Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients

Erica L. Eggers; Brady A. Michel; Hao Wu; Sheng Zhi Wang; Carolyn J. Bevan; Aya Abounasr; Natalie S. Pierson; Antje Bischof; Max Kazer; Elizabeth Leitner; Ariele L. Greenfield; Stanislas Demuth; Michael R. Wilson; Roland G. Henry; Bruce A.C. Cree; Stephen L. Hauser; H. Christian von Büdingen

doi:10.1172/jci.insight.92724

Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients

Erica L. Eggers, Brady A. Michel, Hao Wu, Sheng Zhi Wang, Carolyn J. Bevan, Aya Abounasr, Natalie S. Pierson, Antje Bischof, Max Kazer, Elizabeth Leitner, Ariele L. Greenfield, Stanislas Demuth, Michael R. Wilson^*, Roland G. Henry, Bruce A.C. Cree, Stephen L. Hauser, H. Christian von Büdingen

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

Abstract

A role of B cells in multiple sclerosis (MS) is well established, but there is limited understanding of their involvement during active disease. Here, we examined cerebrospinal fluid (CSF) and peripheral blood (PB) B cells in treatment-naive patients with MS or high-risk clinically isolated syndrome. Using flow cytometry, we found increased CSF lymphocytes with a disproportionate increase of B cells compared with T cells in patients with gadolinium-enhancing (Gd⁺) lesions on brain MRI. Ig gene heavy chain variable region (Ig-VH) repertoire sequencing of CSF and PB B cells revealed clonal relationships between intrathecal and peripheral B cell populations, which could be consistent with migration of B cells to and activation in the CNS in active MS. In addition, we found evidence for bystander immigration of B cells from the periphery, which could be supported by a CXCL13 gradient between CSF and blood. Understanding what triggers B cells to migrate and home to the CNS may ultimately aid in the rational selection of therapeutic strategies to limit progression in MS.

Original language	English (US)
Article number	e92724
Journal	JCI Insight
Volume	2
Issue number	22
DOIs	https://doi.org/10.1172/jci.insight.92724
State	Published - Nov 16 2017

Funding

The authors are deeply grateful to their patients who have agreed to participate in this research study and all members of the UCSF MS Expression, Proteomics, Imaging, Clinical (EPIC) study team who supported this study. Our studies were supported by grants from the National MS Society (RG-4868 to HCVB), the NIH/National Institute of Neurological Disorders and Stroke (K02NS072288, R01NS092835 to HCVB), and the Valhalla Foundation as well as by gifts from the Friends of the Multiple Sclerosis Research Group at UCSF. HCVB was also supported by an endowment from the Rachleff Family Foundation. AB was supported by the Gottfried and Julia Bangerter-Rhyner Foundation and the Freiwillige Akademische Gesellschaft (Basel, Switzerland). conception and execution, HCVB was full-time faculty at the UCSF. At the time of submission, HCVB was a full-time employee of F. Hoffmann-La Roche. HCVB has received compensation for consulting activities from Roche, Novartis, and Genzyme and research funding from Roche, Genentech, and Pfizer. SLH serves on the scientific advisory boards for Symbiotix, Annexon, Bionure, Neurona Therapeutics, and Molecular Stethoscope. SLH reports receiving travel reimbursement and writing assistance from F. Hoffmann-La Roche for CD20-related meetings and presentations. BACC has received compensation for consulting activities from Biogen, EMD Serono, and Teva.

ASJC Scopus subject areas

General Medicine

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Eggers, E. L., Michel, B. A., Wu, H., Wang, S. Z., Bevan, C. J., Abounasr, A., Pierson, N. S., Bischof, A., Kazer, M., Leitner, E., Greenfield, A. L., Demuth, S., Wilson, M. R., Henry, R. G., Cree, B. A. C., Hauser, S. L., & von Büdingen, H. C. (2017). Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients. JCI Insight, 2(22), Article e92724. https://doi.org/10.1172/jci.insight.92724

