1) the phenotypic changes of microglia in various pathological stages after IS and its relationship with inflammatory factors; 2) the relationship between the expression of the TREM2 receptor and inflammatory factors; 3) the relationship between phenotypic changes of microglia and its surface receptor TREM2; 4) the TREM2-related signalling pathway of microglia after IS and treatment for TREM2 receptor; and finally 5) To clarify the relationship among TREM2, inflammation, and microglia phenotype after IS, as well as the mechanism among them and the some possible treatment of IS targeting TREM2. Moreover, the relationship between the new phenotype of microglia such as SAM and TREM2 has also been systematically summarized, but there are no relevant research reports on the relationship between TREM2 and SAM after IS. • This is the first article clarifies the relationship among inflammation, microglial polarization and TREM2 after ischemic stroke, and explores the possible signalling pathways related to TREM2 and the treatment targeting TREM2 after ischemic stroke. • Firstly, the relationship among TREM2, inflammation, and microglial phenotype after IS be described clearly. • Secondly, we also describe TREM2 signalling pathway in microglial and its regulation following ischemic stroke. • Finally, we find that targeting TREM2 as a potential therapeutic strategy for IS. [ABSTRACT FROM AUTHOR]

Natalizumab is being used in recurrent multiple sclerosis despite its history of market withdrawal due to lethal cases. We have carried out a bibliometric analysis of this drug from 1999 to February 2020 in order to assess the real impact of the use natalizumab with the goal to identify the key articles that sustain the current knowledge on the therapeutic possibilities of this compound. We have extracted from the Web of Science the top 100 most cited records (T100) and tabulated data on the journal, authors, publication year, number of citations, countries and institutions of publication, T100-records, citation density and citations per record of the works. The 100 most cited articles were selected from a total of 32,507 citations out of 2817 publications with an h-number of 74, 11.54 citations/publication, and a density of 1544.79 citations/year. Citations ranged from 63 of the paper placed in the 100th position (T100) to 1940 of the paper in the first position (T1). T2 was cited 888 times, and the difference in the number of citations between T1 and T2 was higher than that between T2 and T10. T1, T2 and T3 are clinical trials. When articles are arranged by institution and nationality having more than 10 T100 articles, biotechnology company Biogen and the USA, respectively, lead the ranking, but we also find that 8 out of 10 are academic European institutions. A co-authorship analysis reveals an intense collaborative activity between countries and institutions. We conclude that the clinical and academic communities have shown a sustained interest in natalizumab for the therapy of recurrent multiple sclerosis over the last 20 years. Unlabelled Image • Bibliometric analysis of Natalizumab (1999–2019) to assess the real impact of the use of this drug. • Identify the key articles that sustain the current knowledge on the therapeutic possibilities of natalizumab. • Identify the collaborative activity between countries and institutions. [ABSTRACT FROM AUTHOR]

This paper is a summary of the lecture given by Dr. Racke at a meeting celebrating the 40th anniversary of the Neuroimmunology Branch (NIB). This talk was the keynote address given at the end of the first day of lectures after a toast given by Cedric Raine, Dale McFarlin's “brother from another mother”. Several speakers during the day gave their own musings on the reasons for the success of the NIB, and this lecture attempted to give a sense to those present of the speaker's view for the reason of this success. [ABSTRACT FROM AUTHOR]

This is a brief and purposefully practical approach to the therapeutic and rehabilitative management of patients affected by neurological complications of systemic sarcoidosis. The review notes the drugs used and their monitoring, and their role in the series of clinical subgroups identified to form the condition. Treatment guidelines for individual clinical subtypes of the disorder are provided, and the importance of rehabilitative measures and lifestyle changes are emphasised. • This paper summarises the therapeutic and rehabilitative management in neurosarcoidosis. • The drugs used and their monitoring are noted • Treatment guidelines for individual clinical subtypes of the disorder are provided • The importance of rehabilitative measures and lifestyle changes are emphasised [ABSTRACT FROM AUTHOR]

Exercise training has improved many outcomes in “clinical” research involving persons with multiple sclerosis (MS), but there is limited understanding of the underlying “basic” pathophysiological mechanisms. The animal model of MS, experimental autoimmune encephalomyelitis (EAE), seems ideal for examining the effects of exercise training on MS-disease pathophysiology. EAE is an autoimmune T-helper cell-mediated disease characterized by T-cell and monocyte infiltration and inflammation in the CNS. To that end, this paper briefly describes common models of EAE, reviews existing research on exercise and EAE, and then identifies future research directions for understanding the consequences of exercise training using EAE. [ABSTRACT FROM AUTHOR]

