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Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [BRB-seq]

ABSTRACT: The efficacy of B cell depletion therapies, and association with the B lymphotropic Epstein- Barr virus (EBV) implicate B cells in the demyelinating autoimmune disease multiple sclerosis. After observing myelin-reactive B cells in the naïve human repertoire, we studied how such cells behave in the central nervous system. In mice, viral infections induce infiltration of B cells independent of phenotype and specificity into the otherwise lymphocyte-poor brain, and myelin-reactive B cells then capture antigen directly from parenchyma. Trafficking of these antigen-loaded B cells to draining lymph nodes was not observed, and without T cell help, antigen-capturing B cells die rapidly. CD40L signaling or EBV latent membrane protein 1 (LMP1) can override this checkpoint, leading to in situ plasma cell differentiation and antibody-mediated, demyelinating lesion formation. These observations explain the dependency of disease incidence on prior EBV infection, and the increased risk associated with brain infections, and suggest possible treatment strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE308407 | GEO | 2026/01/13

REPOSITORIES: GEO

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Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [RNA-Seq]

Project description:The efficacy of B cell depletion therapies, and association with the B lymphotropic Epstein- Barr virus (EBV) implicate B cells in the demyelinating autoimmune disease multiple sclerosis. After observing myelin-reactive B cells in the naïve human repertoire, we studied how such cells behave in the central nervous system. In mice, viral infections induce infiltration of B cells independent of phenotype and specificity into the otherwise lymphocyte-poor brain, and myelin-reactive B cells then capture antigen directly from parenchyma. Trafficking of these antigen-loaded B cells to draining lymph nodes was not observed, and without T cell help, antigen-capturing B cells die rapidly. CD40L signaling or EBV latent membrane protein 1 (LMP1) can override this checkpoint, leading to in situ plasma cell differentiation and antibody-mediated, demyelinating lesion formation. These observations explain the dependency of disease incidence on prior EBV infection, and the increased risk associated with brain infections, and suggest possible treatment strategies.

2026-01-13 | GSE308212 | GEO

Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [scRNA-Seq]

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Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [BRB-seq]

Project description:Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [BRB-seq]

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Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation

Project description:Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation

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Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [RNA-Seq]

Project description:Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [RNA-Seq]

| PRJNA1329221 | ENA

Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [scRNA-Seq]

Project description:Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation [scRNA-Seq]

| PRJNA1209885 | ENA

Pro-inflammatory activity following demyelinating injury is required for phagocytic function and oligodendrocyte formation

Project description:Remyelination can occur naturally in demyelinating lesions, but often fails in human demyelinating diseases such as multiple sclerosis (MS). The function of the innate immune system is essential for the regenerative response, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory nuclear factor κB (NF-κB) dependent activation occurs in phagocytes rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88), the canonical adaptor for inflammatory signaling pathways downstream of toll-like receptors (TLRs). MyD88-deficient mice and zebrafish were impaired not only in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of tumor necrosis factor-α (TNF-α) in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is an evolutionary conserved mechanism necessary for degrading myelin debris, essential for inflammation resolution, and for initiating the secretion of pro-inflammatory myelin repair molecules.

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Analysis of the host transcriptome from demyelinating spinal cord of murine coronavirus infected mice

Project description:We use transcriptome analysis to study the spinal cord transcriptome during MHV-induced demyelinating disease and find important biological pathways for demyelinating pathology. We find evidence of a Th1 cytokine response, ongoing antigen presentation and lymphocyte proliferation, lipid metabolism changes, and eicosanoid inflammation. In addition, we report several genes important for osteoclast function have augmented expression in the CNS during demyelination, suggesting a parallel between the osteoclast and microglial functions in maintaining homeostasis and the fidelity of specialized extracellular matrices in their respective compartments. RNA-seq of mock-infected and MHV-infected spinal cord tissue at 33 days post-infection, the peak of demyelination.

2013-06-15 | E-GEOD-44333 | biostudies-arrayexpress

Temporal transcriptomic profiles of brain regions following acute and chronic demyelinating injury

Project description:Purpose: The central nervous system (CNS) possesses intrinsic remyelination capabilities in response to demyelinating injury. However, this remyelination potential is diminished as demyelinating disease such as multiple sclerosis progresses overtime. To better understand myelin repair processes, the goal of this study was to determine temporal transcriptomic changes in cerebral white matter (corpus callosum) and gray matter (cortex and hippocampus) after acute and chronic demyelinating injury. The cuprizone mouse model of de- and remyelination was used for this investigation. Methods: Adult C57BL/6 mice were exposed to cuprizone diet (0.2%) for 3, 5 or 12 weeks followed by returning to normal diet for up to 12 weeks for recovery. Brain regions were dissected for bulk RNA-seq. Conclusion: RNA-seq analyses suggest common and distinct spatiotemporal transcriptional alterations during CNS demyelination and remyelination. Dataset for this study represents the first that covers gene expression landscapes of three brain regions over extended regenerative periods after chronic CNS demyelination.

2023-04-03 | GSE212147 | GEO

Novel Model of Multiple Sclerosis Induced by EBV-like Virus Generates a Unique B Cell Population

Project description:Objective: Multiple sclerosis (MS) is a chronic, autoimmune disease of the central nervous system. Prior infection with Epstein-Barr virus (EBV), a gammaherpesvirus, is deemed a necessary yet insufficient factor in the development of MS. The objective of this study was to determine whether the EBV-like virus, murid gammaherpesvirus 68, is sufficient to induce inflammatory demyelinating disease in a transgenic TCR mouse strain susceptible to CNS autoimmunity. Methods: B10.PL mice that express the myelin basic protein-specific transgenic T cell receptor (TCRMBP) were intranasally inoculated with murid gammaherpesvirus 68 virus (MHV68), PR8 influenza virus, or PBS. Mice were evaluated for the development of neurologic deficits. Flow cytometry and fluorescent microscopy were used to validate the infiltration of immune cells in the brain and spinal cord of TCRMBP mice. Single cell RNA sequencing of splenic B cells was performed to determine transcriptional changes that resulted from MHV68 infection. Results: MHV68-infected mice developed neurological deficits at a significantly higher frequency (70.8%) than the influenza (7.7%) or mock-infected mice (13.3%). MHV68 infected mice exhibited signs including optic neuritis and ataxia, which are infrequently observed in EAE mice, but common in MS patients. MHV68-infected mice exhibited increased focal immune cell infiltration. Single cell RNA sequencing identified the emergence of a novel, MHV68 infection-associated population of memory-like B cells that highly express genes associated with antigen presentation and costimulation. Conclusion: Infecting myelin basic protein specific TCR transgenic mice with the EBV analogue, MHV68, generates encephalitogenic disease without myelin immunization. MHV68 drives a distinct transcriptional program in B cells capable of enhanced antigen presentation and costimulation to drive an autoreactive T cell response.

2024-04-02 | GSE261605 | GEO

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