Autoreactive lymphocytes in multiple sclerosis: Pathogenesis and treatment target

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Сен. 23, 2022

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by destruction myelin sheath structure. The loss leads to damage neuron’s axon and cell body, which identified as brain lesions on magnetic resonance image (MRI). pathogenesis MS remains largely unknown. However, immune mechanisms, especially those linked aberrant lymphocyte activity, are mainly responsible for neuronal damage. Th1 Th17 populations lymphocytes were primarily associated with pathogenesis. These essential differentiation encephalitogenic CD8 + T crossing blood barrier targeting in CNS. B-lymphocytes could also contribute producing anti-myelin basic protein antibodies. In later studies, function Treg Th9 cells was contributing MS. This review summarizes count lymphocyte, contributions these mechanisms Additionally, we have outlined novel therapeutics aimed amend or counts lymphocytes.

Язык: Английский

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Inflammation in multiple sclerosis: consequences for remyelination and disease progression

Nature Reviews Neurology, Год журнала: 2023, Номер 19(5), С. 305 - 320

Опубликована: Апрель 14, 2023

Язык: Английский

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The neuropathobiology of multiple sclerosis

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(7), С. 493 - 513

Опубликована: Май 24, 2024

Язык: Английский

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Th17 cells and inflammation in neurological disorders: Possible mechanisms of action

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Июль 22, 2022

Neurological disorders (NDs) are one of the leading causes global death. A sustained neuroinflammatory response has been reported to be associated with pathogenesis multiple NDs, including Parkinson’s disease (PD), sclerosis (MS), Alzheimer’s (AD), amyotrophic lateral (ALS), and major depressive disorder (MDD). Accumulating evidence shows that recruitment abundant lymphocytes in central nervous system may contribute promoting development progress inflammation neurological disorders. As subset T lymphocytes, CD4 + cells have a critical impact on helper (Th) 17 is most studied Th subpopulations produces cytokines (e.g., IL-17A, IL-23, IL-21, IL-6, IFN-γ), abnormal excessive activation microglia other immune cell types. All these factors involved several However, possible mechanisms Th17 their immunopathology abovementioned not clarified completely. This review will summarize by which encephalitogenic inflammatory related strongly chronic neuroinflammation, thus perpetuating neurodegenerative processes NDs. Finally, potential therapeutic prospects NDs also discussed.

Язык: Английский

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Versican promotes T helper 17 cytotoxic inflammation and impedes oligodendrocyte precursor cell remyelination

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Май 4, 2022

Remyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation exacerbate injury unknown. Here, we correlate high versican-V1 expression MS lesions with premyelinating oligodendrocytes, highlight its selective upregulation amongst members experimental autoimmune encephalomyelitis (EAE) modeling MS. In culture, purified inhibits oligodendrocyte precursor cells (OPCs) promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 are particularly toxic OPCs. NG2CreER:MAPTmGFP mice illuminating newly formed GFP+ oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment peak EAE reduces lesional frequency, while enhancing profiles. We suggest that lesion-elevated directly impedes OPCs it indirectly remyelination through elevating cytotoxic neuroinflammation. propose CSPG-lowering drugs as potential dual pronged immunomodulatory therapeutics for

Язык: Английский

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Impact of aging on treatment considerations for multiple sclerosis patients

Frontiers in Neurology, Год журнала: 2023, Номер 14

Опубликована: Июль 7, 2023

With a rapidly aging global population and improvement of outcomes with newer multiple sclerosis (MS)-specific disease-modifying therapies (DMTs), the epidemiology MS has shifted to an older than previously described population, peak prevalence disease seen in 55–65 years age group. Changes pathophysiology appear be age-dependent. Several studies have identified consistent phase disability worsening around fifth decade life. The latter appears independent prior duration inflammatory activity concomitant pathological changes from acute focal active demyelination chronic smoldering plaques, slow-expanding lesions, compartmentalized inflammation within central nervous system (CNS). On other hand, decreased CNS tissue reserve poorer remyelinating capacity lead loss relapse recovery potential. Aging may imply longer exposure DMTs, although treatment efficacy patients >55 not been evaluated pivotal randomized controlled trials decrease age. Older individuals are more prone adverse effects important aspect individualization. also implies higher burden comorbid illnesses that contribute overall impairments represent crucial confounder interpreting clinical worsening. Discontinuation DMTs after 55, when no evidence or radiological is detected, currently under spotlight. In this review, we will discuss impact on pathobiology, effect comorbidities confounders worsening, focus current therapeutic considerations

Язык: Английский

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Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles

Neuropathology and Applied Neurobiology, Год журнала: 2024, Номер 50(2)

Опубликована: Апрель 1, 2024

Abstract Neuroinflammation, blood–brain barrier (BBB) dysfunction, neuron and glia injury/death myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), its human orthologue SERPINA3, is an acute‐phase inflammatory glycoprotein secreted primarily by the liver into bloodstream response to systemic inflammation. Clinically, SERPINA3 dysregulated brain cells, cerebrospinal fluid plasma conditions. Although it has been widely accepted that Serpina3n/SERPINA3 a reliable biomarker of reactive astrocytes diseased CNS, recent data have challenged this well‐cited concept, suggesting instead oligodendrocytes neurons primary sources Serpina3n/SERPINA3. The debate continues regarding whether induction represents pathogenic or protective mechanism. Here, we propose possible interpretations for previously controversial present perspectives potential role CNS pathologies, including demyelinating disorders where targets. We hypothesise ‘good’ ‘bad’ aspects depend on cellular sources, subcellular distribution (or mis‐localisation) and/or disease/injury types. Furthermore, circulating may cross BBB impact pathologies. Cell‐specific genetic tools critically important tease out roles cell type‐dependent Serpina3n diseases/injuries.