Abstract: In this paper we show for the first time that: i) astrocytes are required for the neuroprotective activity of CX3CL1 against excitotoxicity; ii) inhibition of the glutamate transporter 1 (GLT-1) prejudices CX3CL1-mediated neuroprotection; iii) CX3CL1 increases GLT-1 activity on astrocytes. The modulation of GLT-1 activity induced by CX3CL1 on astrocytes requires the presence and the activity of A1 adenosine receptor (A1R), being blocked by the specific antagonist DPCPX and absent in A1R−/− astrocytes. These data introduce the astrocytes as active players in CX3CL1-mediated signaling between microglia and neurons, identifying GLT-1 as a key mediator of the neuroprotective activity of CX3CL1. [Copyright &y& Elsevier]

Myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG)-associated disorders (MOGAD) is neuroimmunological disorder manifesting as episodes of ADEM, optic neuritis, transverse myelitis, brainstem encephalitis, and other CNS manifestations and notably, distinct from multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Current treatment strategy is high-dose intravenous methylprednisolone followed by maintenance immunotherapy for relapse prevention. The purpose of this study is to systematically create compelling evidence addressing the role of rituximab in relapse prevention among patient with MOGAD. This study follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. We searched PubMed, Embase, and Google Scholar for English language papers published between 2010 and 2021. Individual study proportions were meta-analyzed to yield the pooled relapse-free patient proportion. Individual studies' mean pre- and post-treatment annualized relapse ratio (ARR) and Expanded Disability Status Scale (EDSS) were used to calculate the overall mean difference. Our meta-analysis includes 13 studies with 238 subjects. After rituximab treatment, 55% (95% CI: 0.49–0.61) of MOGAD patients remained relapse-free. Our study found that after rituximab therapy, ARR was lowered by 1.36 (95% CI 1.02–1.71, p < 0.001). Similarly, we detected a 0.52 (95% CI: 0.08 to 0.96, p = 0.02) difference in EDSS score after starting rituximab medication. Because only a handful of the included studies documented adverse events, the safety profile of rituximab for the treatment of MOGAD could not be effectively determined. Our meta-analysis shows that rituximab effectively prevents relapses in MOGAD patients. • The objective of this systematic review was to elucidate the role of rituximab in MOGAD relapse prevention. • Systematically searched publications from 2010 to 2021 were reviewed using PRISMA guideline. • Rituximab therapy kept 55% of MOGAD patients from relapsing. At follow-up, ARR was lowered by 1.36 and EDSS by 0.52. • Because of paucity of data, the safety profile of rituximab for the treatment of MOGAD could not be effectively determined. • We concluded that rituximab effectively prevents relapses in MOGAD patients. [ABSTRACT FROM AUTHOR]

Abstract: Although therapy for multiple sclerosis (MS) has changed substantially over the past few decades, introducing immunomodulatory drugs into everyday clinical practice, it is still not satisfactory enough in halting the disease progression and increasing disability. Moreover, its injection-based administration leads to suboptimal adherence, even further reducing the potential treatment benefits. Emerging disease-modifying oral agents for MS are therefore warranted. In this paper advances in the novel oral therapeutic approaches to MS treatment are reviewed. [Copyright &y& Elsevier]

Abstract: The chemokine CXCL12 and its receptor, CXCR4, regulate neuronal migration, differentiation, and survival. Alterations of CXCL12/CXCR4 signaling are implicated in different neuropathologies, including the neurological complications of HIV infection. Opiates are important co-factors for progression to neuroAIDS and can disrupt the CXCL12/CXCR4 axis in vitro and in vivo. This paper will review recently identified mechanisms of opiate-induced CXCR4 impairment in neurons and introduce results from pilot studies in human brain tissue, which highlight the role of the protein ferritin heavy chain in HIV neuropathology in patients with history of drug abuse. [Copyright &y& Elsevier]

