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3285 Toxicity of Released B Cell Products in Multiple Sclerosis: Effects on Neurons and Oligodendrocytes
- Leah Zuroff, Hanane Touil, Micah Romer, Liljana Nedelkoska, Joyce A. Benjamins, Robert P. Lisak, Judith B. Grinspan, Amit Bar-Or
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- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, p. 116
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- Article
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- Open access
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OBJECTIVES/SPECIFIC AIMS: We previously demonstrated that products released by cultured B cells from patients with Multiple Sclerosis (MS) are cytotoxic to neurons and oligodendrocytes, while minimal toxicity was observed in response to B cell secretory products from age- and sex-matched normal controls. The goal of this proposal is to identify the range of brain cells susceptible to MS B cell-mediated cytotoxicity, to define the cytotoxic factor(s) released by MS B cells, and to determine whether particular subset(s) of MS B cells harbor the greatest pathogenic potential. METHODS/STUDY POPULATION: The toxicity of B cell products will be demonstrated by incubating primary rat cultures of neurons, oligodendrocytes, and oligodendrocyte progenitor cells (OPCs) with B cell supernatants. B cells will be isolated from the peripheral circulation of untreated relapse-remitting MS (RRMS) patients and age- and sex-matched normal controls. The identification of specific toxic factor(s) in MS B cell supernatants will be achieved through a combination of exosome-depletion/enrichment of conditioned media, proteomics, next generation sequencing, and lipidomics. Determining pathogenic B cell subsets will be achieved by cell sorting into memory and naïve B cell subsets prior to collection of supernatants. RESULTS/ANTICIPATED RESULTS: We hypothesize that the toxicity of MS B cell products is mediated, at least in part, by extracellular vesicles, such as exosomes. We expect depletion of these exosomes from the B cell conditioned media or inhibition of their biogenesis will mitigate the observed toxicity. Furthermore, differences in B cell-derived exosomal content, such as proteins, (mi)RNAs, or lipids, likely explain the differences in observed toxicity. Lastly, we hypothesize that memory B cells, which are enriched in the CNS of MS patients and demonstrate a more pro-inflammatory profile than naïve B cells, are responsible for the toxicity observed in supernatants of total B cells. DISCUSSION/SIGNIFICANCE OF IMPACT: MS is the most prevalent chronic inflammatory disease of the CNS, affecting more than 2 million people worldwide. Although over a dozen disease-modifying therapies are approved for the treatment of RRMS, none are meaningfully effective at limiting disease progression. This proposal will provide new insight into immune-CNS interactions in progressive MS and provide much-needed novel targets for therapeutic intervention, either via blocking identified toxic molecule(s) or by selectively depleting pathogenic B cell subsets.
6 - Cytokine and chemokine interactions with Schwann cells: the neuroimmunology of Schwann cells
- Edited by Patricia Armati, University of Sydney
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- Book:
- The Biology of Schwann Cells
- Published online:
- 13 August 2009
- Print publication:
- 15 February 2007, pp 100-117
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Summary
INTRODUCTION
Cytokines, first described as products of the cells of the inflammatory/immune system, are increasingly recognised as acting on non-inflammatory cells as well as being produced by non-inflammatory cells. Nowhere is this more apparent than with cells of the peripheral (PNS) and central (CNS) nervous systems. Studies have clearly indicated that neuroglial cells are targets of cytokines produced by infiltrating immune/inflammatory cells in inflammatory diseases of the PNS and CNS, and are not simply passive targets of lytic destructive processes. In addition there is evidence to show that neuroglial cells, in particular astrocytes, Schwann cells and microglia (cells of the monocyte/macrophage lineage), respond to cytokines by changes in function and phenotype and can themselves produce many of the classically described inflammatory cell cytokines. Perhaps even more interesting are recent studies showing that such cytokines, particularly when produced by cells that are endogenous to the PNS and CNS, are important in PNS and CNS development and perhaps in protection and regeneration of the PNS and CNS in inflammatory, traumatic and even some degenerative diseases.
We and others have been interested in the interactions of Schwann cells and cytokines in the pathogenesis of diseases, modulation and recovery from disease, and regeneration, as well as in normal PNS development and function. Schwann cell–cytokine interactions can be studied in various ways: examining tissue obtained at different stages of development, and at different phases of experimental and naturally occurring diseases, including human disorders of the PNS, and employing different in vitro models.