Pathways to Progressive Disability in Multiple Sclerosis: The Role of Glial Cells in Chronic CNS Inflammation DOI Creative Commons
Volker Siffrin

Glia, Journal Year: 2025, Volume and Issue: unknown

Published: May 23, 2025

ABSTRACT Multiple sclerosis (MS) is the most common non‐infectious inflammatory CNS disease, characterized by progressive neurodegeneration and focal demyelinated lesions. Traditionally considered an autoimmune MS driven immune system's attack on myelin, resulting in cumulative disability. However, conventional anti‐inflammatory treatments often fail to prevent deterioration, particularly absence of overt inflammation, highlighting need for a deeper understanding its pathogenesis. Recent research has revealed more complex disease mechanism involving both peripheral responses intrinsic factors, with glial cells playing central role. Persistent inflammation associated mixed active/inactive lesions dominated microglia astrocyte dysregulation. These populations exhibit maladaptive activation, contributing failed remyelination ongoing neurodegeneration. Transcriptomic epigenomic alterations as well aging further exacerbate dysfunction, creating self‐perpetuating cycle damage. Emerging evidence suggests that interplay between potential dual‐use nature molecular tools shared system disrupts homeostatic signaling, leading loss tissue integrity. This review synthesizes findings cell biology MS, focus astrocytes, while addressing their roles demyelination, synapse loss, The limitations animal models, EAE, replicating complexity are also addressed. Finally, critical questions outlined guide future into pathology identify novel therapeutic approaches targeting MS.

Language: Английский

Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis DOI
Robert J. Fox,

Amit Bar-Or,

Anthony Traboulsee

et al.

New England Journal of Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 8, 2025

Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for sclerosis have limited effects on accrual unrelated to relapses, is thought be partially caused by chronic, nonresolving neuroinflammation within central nervous system. Tolebrutinib an oral, brain-penetrant Bruton's tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B in both periphery There are no approved treatments nonrelapsing secondary sclerosis. In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with 2:1 ratio, receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed progression sustained at least 6 months, assessed time-to-event analysis. A total 1131 underwent randomization: 754 were 377 median follow-up 133 weeks. smaller percentage group than placebo had months (22.6% vs. 30.7%; hazard 0.69; 95% confidence interval, 0.55 0.88; P = 0.003). Serious adverse events occurred 15.0% 10.4% those group. 4.0% 1.6% increases alanine aminotransferase levels more 3 times upper limit normal range. risk lower among who received treatment (Funded Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.).

Language: Английский

Citations

5
Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis DOI
Jiwon Oh, Douglas L. Arnold, Bruce Cree

et al.

New England Journal of Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 8, 2025

Tolebrutinib is an oral, brain-penetrant, and bioactive Bruton's tyrosine kinase inhibitor that modulates peripheral inflammation persistent immune activation within the central nervous system, including disease-associated microglia B cells. More data are needed on its efficacy safety in treating relapsing multiple sclerosis. In two phase 3, double-blind, double-dummy, event-driven trials (GEMINI 1 GEMINI 2), participants with sclerosis were randomly assigned a 1:1 ratio to receive tolebrutinib (60 mg once daily) or teriflunomide (14 daily), each matching placebo. The primary end point was annualized relapse rate. key secondary confirmed worsening of disability sustained for at least 6 months, which assessed time-to-event analysis pooled across trials. A total 974 enrolled 1, 899 2. median follow-up 139 weeks. rate groups 0.13 0.12, respectively, (rate ratio, 1.06; 95% confidence interval [CI], 0.81 1.39; P = 0.67) 0.11 0.11, 2 1.00; CI, 0.75 1.32; 0.98). percentage months 8.3% 11.3% (hazard 0.71; 0.53 0.95; no formal hypothesis testing conducted owing prespecified hierarchical plan, width not adjusted testing). who had adverse events similar treatment groups, although minor bleeding higher group than (petechiae occurred 4.5% vs. 0.3%, heavy menses 2.6% 1.0%). superior decreasing rates among (Funded by Sanofi; ClinicalTrials.gov numbers, NCT04410978 NCT04410991, respectively.).

Language: Английский

Citations

5
Identification of BTK as an immune-related biomarker for Hashimoto’s thyroiditis by integrated bioinformatic analysis DOI Creative Commons
Yingzhao Liu, Zhichao Zhu, Qian Xu

et al.