Abstract: The role of astrocytes as structural and metabolic support for neurons is known since the beginning of the last century. Because of their strategic localization between neurons and capillaries they can monitor and control the level of synaptic activity by providing energetic metabolites to neurons and remove excess of neurotransmitters. During the last two decades number of papers further established that the astrocytic plasma-membrane G-protein coupled receptors (GPCR) can sense external inputs (such as the spillover of neurotransmitters) and transduce them as intracellular calcium elevations and release of chemical transmitters such as glutamate. The chemokine CXCR4 receptor is a GPCR widely expressed on glial cells (especially astrocytes and microglia). Activation of the astrocytic CXCR4 by its natural ligand CXCL12 (or SDF1α) results in a long chain of intracellular and extracellular events (including the release of the pro-inflammatory cytokine TNFα and prostanglandins) leading to glutamate release. The emerging role of CXCR4–CXCL12 signalling axis in brain physiology came from the recent observation that glutamate in astrocytes is released via a regulated exocytosis process and occurs with a relatively fast time-scale, in the order of few hundred milliseconds. Taking into account that astrocytes are electrically non-excitable and thus exocytosis rely only on a signalling pathway that involves the release Ca2+ from the internal stores, these results suggested a close relationship between sites of Ca2+ release and those of fusion events. Indeed, a recent observation describes structural sub-membrane microdomains where fast ER-dependent calcium elevations occur in spatial and temporal correlation with fusion events. [Copyright &y& Elsevier]

Abstract: In this paper we show that rat peritoneal mast cells (RPMC) adhere to rat oligodendrocytes (ODC) in culture and switch on a bi-directional signal affecting both adhering cell and its target. Following heterotypic interaction, RPMC release granule content and ODC show morphological changes and enter the apoptotic programme. Altogether, these findings indicate that the interaction of MC with ODC could play a role in the mechanism of CNS damage induced by the inflammatory reaction. [Copyright &y& Elsevier]

The present study aims to develop a bioluminescence Cronobacter muytjensii (C. muytjensii) infection animal model for use to evaluate the spatiotemporal acetylation and cytokine levels of brain. Frist, we cultured a luciferase expressing C. muytjensii that could be used for real-time monitoring in BALB/c mice. Then we performed a comparative acetylation analysis and cytokine levels analysis of the host's brain tissue. Further bioinformatic analysis studies have revealed that that some key acetylation proteins and inflammatory mediators involve in C. muytjensii infection. In this paper, the integration of bioluminescence imaging with Liquid Chromatography and Mass Spectrometry (LC-MS) based proteomics and quantitative analysis cytokine levels provide a systems-level understanding of infected brain response caused by C. muytjensii. [Display omitted] • The integration of proteomics with an accurate and dynamic bioluminescence model. • A system-level understanding of protein acetylation and cytokine levels in the Cronobacter muytjensii infection. • The brain images involving the colonization and clearance dynamics of Cronobacter muytjensii infection. [ABSTRACT FROM AUTHOR]

Gut microbiota composition may affect the central nervous system (CNS) and immune function. Several studies have recently examined the possible link between gut microbiota composition and multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Most of these studies agree that patients with MS suffer from dysbiosis. Moreover, an altered proportion of certain phyla of bacteria was detected in the digestive tracts of these patients compared to healthy individuals. This review article gathers information from research papers that have examined the relationship between gut microbiota composition and MS and its possible mechanisms. • Gut microbiota diversity in patients diagnosed with multiple sclerosis (MS) is similar to that of healthy controls. • The overall composition of the gut microbiota seems to be significantly different in MS patients from healthy controls. • The gut microbiota of MS patients in the active state of the disease has lower diversity than healthy controls. • Disease-modifying therapies (DMTs) for MS patients change the gut microbiome composition. [ABSTRACT FROM AUTHOR]

Abstract: Chemokines are small chemotactic molecules widely expressed throughout the central nervous system. A number of papers, during the past few years, have suggested that they have physiological functions in addition to their roles in neuroinflammatory diseases. In this context, the best evidence concerns the CXC-chemokine stromal cell-derived factor (SDF-1α or CXCL12) and its receptor CXCR4, whose signalling cascade is also implicated in the glutamate release process from astrocytes. Recently, astrocytic synaptic like microvesicles (SLMVs) that express vesicular glutamate transporters (VGLUTs) and are able to release glutamate by Ca2+-dependent regulated exocytosis, have been described both in tissue and in cultured astrocytes. Here, in order to elucidate whether SDF-1α/CXCR4 system can participate to the brain fast communication systems, we investigated whether the activation of CXCR4 receptor triggers glutamate exocytosis in astrocytes. By using total internal reflection (TIRF) microscopy and the membrane-fluorescent styryl dye FM4-64, we adapted an imaging methodology recently developed to measure exocytosis and recycling in synaptic terminals, and monitored the CXCR4-mediated exocytosis of SLMVs in astrocytes. We analyzed the co-localization of VGLUT with the FM dye at single-vesicle level, and observed the kinetics of the FM dye release during single fusion events. We found that the activation of CXCR4 receptors triggered a burst of exocytosis on a millisecond time scale that involved the release of Ca2+ from internal stores. These results support the idea that astrocytes can respond to external stimuli and communicate with the neighboring cells via fast release of glutamate. [Copyright &y& Elsevier]