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abstract = "A role of B cells in multiple sclerosis (MS) is well established, but there is limited understanding of their involvement during active disease. Here, we examined cerebrospinal fluid (CSF) and peripheral blood (PB) B cells in treatment-naive patients with MS or high-risk clinically isolated syndrome. Using flow cytometry, we found increased CSF lymphocytes with a disproportionate increase of B cells compared with T cells in patients with gadolinium-enhancing (Gd+) lesions on brain MRI. Ig gene heavy chain variable region (Ig-VH) repertoire sequencing of CSF and PB B cells revealed clonal relationships between intrathecal and peripheral B cell populations, which could be consistent with migration of B cells to and activation in the CNS in active MS. In addition, we found evidence for bystander immigration of B cells from the periphery, which could be supported by a CXCL13 gradient between CSF and blood. Understanding what triggers B cells to migrate and home to the CNS may ultimately aid in the rational selection of therapeutic strategies to limit progression in MS.",

author = "Eggers, {Erica L.} and Michel, {Brady A.} and Hao Wu and Wang, {Sheng Zhi} and Bevan, {Carolyn J.} and Aya Abounasr and Pierson, {Natalie S.} and Antje Bischof and Max Kazer and Elizabeth Leitner and Greenfield, {Ariele L.} and Stanislas Demuth and Wilson, {Michael R.} and Henry, {Roland G.} and Cree, {Bruce A.C.} and Hauser, {Stephen L.} and {von B{\"u}dingen}, {H. Christian}",

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Eggers, EL, Michel, BA, Wu, H, Wang, SZ, Bevan, CJ, Abounasr, A, Pierson, NS, Bischof, A, Kazer, M, Leitner, E, Greenfield, AL, Demuth, S, Wilson, MR, Henry, RG, Cree, BAC, Hauser, SL & von Büdingen, HC 2017, 'Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients', JCI Insight, vol. 2, no. 22, e92724. https://doi.org/10.1172/jci.insight.92724

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AU - Leitner, Elizabeth

AU - Greenfield, Ariele L.

AU - Demuth, Stanislas

AU - Wilson, Michael R.

AU - Henry, Roland G.

AU - Cree, Bruce A.C.

AU - Hauser, Stephen L.

AU - von Büdingen, H. Christian

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N2 - A role of B cells in multiple sclerosis (MS) is well established, but there is limited understanding of their involvement during active disease. Here, we examined cerebrospinal fluid (CSF) and peripheral blood (PB) B cells in treatment-naive patients with MS or high-risk clinically isolated syndrome. Using flow cytometry, we found increased CSF lymphocytes with a disproportionate increase of B cells compared with T cells in patients with gadolinium-enhancing (Gd+) lesions on brain MRI. Ig gene heavy chain variable region (Ig-VH) repertoire sequencing of CSF and PB B cells revealed clonal relationships between intrathecal and peripheral B cell populations, which could be consistent with migration of B cells to and activation in the CNS in active MS. In addition, we found evidence for bystander immigration of B cells from the periphery, which could be supported by a CXCL13 gradient between CSF and blood. Understanding what triggers B cells to migrate and home to the CNS may ultimately aid in the rational selection of therapeutic strategies to limit progression in MS.

AB - A role of B cells in multiple sclerosis (MS) is well established, but there is limited understanding of their involvement during active disease. Here, we examined cerebrospinal fluid (CSF) and peripheral blood (PB) B cells in treatment-naive patients with MS or high-risk clinically isolated syndrome. Using flow cytometry, we found increased CSF lymphocytes with a disproportionate increase of B cells compared with T cells in patients with gadolinium-enhancing (Gd+) lesions on brain MRI. Ig gene heavy chain variable region (Ig-VH) repertoire sequencing of CSF and PB B cells revealed clonal relationships between intrathecal and peripheral B cell populations, which could be consistent with migration of B cells to and activation in the CNS in active MS. In addition, we found evidence for bystander immigration of B cells from the periphery, which could be supported by a CXCL13 gradient between CSF and blood. Understanding what triggers B cells to migrate and home to the CNS may ultimately aid in the rational selection of therapeutic strategies to limit progression in MS.

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Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients

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