B cell exchange across the blood-brain barrier in multiple sclerosis

Büdingen, Hans‐Christian von; Kuo, Tracy C.; Sirota, Marina; Belle, Christopher van; Apeltsin, Leonard; Glanville, Jacob; Cree, Bruce A.C.; Gourraud, Pierre-Antoine; Schwartzburg, Amy; Huerta, Gabriella; Telman, Dilduz; Sundar, Purnima; Casey, Tyler; Cox, David; Hauser, Stephen L.

doi:10.1172/jci63842

Cited by 214 publications

(239 citation statements)

References 36 publications

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“…We and others have shown that the IgG‐producing B cells in CSF are somatically hypermutated and have identical or clonally related counterparts in blood,10, 13 and it was recently shown that the maturation of CNS B cells could be initiated in cervical lymph nodes 14. Although it is possible that the selection of B cells carrying the G1m1 allotype occurs during the initiation of the B‐cell response in the periphery, the lack of any allotype restriction in the blood could indicate a selection at the blood–brain barrier or within the intrathecal compartment.…”

Section: Discussionmentioning

confidence: 97%

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

Lossius

Tomescu-Baciu

Holmøy

et al. 2017

Ann Clin Transl Neurol

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Immunoglobulin gamma (IgG) heavy chain genes are associated with susceptibility to multiple sclerosis (MS) and IgG levels in the cerebrospinal fluid (CSF). However, how these variants are implicated in disease mechanisms remains unknown. Here, we show that proliferating plasmablasts expressing the G1m1 allotype of IgG1 are selectively enriched in CSF of G1m1/G1m3 heterozygous MS patients, whereas plasmablasts expressing either G1m1 or G1m3 are evenly distributed in blood. Moreover, there was a preferential intrathecal synthesis of oligoclonal IgG1 of the G1m1 allotype in heterozygous patients, whereas controls with Lyme neuroborreliosis displayed oligoclonal IgG1 of both allotypes. This points to a disease‐specific mechanism involved in B‐cell establishment within the central nervous system in MS.

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Section: Discussionmentioning

confidence: 97%

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

Lossius

Tomescu-Baciu

Holmøy

et al. 2017

Ann Clin Transl Neurol

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“…In both disorders, the patterns of mutations in VH sequences in bicompartmental clones are consistent with a migration of multiple antigen‐experienced peripheral B‐cell populations across the blood‐brain barrier. In MS, lineage analysis suggests a bidirectional exchange of B‐cell clones 18, 19, 20. While B cell maturation into ASCs occurs in both compartments, antigen‐specific maturation predominates in the periphery 20.…”

Section: Discussionmentioning

confidence: 99%

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

Kowarik

Astling

Gasperi

et al. 2017

Ann Clin Transl Neurol

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ObjectivesNeuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disorder of the central nervous system (CNS) targeted against aquaporin‐4 (AQP4). The origin and trafficking of AQP4‐specific B cells in NMOSD remains unknown.MethodsPeripheral (n = 7) and splenic B cells (n = 1) recovered from seven NMOSD patients were sorted into plasmablasts, naïve, memory, and CD27‐IgD‐ double negative (DN) B cells, and variable heavy chain (VH) transcriptome sequences were generated by deep sequencing. Peripheral blood (PB) VH repertoires were compared to the same patient's single‐cell cerebrospinal fluid (CSF) plasmablast (PB) VH transcriptome, CSF immunoglobulin (Ig) proteome, and serum Ig proteome. Recombinant antibodies were generated from paired CSF heavy‐ and light chains and tested for AQP4 reactivity.ResultsApproximately 9% of the CSF VH sequences aligned with PB memory B cells, DN B cells, and plasmablast VH sequences. AQP4‐specific VH sequences were observed in each peripheral B‐cell compartment. Lineage analysis of clonally related VH sequences indicates that CSF AQP4‐specific B cells are closely related to an expanded population of DN B cells that may undergo antigen‐specific B‐cell maturation within the CNS. CSF and serum Ig proteomes overlapped with the VH sequences from each B‐cell compartment; the majority of matches occurring between the PB VH sequences and serum Ig proteome.InterpretationDuring an acute NMOSD relapse, a dynamic exchange of B cells occurs between the periphery and CNS with AQP4‐specific CSF B cells emerging from postgerminal center memory B cells and plasmablasts. Expansion of the PB DN B‐cell compartment may be a potential biomarker of NMOSD activity.

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“…Different studies investigated the VH repertoire in the peripheral blood, cervical lymph nodes, meninges, CNS parenchyma and CSF [Von Budingen et al 2012;Palanichamy et al 2014a;Stern et al 2014]. A common observation of all studies were overlapping clonal B-cell populations common to peripheral and CNS compartments.…”

Section: Targeting B Cells In Relapsing-remitting Multiple Sclerosis:mentioning

confidence: 99%

Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

Bittner

Ruck

Wiendl

et al. 2016

Ther Adv Neurol Disord

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that is caused by an autoimmune response against central nervous system (CNS) structures. Traditionally considered a T-cell-mediated disorder, the contribution of B cells to the pathogenesis of MS has long been debated. Based on recent promising clinical results from CD20-depleting strategies by three therapeutic monoclonal antibodies in clinical phase II and III trials (rituximab, ocrelizumab and ofatumumab), targeting B cells in MS is currently attracting growing interest among basic researchers and clinicians. Many questions about the role of B and plasma cells in MS remain still unanswered, ranging from the role of specific B-cell subsets and functions to the optimal treatment regimen of B-cell depletion and monitoring thereafter. Here, we will assess our current knowledge of the mechanisms implicating B cells in multiple steps of disease pathology and examine current and future therapeutic approaches for the treatment of MS.

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B cell exchange across the blood-brain barrier in multiple sclerosis

Cited by 214 publications

References 36 publications

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

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