Longitudinally persistent cerebrospinal fluid B-cells can resist treatment in multiple sclerosis

Greenfield, Ariele L.; Dandekar, Ravi; Ramesh, Akshaya; Eggers, Erica L.; Wu, Hao; Laurent, Sarah; Harkin, William; Pierson, Natalie S.; Weber, Martin; Henry, Roland G.; Bischof, Antje; Cree, Bruce A.C.; Hauser, Stephen L.; Wilson, Michael R.; Büdingen, Hans‐Christian von

doi:10.1172/jci.insight.126599

Cited by 25 publications

(26 citation statements)

References 55 publications

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“…This is consistent with a highly stable humoral immune response in the CSF of MS patients and underscores that finite samples of CSF cells only represent a small proportion of the IgG-producing B lineage cells in the CNS. The results corroborate early observations of stable OCB patterns on electrophoretic gels (Walsh and Tourtellotte, 1986), and shed new light on previous and contemporary studies detecting a limited overlap in B lineage cell samples collected at different time points (Colombo et al, 2003, Greenfield et al, 2019.…”

Section: Discussionsupporting

confidence: 88%

Persistence of intrathecal oligoclonal B cells and IgG in multiple sclerosis

Tomescu-Baciu

Johansen

Holmøy

et al. 2019

Journal of Neuroimmunology

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In multiple sclerosis (MS), B cells are trafficking across the blood-brain barrier, but it is not known how this relates to the synthesis of oligoclonal IgG. We used quantitative mass spectrometry of oligoclonal bands and high-throughput sequencing of immunoglobulin heavy-chain variable transcripts to study the longitudinal B cell response in the cerebrospinal fluid (CSF) and blood of two MS patients. Twenty of 22 (91%) and 25 of 28 (89%) of oligoclonal band peptides persisted in samples collected 18 months apart, in spite of a dynamic exchange across the blood-CSF barrier of B lineage cells connecting to oligoclonal IgG.

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Section: Discussionsupporting

confidence: 88%

Persistence of intrathecal oligoclonal B cells and IgG in multiple sclerosis

Tomescu-Baciu

Johansen

Holmøy

et al. 2019

Journal of Neuroimmunology

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“…Recent studies have shown that in MS identical B‐cell clones are present in both the periphery and CNS . That these B‐cell populations further undergo somatic hypermutation in the brain implies the presence of functional germinal centers within the CNS.…”

Section: Discussionmentioning

confidence: 99%

“…B cells are one of the main contributors to chronic autoimmune pathology in multiple sclerosis (MS), as supported by results from large genome‐wide association studies . B‐cell repertoires in the central nervous system (CNS) and the periphery are closely connected, suggesting that disease‐relevant B‐cell networks interact at both sides of the blood–brain barrier . There is evidence that the beneficial effects of anti‐CD20 monoclonal antibody therapy are related to the ablation of functional B cells interacting with T cells .…”

mentioning

confidence: 99%

Induction of brain‐infiltrating T‐bet–expressing B cells in multiple sclerosis

Langelaar

Rijvers

Janssen

et al. 2019

Annals of Neurology

136

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Objective Results from anti‐CD20 therapies demonstrate that B‐ and T‐cell interaction is a major driver of multiple sclerosis (MS). The local presence of B‐cell follicle‐like structures and oligoclonal bands in MS patients indicates that certain B cells infiltrate the central nervous system (CNS) to mediate pathology. Which peripheral triggers underlie the development of CNS‐infiltrating B cells is not fully understood. Methods Ex vivo flow cytometry was used to assess chemokine receptor profiles of B cells in blood, cerebrospinal fluid, meningeal, and brain tissues of MS patients (n = 10). Similar analyses were performed for distinct memory subsets in the blood of untreated and natalizumab‐treated MS patients (n = 38). To assess T‐bet(CXCR3)+ B‐cell differentiation, we cultured B cells from MS patients (n = 21) and healthy individuals (n = 34) under T helper 1‐ and TLR9‐inducing conditions. Their CNS transmigration capacity was confirmed using brain endothelial monolayers. Results CXC chemokine receptor 3 (CXCR3)‐expressing B cells were enriched in different CNS compartments of MS patients. Treatment with the clinically effective drug natalizumab prevented the recruitment of CXCR3high IgG1+ subsets, corresponding to their increased ability to cross CNS barriers in vitro. Blocking of interferon‐γ (IFNγ) reduced the transmigration potential and antigen‐presenting function of these cells. IFNγ‐induced B cells from MS patients showed increased T‐bet expression and plasmablast development. Additional TLR9 triggering further upregulated T‐bet and CXCR3, and was essential for IgG1 switching. Interpretation This study demonstrates that T‐bethigh IgG1+ B cells are triggered by IFNγ and TLR9 signals, likely contributing to enhanced CXCR3‐mediated recruitment and local reactivity in the CNS of MS patients. ANN NEUROL 2019;86:264–278

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“…Fresh whole CSF and blood lymphocytes were labeled with the following antibodies: CD3, CD19, CD27, CD38, CD138, and IgD. Using a Beckman MoFlo Astrios cell sorter, CSF and blood B cell subsets were sorted directly into lysis buffer as previously described ( 17 , 31 ): naïve B cells (N; CD19+IgD+CD27–), unswitched memory B cells (USM; CD19+IgD+CD27+), switched memory B cells (SM; CD19+IgD–CD27+), double-negative B cells (DN; CD19+IgD–CD27–), CSF plasmablast/plasma cells (CD19+IgD–CD27hi), and blood plasmablast/plasma cells (CD19+IgD–CD27hiCD38hi) ( Dataset S1 C ). These distinct B cell populations represent classic B cell subsets, as described previously ( 17 , 32 – 34 ).…”

Section: Methodsmentioning

confidence: 99%

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

Ramesh

Schubert

Greenfield

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood–brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein–Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.

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Longitudinally persistent cerebrospinal fluid B-cells can resist treatment in multiple sclerosis

Abstract: and reports equity in Roche and income as full-time employee.

Cited by 25 publications

References 55 publications

Persistence of intrathecal oligoclonal B cells and IgG in multiple sclerosis

Persistence of intrathecal oligoclonal B cells and IgG in multiple sclerosis

Induction of brain‐infiltrating T‐bet–expressing B cells in multiple sclerosis

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

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