Abstract: Direct intra-cerebral administration of substances into the brain parenchyma is a common technique used by researchers in neuroscience. However, inflammatory responses to the needle may confound the results obtained following injection of these substances. In this paper we show that the use of a glass micro-needle for intra-cerebral injection reduces mechanical injury, blood–brain barrier breakdown and neutrophil recruitment in response to the injection of vehicle or interleukin-1, compared to using a 26-gauge Hamilton syringe. Therefore, the use of a glass micro-needle to inject substances intra-cerebrally appears to cause minimal injection artefact and should be the method of choice. [Copyright &y& Elsevier]

Abstract: Experimental autoimmune encephalomyelitis (EAE) is an organ-specific autoimmune disease model used to investigate mechanisms involved in the activation of self-reactive T cells. Preproenkephalin (PPNK) is the gene that encodes the protein proenkephalin A that has been detected in the brain, adrenal cells and cells of the immune system. In this paper, whether PPNK plays a role in the development of EAE was investigated. PPNK-deficient and wild-type mice were immunized with the MOG35–55 peptide and the development of EAE observed. Our results show that PPNK-deficient mice developed less severe clinical signs of disease than wild-type mice, and with lower incidence. MOG35–55-specific T cells from PPNK-deficient and wild-type mice produced IFNγ and TNFα but no IL-4 or IL-10, indicative of a Th1 phenotype. However, the numbers of MOG35–55-specific IFNγ-producing cells from immunized PPNK-deficient mice were largely reduced at early stages of disease. Interestingly, there was no difference in clinical signs or infiltrating mononuclear cells in the CNS between wild-type and PPNK-deficient mice at the later stage of disease. Our results suggest that PPNK accelerates the generation of autoimmune IFNγ-producing T cells and MOG35–55-induced EAE. [Copyright &y& Elsevier]

Abstract: Research in multiple sclerosis often employs animal models of the disease, especially experimental autoimmune encephalomyelitis (EAE) in rodents. The statistical analysis procedures chosen for these studies are often suboptimal, either because of violations of the assumptions of the procedure or because the analysis selected is inappropriate for the research question. In this paper, we discuss the types of research questions frequently asked in EAE studies and suggest appropriate and useful research designs and statistical methods that will optimize the information contained within the data. We also discuss other troublesome issues such as missing data, atypical disease profiles, and power analysis. [Copyright &y& Elsevier]

Abstract: In 1972 Guido Biozzi selectively bred mice to study the immunopathological mechanisms underlying polygenic diseases. One line, the Biozzi antibody high (AB/H) mouse (now designated the ABH strain) was later found to be highly susceptible to many experimentally induced diseases such as autoimmune encephalomyelitis, autoimmune neuritis, autoimmune uveitis, as well as virus-induced demyelination and has thus been a key mouse strain to study human inflammatory neurological diseases. In this paper we discuss the background of the Biozzi ABH mouse and review how studies with these mice have shed light on the pathogenic mechanisms operating in chronic neurological disease. [Copyright &y& Elsevier]

Abstract: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system white matter characterized by inflammation, demyelination and axonal damage. The cytotoxic T lymphocyte antigen-4 (CTLA-4) protein plays a key role in the down-regulation of T cell activation. We analysed the CTLA4 +49A/G and CT60 polymorphisms in a cohort of 120 MS trio families recruited from the Flanders region in Belgium. Both polymorphisms were genotyped by polymerase chain reaction—restriction fragment length polymorphism (RFLP). The +49 G-allele was significantly more transmitted to affected probands (P =0.005). No transmission distortion was observed for the CT60 polymorphism. Haplotype analysis revealed significant overtransmission of the +49 A/G*G–CT60*G haplotype (P =0.0025), and undertransmission of the +49 A/G*A–CT60*G haplotype (P =0.015). The CTLA4 gene has been the focus of intense investigation in MS. Of 15 recently published papers, only six reported significant associations of various CTLA4 polymorphisms with MS, with the remainder being negative. Ours is the first report investigating the CT60 polymorphism in MS. Our data highlight a need for further scrutiny of the CTLA4 gene in MS. [Copyright &y& Elsevier]

