Abstract Details

Title B Cell-mediated Neurotoxicity in Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) P7 - Poster Session 7 (11:45 AM-12:45 PM)

Poster/Presentation
Number 6-003

Objective

To assess the effects of secreted factors from human B cells on neuronal viability in vitro.

Background In multiple sclerosis (MS), B cell rich lymphoid aggregates form in the meninges adjacent to cerebral sulci, and contribute to underlying cortical neurodegeneration, demyelination, and clinical progression. Little is known regarding how these B cells produce pathology.

Design/Methods CD19⁺ B cells were isolated from peripheral blood of treatment-naïve MS patients and age/sex matched healthy controls (HC), and cultured under unstimulated conditions, or following stimulation with anti-IgM/G/A and recombinant human CD40L with or without CpG. After 3 days, supernatants were added to human induced pluripotent stem cell (iPSC) derived day 14 glutamatergic neurons (iNeurons). Neurotoxicity was quantitated by thiazol red staining and neurofilament light chain levels. Size fractionation, Ig depletion, and blocking experiments were performed to identify factors responsible for the B cell mediated toxicity.

Results Unstimulated B cell supernatants were consistently neurotoxic to iNeurons. In approximately half of MS subjects, levels of neurotoxicity were higher than in HC and were present under unstimulated culture conditions, as reported earlier using different assays (Lisak et al. J. Neuroimmunol 309:88, 2017). Selective depletion and fractionation studies indicated that B cell mediated neurotoxic activities were predominantly present in the low molecular weight (e.g. lower than 30kD) fractions and were absent from Ig-containing or high molecular weight (including exosome) supernates. Increased B cell mediated neurotoxicity in MS was associated with production of higher levels of proinflammatory molecules, including TNF-α, IL-8, RANTES, MDC, and MIP-1β, and neurotoxicity could be partially blocked by inhibitors of TNF-α.

Conclusions B cells can directly injure nearby neurons through secreted factors including TNF-α. These data build upon evidence that the B cell transcriptome is fundamentally dysregulated in MS, and demonstrate that one consequence may be a more neurotoxic secretome.

Authors/Disclosures
Chaitrali Saha, PhD (University of California San Francisco) PRESENTER	Dr. Saha has nothing to disclose.
Amy Zhang (UCSF Weill Institute for Neurosciences)	No disclosure on file
Kun Leng	No disclosure on file
Chloe Gerungan	Chloe Gerungan has nothing to disclose.
Ahmed Abdelhak, MD (UCSF Weill Institute of Neuroscience)	The institution of Dr. Abdelhak has received research support from German Multiple Sclerosis Society.
Refujia Gomez	Refujia Gomez has nothing to disclose.
Meagan Harms (University of California, San Francisco)	Meagan Harms has nothing to disclose.
Asritha Tubati (University of California, San Francisco)	Asritha Tubati has nothing to disclose.
Tiffany Cooper (University of San Francisco California)	Tiffany Cooper has nothing to disclose.
Martineau Louine, MD	Dr. Louine has nothing to disclose.
Joseph J. Sabatino, Jr., MD (University of California San Francisco)	The institution of Dr. Sabatino has received research support from Roche/Genentech.
Martin Kampmann (UCSF)	No disclosure on file
Ari Green, MD (UCSF)	Dr. Green has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pipeline Therapeutics. Dr. Green has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Bionure. Dr. Green has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA Neurology. The institution of Dr. Green has received research support from NINDS. The institution of Dr. Green has received research support from NMSS. The institution of Dr. Green has received research support from NIA. The institution of Dr. Green has received research support from Adelson Research Foundation. Dr. Green has received intellectual property interests from a discovery or technology relating to health care. Dr. Green has received personal compensation in the range of $500-$4,999 for serving as a Study Section with NINDS. Dr. Green has a non-compensated relationship as a Author with Viela Bio that is relevant to AAN interests or activities.
Jorge Oksenberg, MD (UCSF)	No disclosure on file
Bruce A. Cree, MD, PhD, MAS, FAAN (UCSF, Multiple Sclerosis Center)	The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for TG Therapeutics. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neuron23. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Pharma. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Hexal/Sandoz. Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic AG. The institution of Dr. Cree has received research support from Genentech. The institution of Dr. Cree has received research support from Kyverna. Dr. Cree has received publishing royalties from a publication relating to health care.
Michael R. Wilson, MD, FAAN (University of California San Francisco)	Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ouro Medicines. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vertex Pharmaceuticals. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Indapta Therapeutics. Dr. Wilson has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Delve Bio. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Cambridge Medical Experts. Dr. Wilson has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Dunham Hallmark. Dr. Wilson has stock in Delve Bio. The institution of Dr. Wilson has received research support from Genentech / Roche. The institution of Dr. Wilson has received research support from NIH. The institution of Dr. Wilson has received research support from Novartis. The institution of Dr. Wilson has received research support from National Multiple Sclerosis Society. The institution of Dr. Wilson has received research support from Fanconi Anemia Research Foundation. The institution of Dr. Wilson has received research support from Department of Defense. The institution of Dr. Wilson has received research support from Chan Zuckerberg Initiative. The institution of Dr. Wilson has received research support from Kyverna Therapeutics. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as a Expert Witness with US Dept of Justice.
Stephen L. Hauser, MD (UCSF Weill Institute for Neurosciences)	Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NGM Bio. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BD. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pheno Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nurix Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gilead. Dr. Hauser has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Accure. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alector. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hinge Therapeutics. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Neurona. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Roche that is relevant to AAN interests or activities. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Novartis that is relevant to AAN interests or activities.

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