Anti-CD19 CAR T cell therapy induces CNS-specific immune alterations in multiple sclerosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE324824 | GEO | 2026/09/15
REPOSITORIES: GEO
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Project description:Despite decades of research, the cellular and molecular events preceding multiple sclerosis (MS) relapse remain incompletely understood. Here, in this observational study of longitudinal blood samples from patients with relapsing-remitting MS, we used single-cell RNA sequencing, bulk transcriptomics, multiparameter flow cytometry and targeted viral reverse transcription quantitative polymerase chain reaction (RT−qPCR) to construct a time-resolved atlas of immune perturbations surrounding relapse. A reproducible pre-relapse signature in monocytes and B cells, emerging up to 3 months before clinical onset, was enriched for host genes responsive to Epstein−Barr virus (EBV) lytic reactivation factors. RT−qPCR confirmed elevated EBV LMP-1 transcripts in pre-relapse B cells, and flow cytometry demonstrated expansion of CD11c+ atypical B cell populations displaying EBV surface protein gp350. Pre-relapse transcriptional modules overlapped with MS genome-wide association study (GWAS) risk loci and EBNA-2-bound enhancers, suggesting that inherited MS susceptibility and EBV-responsive programs operate through shared regulatory elements. How this peripheral activation relates to central nervous system lesion formation remains to be established. These findings nonetheless suggest that EBV reactivation, when occurring within a genetically predisposed peripheral immune environment, is a proximal precursor of MS relapse.
2026-08-25 | GSE344578 | GEO
Project description:Clinically Isolated Syndromes (CIS)represent the first clinical episode of an inflammatory demyelinating disorder suggestive of MS. Most CIS will develop relapsing-remitting MS (RR), characterized by clinical and inflammatory attacks followed by periods of recovery and stability. With time, most RR-MS subjects will evolve to secondary progressive MS (SP), with advancing neurological impairment in absence of recognizable relapses. A small fraction of MS subjects experience worsening of neurologic function from the onset and are thus defined primary progressive MS (PP). We analysed PBMC transcriptomes relative to 41 healthy subjects, 47 CIS, 49 RR, 22 SP and 27 PP patients and applied a semi-automated pipeline in R Bioconductor platform to perform preprocessing and differential expression analysis.
2023-01-31 | E-MTAB-11415 | biostudies-arrayexpress
Project description:<p>Background: Growing evidence indicates significant alterations in fatty acid metabolism in patients with relapsing-remitting multiple sclerosis (RRMS). However, the metabolic status of long-chain fatty acids (LCFAs), including mono-unsaturated fatty acids (MUFAs) and poly-unsaturated fatty acids (PUFAs), and their potential link to immune-inflammatory responses during RRMS relapses, remain unclear. This study aims to uncover the aberrant metabolic signatures of LCFAs, potential LCFA biomarkers during RRMS relapses, and their interactive network with peripheral inflammatory responses.</p><p>Methods: In this study, plasma samples from 20 RRMS patients and 22 age- and sex-matched healthy controls (HCs) were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based untargeted metabolomics method.</p><p>Results: Metabolomics analysis revealed marked changes in the LCFA metabolic profile of RRMS patients. Compared to HCs, 26 differentially abundant metabolites (DAMs) belonging to amino acids, fatty acids, and their derivatives were identified in RRMS samples, including significantly upregulated LCFA palmitic acid (FA 16:0) (Padj < 0.001), MUFA oleic acid (FA 18:1) (Padj < 0.05), PUFA arachidonic acid (FA 20:4) (Padj < 0.01), and significantly downregulated dodecanoic acid (FA 12:0) (Padj < 0.01). These DAMs were mainly enriched in amino acid, fatty acid, and lipid synthesis/metabolism pathways. Additionally, the circulating levels of pro-inflammatory factors TNF-α and IL17A were significantly elevated (Padj < 0.001), while the concentrations of chemokines such as IL1RA, CCL2, CCL3, CCL4, CCL5, PDGFB, IL7, CXCL8, IL9, and IL12A were significantly reduced (Padj < 0.01) in RRMS compared to HC samples. Linear regression analysis showed significant positive correlations between FA 20:4 and IL17A (r = 0.370, Padj < 0.05), and significant negative correlations between FA 16:0 and PDGFB (r = -0.339, Padj < 0.05). Receiver operating characteristic (ROC) curve analysis indicated that individual fatty acids (e.g., FA 12:0 [AUC=0.881], FA 18:1 [AUC=0.833], FA 16:0 [AUC=0.881]) have high potential for predicting RRMS, with higher accuracy, specificity, and sensitivity when combining two (FA 12:0 and FA 18:1 [AUC=0.929]) or four (FA 12:0, FA 18:1, FA 16:0, and FA 20:4 [AUC=0.952]) fatty acids.</p><p>Conclusion: Our results uncover the aberrant metabolic features of LCFAs and potential biomarkers in RRMS patients, and the interactive network and key molecular nodes between LCFAs and peripheral immune-inflammatory responses. The interplay between LCFAs and immuno-inflammation may drive the migration of inflammatory events from the periphery to the CNS, reigniting CNS neuroinflammation and causing RRMS relapses. These findings offer valuable insights for RRMS diagnosis and novel therapeutic development.</p>
2026-03-23 | MTBLS13949 | MetaboLights
Project description:Background: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood brain barrier. Methods: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA-sequencing we localize these cells in post-mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes). Findings: We identify a specific pathogenic CD161+/LTB+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients. Conclusions: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression. Funding: This study was supported by funding from the University Medical Center Hamburg-Eppendorf, the Stifterverband für die Deutsche Wissenschaft, the OAK Foundation, Medical Research Council UK and Wellcome.