Chronic morphine treatment in animal models has been shown to alter a number of immune parameters including suppression of cellular immunity. T helper cell differentiation into Th2 effector cell may be a major contributing factor to impaired cellular immunity following chronic drug abuse. We had previously shown that chronic morphine treatment in vivo and in vitro decreases IL-2 and IFNγ (Th1) protein levels and increases IL-4 and IL-5 (Th2) protein levels in a time-dependent manner. In addition in this paper, we show that chronic morphine treatment resulted in a decrease in IFNγ and IL-2 mRNA and an increase in IL-4 and IL-5 mRNA accumulation in murine splenocytes. Furthermore, chronic morphine treatment inhibited IFNγ promoter activity and increased IL-4 promoter activity in respective promoter transfected primary T cells. In addition, we also demonstrate that chronic morphine treatment resulted in an increase in GATA 3 binding to DNA consensus elements in electromobility shift assays and an increase in GATA 3 protein and mRNA levels. In contrast, chronic morphine treatment resulted in a decrease in T-bet mRNA levels. From these data, we conclude that chronic morphine treatment differentiates T helper cell to Th2 effector cells by modulating key master switches that results in committing T helper cell to a Th2 phenotype. [Copyright &y& Elsevier]

It has been proposed that the positioning of mobile cells within a tissue is determined by their overall profile of chemokine receptors. This study examines the profiles of chemokine receptors expressed on resting and activated adult human microglial cells, astrocytes and a microglial cell line, CHME3. Microglia express highest levels of CXCR1, CXCR3 and CCR3. Astrocytes also have moderate levels of CXCR1 and CXCR3, and some CCR3, while both cell types also expressed CCR4, CCR5, CCR6, CXCR2, CXCR4 and CXCR5 at lower levels. Activation of the cells with the inflammatory cytokine tumour necrosis factor-α (TNFα) and interferon-γ (IFNγ) increased the expression of some but not all receptors over a period of 24 h. Microglia showed moderate enhancement of receptor expression, while astrocytes responded particularly strongly to TNFα with enhanced CXCR3, CCR3 and CXCR1. However, the migratory and proliferative responses of the microglia and astrocytes to the same chemokine were different, with microglia migrating and astrocytes proliferating in response to CXCL10. The data indicates a mechanism by which activated microglia and astrocytes become selectively more sensitive to inflammatory chemokines during CNS disease, and the paper discusses which of the many chemokines present in CNS would have priority of action on microglia and astrocytes. [Copyright &y& Elsevier]

We have previously shown that interleukin (IL)-1β and other inflammatory cytokines are able to induce the expression of membrane and soluble intercellular adhesion molecule (ICAM)-1 on human myoblasts. In this paper we found that IL-10 and transforming growth factor (TGF)-β1 are able to prevent IL-1β-induced membrane and soluble ICAM-1 protein expression on human myoblasts, with different time courses. The effect of both cytokines is associated to a reduction in ICAM-1 mRNA. Our findings suggest that IL-10 and TGF-β1 are able to influence the inflammatory process in muscle tissue at least in part by means of control of membrane and soluble ICAM-1. [Copyright &y& Elsevier]

The golli–myelin basic proteins (MBPs) have been known to mark the nerve fiber extensions in both the peripheral nervous system (PNS) and the central nervous system. In this paper, we show that the nerve fibers revealed by neurofilament (NF) antibody staining in thymus and spleen, colocalized with golli in the capsular, trabecular (tr), and vasculature (v) systems. In the thymus, the density of these fibers was greater in the medulla than in the cortex. In the spleen, the golli immunoreactive fibers were seen within the capsule (ca), trabeculae, and along the artery tree, as well as the fine nerve fiber networks in the periarteriolar lymphoid sheath (PALS). Golli immunoreactivity appeared to colocalize with ER-TR7, a putative marker of connective tissue in lymphoid organs. However, further examination by Western blot analysis and immunohistochemistry performed on golli “knock out” mice showed that the antigens recognized by these two antibodies were different. The reason for the apparent colocalization of golli and ER-TR7 appears to be due to the close physical association of nerve fibers with connective tissue in these organs. These results suggest that golli immunoreactivity can visualize the distribution of nerve fibers in these lymphoid organs. [Copyright &y& Elsevier]