Язык: Английский

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The Role of Neuroinflammation and Network Anomalies in Drug-Resistant Epilepsy

Neuroscience Bulletin, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Epilepsy affects over 50 million people worldwide. Drug-resistant epilepsy (DRE) accounts for up to a third of these cases, and neuro-inflammation is thought play role in such cases. Despite being long-debated issue the field DRE, mechanisms underlying neuroinflammation have yet be fully elucidated. The pro-inflammatory microenvironment within brain tissue with DRE has been probed using single-cell multimodal transcriptomics. Evidence suggests that inflammatory cells cytokines nervous system can lead extensive biochemical changes, as connexin hemichannel excitability disruption neurotransmitter homeostasis. presence inflammation may give rise neuronal network abnormalities suppress endogenous antiepileptic systems. We focus on anomalies from multiple perspectives identify critical points clinical application. hope provide an insightful overview advance quest better treatments.

Язык: Английский

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Cumulative Roles for Epstein-Barr Virus, Human Endogenous Retroviruses, and Human Herpes Virus-6 in Driving an Inflammatory Cascade Underlying MS Pathogenesis

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Ноя. 1, 2021

Roles for viral infections and aberrant immune responses in driving localized neuroinflammation neurodegeneration multiple sclerosis (MS) are the focus of intense research. Epstein-Barr virus (EBV), as a persistent frequently reactivating with major immunogenic influences near 100% epidemiological association MS, is considered to play leading role MS pathogenesis, triggering inflammation or within central nervous system (CNS). This may occur directly via products (RNA protein) and/or indirectly antigenic mimicry involving B-cells, T-cells cytokine-activated astrocytes microglia cells damaging myelin sheath neurons. The genetic MS-risk factor HLA-DR2b (DRB1*1501β, DRA1*0101α) contribute EBV antigen-presentation anti-EBV reactivity but also mimicry-induced autoimmune characteristic MS. A proposed inflammatory EBER1, EBV-miRNA LMP1 containing exosomes secreted by viable EBV+ B-cells repetitive release EBNA1-DNA complexes from apoptotic forming reactive EBNA1-IgG complement. be accompanied cytokine- EBV-induced expression human endogenous retrovirus-W/-K (HERV-W/-K) elements possibly activation herpesvirus-6A (HHV-6A) early-stage CNS lesions, each contributing an cascade causing relapsing-remitting neuro-inflammatory progressive features Elimination EBV-carrying antibody- EBV-specific T-cell therapy hold promise reducing activity CNS, thereby limiting inflammation, symptoms reversing disease. Other approaches targeting HHV-6 HERV-W kinase-signaling treat being tested promising results. article presents overview evidence that EBV, HHV-6, have pathogenic initiating promoting possible mitigate development

Язык: Английский

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Immunoregulatory and/or Anti-inflammatory Agents for the Management of Core and Associated Symptoms in Individuals with Autism Spectrum Disorder: A Narrative Review of Randomized, Placebo-Controlled Trials

CNS Drugs, Год журнала: 2023, Номер 37(3), С. 215 - 229

Опубликована: Март 1, 2023

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with so far poorly understood underlying pathogenesis, and few effective therapies for core symptoms. Accumulating evidence supports an association between ASD immune/inflammatory processes, arising as possible pathway new drug intervention. However, current literature on the efficacy of immunoregulatory/anti-inflammatory interventions symptoms still limited. The aim this narrative review was to summarize discuss latest use immunoregulatory and/or anti-inflammatory agents management condition. During last 10 years, several randomized, placebo-controlled trials effectiveness (add-on) treatment prednisolone, pregnenolone, celecoxib, minocycline, N-acetylcysteine (NAC), sulforaphane (SFN), omega-3 fatty acids have been performed. Overall, beneficial effect symptoms, such stereotyped behavior, found. (Add-on) NAC, SFN, also associated significantly higher improvement in other irritability, hyperactivity, lethargy when compared placebo. mechanisms by which these exert their action improve are not fully understood. Interestingly, studies suggested that all may suppress microglial/monocyte proinflammatory activation restore immune cell imbalances (e.g., T regulatory/T helper-17 imbalances), decreasing levels cytokines, interleukin (IL)-6 IL-17A, both blood brain individuals ASD. Although encouraging, performance larger randomized trials, including more homogeneous populations, dosages, longer periods follow-up, urgently needed order confirm findings provide stronger evidence.

Язык: Английский

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