BMC Immunology, Journal Year: 2025, Volume and Issue: 26(1)

Published: Feb. 28, 2025

Hashimoto's thyroiditis (HT) is one of the most common autoimmune disorders characterized by diffuse enlargement thyroid gland, lymphocyte infiltration, and thyroid-specific autoantibodies. Cellular humoral immune have been implicated in development HT. However, little known regarding role immune-related molecules This study was aimed to identify key biomarkers HT using bioinformatic analysis. Integration sequencing data from normal control (NC) GSA GTEx databases yielded a dataset named NGS. The GSE138198 GEO database downloaded as validation set. WGCNA analysis performed modules associated with Lasso regression (LASSO) random forest (RF) were determine potential diagnostic biomarkers. value assessed receiver operating characteristic (ROC) curve CIBERSORT algorithm used evaluate infiltration cells NC samples. transcript levels verified genes expanded samples detected quantitative real-time PCR. A total 1,401 differentially expressed (DEGs) identified patients. Gene Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) pathway analyses indicated that these DEGs predominantly enriched pathways. Furthermore, 192 through intersection modules, DEGs, IRGs. Among them, two upregulated ((Bruton's tyrosine kinase, BTK) CD19) showed for machine learning. ROC revealed BTK had higher than CD19 across datasets. Intriguingly, only expression peripheral blood mononuclear patients, significantly positively correlated serum Further studies confirmed significant positive correlation between increased proportions plasma which might be involved pathogenesis regulating represented biomarker

Language: Английский

Citations

0
Positive effect of evobrutinib in CNS remyelination models and lack of synergy with clemastine—A dose response study DOI Creative Commons
Elodie Martin, Marie‐Stéphane Aigrot,

N. Frère

et al.

Multiple Sclerosis Journal - Experimental Translational and Clinical, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 1, 2025

Background To recover normal functions, remyelination in multiple sclerosis is crucial. Although endogenous occurs, it often insufficient, and finding molecules promoting repair of demyelinated lesions needed. Objectives compare the potential evobrutinib, an inhibitor Bruton's tyrosine kinase clemastine, antagonist M1 muscarinic acetylcholine receptor. Methods Remyelination was investigated lysolecithin organotypic mouse cerebellar slices a transgenic Xenopus model inducible-demyelination. Results Evobrutinib (100 nM) clemastine (200 potentiated by factor 2.9 1.76, respectively. In conditionally , evobrutinib increased 1.61 1.92, targets expressed microglia, we showed that increase number myeloid cells following demyelination due to extravasation from nearby vessels macrophages migrating toward optic nerve. contrast, expected antagonize receptor 1 expressing oligodendroglial lineage. We possible synergistic effect on adding simultaneously both molecules. experimental models tested no significative improvement co-treatment with plus observed. Discussion While 1.59 fold microglia/macrophages, presence innate immune decreased 0.39 fold, therefore counteracting beneficial microglia/macrophages remyelination.

Language: Английский

Citations

0
Revisiting X-linked agammaglobulinemia DOI Creative Commons
Hirokazu Kanegane, Kay Tanita, Madoka Nishimura

et al.

Published: April 28, 2025

Discovered >70 years ago by Ogden Bruton, X-linked agammaglobulinemia (XLA), characterized recurrent bacterial infections, hypo/agammaglobulinemia, and peripheral blood B-cell deficiency, is among the best-established inborn errors of immunity (IEIs) one most well-documented single types IEIs, incidence which estimated to be between 1:100,000 1:200,000. However, although pathogenesis XLA well understood, several issues remain open for discussion. In this review, we describe unresolved issues, including noncoding BTK variants, contiguous deletion syndrome, Helicobacter infection, noninfectious neurodegeneration, renal involvement, malignancies. The primary treatment XLA, immunoglobulin replacement therapy, administered either intravenously or subcutaneously, has remained unchanged since its discovery. Allogeneic hematopoietic cell transplantation been successful in some patients, but there are still few reports. it may considered as a option future. Given that common resolving these priority.

Language: Английский

Citations

0
Progress toward Mitigating Disability Progression in Multiple Sclerosis DOI
Peter A. Calabresi

New England Journal of Medicine, Journal Year: 2025, Volume and Issue: 392(19), P. 1966 - 1968

Published: May 14, 2025

Language: Английский

Citations

0
Pathways to Progressive Disability in Multiple Sclerosis: The Role of Glial Cells in Chronic CNS Inflammation DOI Creative Commons
Volker Siffrin

Glia, Journal Year: 2025, Volume and Issue: unknown

Published: May 23, 2025

ABSTRACT Multiple sclerosis (MS) is the most common non‐infectious inflammatory CNS disease, characterized by progressive neurodegeneration and focal demyelinated lesions. Traditionally considered an autoimmune MS driven immune system's attack on myelin, resulting in cumulative disability. However, conventional anti‐inflammatory treatments often fail to prevent deterioration, particularly absence of overt inflammation, highlighting need for a deeper understanding its pathogenesis. Recent research has revealed more complex disease mechanism involving both peripheral responses intrinsic factors, with glial cells playing central role. Persistent inflammation associated mixed active/inactive lesions dominated microglia astrocyte dysregulation. These populations exhibit maladaptive activation, contributing failed remyelination ongoing neurodegeneration. Transcriptomic epigenomic alterations as well aging further exacerbate dysfunction, creating self‐perpetuating cycle damage. Emerging evidence suggests that interplay between potential dual‐use nature molecular tools shared system disrupts homeostatic signaling, leading loss tissue integrity. This review synthesizes findings cell biology MS, focus astrocytes, while addressing their roles demyelination, synapse loss, The limitations animal models, EAE, replicating complexity are also addressed. Finally, critical questions outlined guide future into pathology identify novel therapeutic approaches targeting MS.

Language: Английский

Citations

0