The functional characteristics of glial cells, in particular microglia, have attained considerable importance in several diseases, including glioblastoma, the most hostile and malignant type of intracranial tumor. Microglia performs a highly significant role in the brain's inflammatory response mechanism. They exhibit anti-tumor properties via phagocytosis and the activation of a number of different cytotoxic substances. Some tumor-derived factors, however, transform these microglial cells into immunosuppressive and tumor-supportive, facilitating survival and progression of tumorigenic cells. Glioma-associated microglia and/or macrophages (GAMs) accounts for a large proportion of glioma infiltrating cells. Once within the tumor, GAMs exhibit a distinct phenotype of initiation that subsequently supports the growth and development of tumorigenic cells, angiogenesis and stimulates the infiltration of healthy brain regions. Interventions that suppress or prohibit the induction of GAMs at the tumor site or attenuate their immunological activities accommodating anti-tumor actions are likely to exert positive impact on glioblastoma treatment. In the present paper, we aim to summarize the most recent knowledge of microglia and its physiology, as well as include a very brief description of different molecular factors involved in microglia and glioblastoma interplay. We further address some of the major signaling pathways that regulate the baseline motility of glioblastoma progression. Finally, we discussed a number of therapeutic approaches regarding glioblastoma treatment. • Microglia and macrophages are the most prevalent types of cells in glioblastoma (GB). • Microglial cells are recruited at the tumor site by a variety of cytotoxic factors. • Interaction between GSC and microglia/macrophages promotes GSCs invasion and proliferation properties. • Silencing of multiple signal transduction pathways may be an efficient way to deliver a therapeutic effect in GB. [ABSTRACT FROM AUTHOR]

N -methyl- d -aspartate receptor (NMDAR) encephalitis is a potentially treatable condition, although a small proportion of patients remains refractory to immunotherapy. Bortezomib is a proteasome inhibitor that has a promising role in autoimmune conditions. We performed an independent PubMed search employing "Anti-N-Methyl‑D-Aspartate encephalitis AND bortezomib", including papers published between January 1st, 2007 to April 15th, 2021. Fourteen articles were included, with 29 patients. 16 patients (55,2%) had a favorable outcome after bortezomib and 11 (37,9%) patients developed side effects. Quality of studies was overall poor and future trials should aim to include more homogeneous and larger cohorts. • Proteasome inhibitor bortezomib could have a role in anti NMDA receptor encephalitis. • Half of patients treated with bortezomib improved, but side effects were common. • Larger and more homogeneous cohorts should be included in future trials. [ABSTRACT FROM AUTHOR]

GNbAC1 is a humanized monoclonal antibody targeting MSRV-Env, an endogenous retroviral protein, which is expressed in multiple sclerosis (MS) lesions, is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This paper describes the open-label extension up to 12 months of a trial testing GNbAC1 in 10 MS patients at 2 and 6 mg/kg. The primary objective was to assess GNbAC1 safety, and other objectives were pharmacokinetic and pharmacodynamic assessments. During the extended study, no safety issues occurred in the 8 remaining patients. No anti-GNbAC1 antibodies were detected. GNbAC1 appears well tolerated. [ABSTRACT FROM AUTHOR]

Nerve conduction studies (NCS) are essential to assess peripheral nerve fiber function in research models of immune-mediated neuritis. However, the current lack of standard protocols and reference values impedes data comparability across models and studies. We performed a systematic review and subsequent meta-analysis of the last 30 years of NCS of immune-mediated neuritis in Lewis-rats. Twenty-six papers met the inclusion criteria for meta-analysis. Extracted data showed considerable heterogeneity of recorded nerve conduction velocity (NCV) and compound muscle action potential (CMAP). Studies also significantly differed in terms of technical, methodical, and data reporting issues. The heterogeneity of the underlying studies emphasizes the need for standardization when conducting and reporting NCS in rats. We provide normative values for NCS of the sciatic nerve of Lewis rats and propose seven items that should be addressed when NCS are performed when studying immune paradigms in Lewis rats. Unlabelled Image • Nerve conduction studies showed considerable heterogeneity. • Normative values of the sciatic nerve of Lewis rats are provided. • Seven items should be addressed performing nerve conduction studies. [ABSTRACT FROM AUTHOR]