2021-02-16 | GSE144744 | GEO
Project description:Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38M-NM-1 signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38M-NM-1 in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38M-NM-1-controlled transcripts comprising female- and male-specific gene modules, with greater p38M-NM-1 dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38M-NM-1 in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS WT vs. p38alphaCKO macrophages, male vs. female
2013-10-29 | E-GEOD-51707 | biostudies-arrayexpress
Project description:Chimeric antigen receptor-T (CAR-T) cells directed against B-cell maturation antigen (BCMA) are an effective treatment for multiple myeloma, but short persistence and frequent relapses are challenges for this immunotherapy. This lack of durability has been attributed to the premature terminal differentiation of CAR-T cells which prevents the formation of long-lived memory cells that maintain anti-tumour responses. To improve long-term efficacy, we used CRISPR/Cas9-mediated gene editing to ablate the expression of the transcription factor Blimp-1 (Prdm1). In a murine model of advanced myeloma, Blimp-1 knockout (KO) CAR-T cells effectively slowed or even prevented disease progression, significantly outperforming control (Mock) CAR-T cells in improving survival. To understand this enhanced in vivo effectiveness, Blimp-1 KO CAR-T cells were characterised after being repeatedly challenged with tumour cells in vitro and subject to gene expression analysis.
2024-11-20 | GSE255977 | GEO
Project description:Chimeric antigen receptor (CAR) T-cells induce responses in patients with relapsed/refractory leukemia; however, long-term efficacy is frequently limited by post-CAR relapses. The inability to target antigen-low cells is an intrinsic vulnerability of second-generation CAR T-cells and underlies the majority of relapses following CD22BBz CAR T-cell therapy. We interrogated CD22BBz CAR signaling in response to low antigen and found inefficient phosphorylation of LAT, limiting downstream signaling. To overcome this, we designed the Adjunctive LAT-Activating CAR T-cell (ALA-CART) platform, pairing a second-generation CAR with a LAT-CAR incorporating the intracellular domain of LAT. ALA-CART cells demonstrated reduced differentiation during manufacturing and increased LAT phosphorylation, MAPK signaling and AP-1 activity. Consequently, ALA-CART cells showed improved cytotoxicity, proliferation, persistence and efficacy against antigen-low leukemias that were refractory to clinically-active CD22BBz CAR T-cells. These data suggest restoration of LAT signaling through the ALA-CART platform represents a promising strategy for overcoming multiple mechanisms of CAR T-cell failure.
2025-05-02 | PXD058699 | Pride
Project description:Although chimeric antigen receptor (CAR) T cell therapy has revolutionised individualised cancer therapies for relapsed/refractory lymphomas, low long-term retention due to basal signalling (antigen-independent activation in the absence of cognate antigen) and off-target toxicity limit the broad applicability of CAR-T products. During CAR development, researchers use model systems, like Jurkat T cells (Jurkats), to screen intracellular signalling arrangements based on their ability to activate (e.g., CD69 expression) and withstand repeated antigen encounters. Although Jurkats are standard for CAR screening, the mapping of CAR generations to Jurkat-specific pTyr networks relative to key TCR nodes and CD69 readouts is not well defined, blurring how hierarchical signalling drives activation. Here, we investigated how costimulation influenced tyrosine phosphorylation cascades using LC-MS/MS based phosphotyrosine (pY) proteomics and CD69 expression in the presence of small molecule inhibitors of key TCR signalling regulators. We found that including TCRζ (CD3ζ; gene CD247) in first (ζ-CAR), second (28ζ-CAR and BBζ-CAR), and third (28BBζ-CAR) generation CARs largely determined pY signalling, irrespective of costimulation. Further, we showed that the phosphatase activity of PTPN22 and SHP-1 were largely negligible for activation of CARs, but indiscriminate inhibition of phosphatases using pervanadate (PV) selectively activated BBζ-CARs without antigen encounter. Finally, we found that selective, partial inhibition of Itk using Soquelitinib reduced basal CD69 expression in CAR-Jurkat cells while maintaining their ability to activate in response to antigen. These data suggest that TCRζ determines the pY signalling profile and that Itk drives basal activation of CD19-CAR Jurkats, which may impact evaluation of new CAR designs in CAR-Jurkat screens.
2025-11-21 | PXD065669 | Pride
Project description:Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38α signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38α in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38α-controlled transcripts comprising female- and male-specific gene modules, with greater p38α dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38α in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS
2013-10-29 | GSE51707 | GEO
Project description:Short chain fatty acids were shown to affect regulatory immune response in context of autoimmune diseases like multiple sclerosis (MS). Recent studies in an animal model of MS revealed significant impact of short chain fatty acid propionate (PA) on the differentiation towards regulatory Tcells (Treg). In a translational proof of concept study, PA was administered to relapse remitting MS patients. We observed an increase of Treg in peripheral blood as well as functional improvement in Treg suppressive capacity beside a decrease of proinflammatory Thelper1 and 17 cells. To investigate underlying mechanisms of the observed shift in immune cell balance, intensive transcriptomic analysis on whole blood of PA treated relapse remitting MS patients was performed.
2020-09-29 | GSE116835 | GEO