A marked prozone effect was observed in indirect immunofluorescence with human sera and human cerebrospinal fluid in two clinical cases involving breast carcinoma with paraneoplastic neuronal antibodies, and anti- N -methyl-D-aspartic acid (NMDA) receptor antibodies. Anti-Yo antibodies and anti-NMDA antibodies were not detectable under high concentrations (1:10 serum dilution and neat CSF respectively) but showed a true effect when sufficiently diluted at 1:80 and 1:5 respectively. This paper demonstrates that prozone effects have their occurrences in indirect immunofluorescence, and clinicians and laboratory technicians should be wary of its implications during screening of autoantibody markers in neurological diseases. Unlabelled Image • Prozone phenomenon is well described with immunoprecipitation. • Less so with Indirect Immunofluorescence Assay (IFA). • We report prozone phenomenon in neuroimmunology laboratory evaluation with IFA. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS) with various clinical manifestations. The characteristic of MS is that myelin is attacked by the body's immune system and increases the electrical capacity of axons, and is the primary pathophysiological mechanism of the transmission block. Studies have shown that epigenetic factors participate in the development of MS. LncRNAs are highly abundant and heterogeneous linear RNA transcripts with lengths exceeding 200 nucleotides and no protein-coding potential. Currently, pieces of evidence have demonstrated that lncRNAs have fundamental actions in multiple cellular pathways, including immune system regulation, epithelial-mesenchymal transition (EMT), cancer cell growth and metastasis, cellular homeostasis, and embryo development. It has been demonstrated that epigenetic mechanisms have an abundant role in the pathogenesis of MS in which the role of lncRNAs as epigenetic regulatory molecules in molecular processes has been proven. In this paper, we have focused on the correlation between MS and lncRNAs, the role of lncRNA in the pathogenesis of the disease, and the diagnostic and prognostic potential of lncRNA in MS. • The epigenetic factors in the development of MS has recently been considered. • LncRNAs exhibit epigenetic characteristics which may lead to the initiation of MS. • Involvement of LncRNAs in the pathogenesis of MS have been proved. • LncRNAs are involved in the abnormalities immune-related signaling pathways. • Aberrant expression of lncRNAs participates in the advancement of MS via influencing immunological pathways. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is the most common demyelinating disease which mainly impacts the integrity of central nervous system (CNS). MS etiology is not clearly known but genetic, environmental factors and immune system are the most frequently explored risk factors. Adaptive immune responses have a critical role in MS pathogenesis in which auto-reactive T-cells and autoantibodies are main orchestrators. Immune responses are modulated by inhibitory molecules which regulates adaptive system activation and hemostasis interface. These molecules suppress immune responses through inhibition of cytokine secretion and T cell proliferation and subsequently reducing the inflammation and respective damage. Therefore the critical role of inhibitory molecules in regulating the healthy and safe immune responses make them very attractive target for immunotherapy. In this review paper, the role of inhibitory molecules expressed on the various immune cell types in MS pathogenesis and experimental autoimmune encephalomyelitis (EAE) animal model will be summarized. • VISTA is one of the goals in the therapeutic target for MS treatment. • CTLA-4 polymorphisms do not correlate with MS susceptibility. • Modulating Lag-3 can affect the autoimmune disease as well as MS. • TIM3–galectin-9 pathway associated with auto-reactive T cells. • Modulation of PD1 and PD-L1 pathways holds promise in MS therapeutic potential. [ABSTRACT FROM AUTHOR]

Encephalopathy associated with autoantibodies to IgLON5 is a novel syndrome characterized by a distinct sleep disorder and brain-stem involvement. Since the initial description of this encephalopathy in 2014, only a few additional patients have been reported ( Simabukuro et al., 2015 ). In this paper, we report a new case of anti-IgLON5 antibodies with major symptoms of chorea and parkinsonism, and responsive to immunotherapy. [ABSTRACT FROM AUTHOR]

• We comment on work by Schinkelshoek et al "H1N1 hemagglutinin-specific HLA-DQ6 restricted CD4+ T cells can be readily detected in narcolepsy type 1 patients and healthy controls. " in J. Neuroimmunology • These authors found no evidence of mimicry between flu hemagglutinin (HA) and Hypocretin (HCRT) • Referring to a paper by Luo et al. Proc. Natl. Acad. Sci. 115(52): E12323-E12332, 2018, we report that by sequencing 100 times more cells we do in fact find evidence for cross reacting TCR sequences, suggesting mimicry. [ABSTRACT FROM AUTHOR]

Few T cells infiltrate into primary brain tumors, fundamentally hampering the effectiveness of immunotherapy. We hypothesized that Toxoplasma gondii, a microorganism that naturally elicits a Th1 response in the brain, can promote T cell infiltration into brain tumors despite their immune suppressive microenvironment. Using a mouse genetic model for medulloblastoma, we found that T. gondii infection induced the infiltration of activatable T cells into the tumor mass and led to myeloid cell reprogramming toward a T cell-supportive state, without causing severe health issues in mice. The study provides a concrete foundation for future studies to take advantage of the immune modulatory capacity of T. gondii to facilitate brain tumor immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sleep insufficiency is a significant health problem worldwide, and adolescent sleep restriction (SR) could induce multiple neurodevelopmental disorders in the central nervous system (CNS). Microglial-mediated neuroinflammation plays a vital role in multiple neurological diseases, and recent research showed the regulation effect of immunoproteasome on microglia functions. Geraniol (GER), an important ingredient in many essential oils, possesses diverse pharmacological properties like anti-inflammatory and antioxidant. The present study was designed to evaluate the neuroprotective effect of GER on SR in adolescent mice and further investigate the underlying mechanisms. Our results displayed that 14 days of chronic sleep restriction (CSR) induced cognitive decline, and anxiety-like and attention-deficit behaviors, which were mitigated by GER pretreatment. GER administration also reversed microglial pro-inflammatory response under CSR stimulation in the anterior cingulate cortex (ACC) regions by reducing the expression and secretion of cytokines like IL-1β and TNF-α. Mechanism research showed that LMP7 mRNA was selectively up-regulated under CSR treatment but down-regulated by GER administration. Proteasome activity and protein expression of LMP7 were consistent with mRNA data. ONX-0914 was applied to inhibit LMP7 selectively, and data validated that GER might alleviate CSR-induced neuroinflammation by regulating LMP7. Our study provides evidence that LMP7 is a critical regulator of CSR-induced proinflammation, and geraniol might be a promising therapy against CSR-induced neurodevelopmental disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study investigated the impact of two-hit inflammation on postoperative cognitive dysfunction (POCD) in mice and the role of macrophage-derived exosomes in regulating this process. Mice models were used to mimic the state of two-hit inflammation, and cognitive function was assessed through behavioral experiments. Proinflammatory cytokine expression levels and blood-brain barrier (BBB)-associated functional proteins were measured using ELISA and Western blot, respectively. An in vitro macrophage inflammation two-hit model was created, and the role of exosomes was examined using the previously mentioned assays. Additionally, exosomes were injected into mice to further understand their impact in the two-hit inflammation model. Mice exposed to two-hit inflammation experienced impaired cognitive function, increased BBB permeability, and elevated levels of proinflammatory cytokines. Macrophages subjected to two-hit inflammation released higher levels of proinflammatory cytokines compared to the control group and other treatment groups. Treatment with an exosome inhibitor GW4869 effectively reduced the expression levels of proinflammatory cytokines in macrophages exposed to two-hit inflammation. Moreover, injection of macrophage-released exosomes into healthy mice induced inflammation, hippocampal damage, and cognitive disorders, which were mitigated by treatment with GW4869. In mice with two-hit inflammation, macrophage-released exosomes worsened cognitive disorders by promoting inflammation in the peripheral blood and central nervous system. However, treatment with GW4869 protected cognitive function by suppressing exosome release. These findings highlight the importance of two-hit inflammation in POCD and emphasize the critical role of exosomes as regulatory factors. This research provides valuable insights into the pathogenesis of POCD and potential intervention strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The extracellular matrix protein tenascin-C has been discovered to be an important regulator of the response to tissue injury and repair in cerebrovascular diseases. This study investigated if tenascin-C is released in response to infections in the central nervous system (CNS)., Methods: Tenascin-C concentration in the cerebrospinal fluid (CSF) was measured in patients, (>18 years) with and without CNS infections, admitted to a department of infectious diseases in Denmark. CSF tenascin-C was measured on the Meso-scale platform., Results: 174 patients were included of which 140 were diagnosed with a CNS infection and 34 where this was ruled out (control group). Median CSF tenascin-C levels were significantly higher among patients with bacterial meningitis (147 pg/mL), viral meningitis (33 mg/mL), viral encephalitis (39 pg/mL) and Lyme neuroborreliosis (45 pg/mL) when compared to controls (21 pg/mL). Correlations between tenascin-C and CSF markers of inflammation and age were only moderate., Conclusion: Levels of CSF tenascin-C are higher among patients with bacterial and viral neuroinfections, already on admission, but exhibit only a modest correlation with baseline indices of neuroinflammation. CSF tenascin-C is highest among patients with bacterial meningitis compared to the other CNS infections. Patients with unfavorable outcomes presented with higher median CSF tenascin-C than their counterparts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)