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
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
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Research Article Neuroscience

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

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.

Authors

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

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Figure 4

Hierarchical clustering of SHM profiles.

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Hierarchical clustering of SHM profiles. Profiles of SHM along the analy...
Profiles of SHM along the analyzed IGHV portion of Ig-VH were normalized to the peak (=1, red) and subjected to unsupervised hierarchical clustering. In general, post-GC subsets display higher and naive B cells display lower levels of SHM. (A) Higher level SHM can be found in IgG-expressing SM B cells and PCs. (B) Lower level SHM can be found in IgM-expressing SM B cells and PCs. (C and D) Predominantly IgG-expressing CSF-derived SM B cells and PCs form separate clusters. (E) Lowest level SHM can be found among mostly IgM-expressing naive B cells. Each row represents an individual B cell sample, as indicated by sample names containing patient ID, B cell subset, number of cells analyzed, and Ig isotype separated by “_”. CSF B cells subsets are indicated by “CSF” before the subset designation and blue type. N, naive B cells; USM, unswitched-memory B cells; DN, double-negative B cells; SM, switched-memory B cells; PC, plasma cells/plasmablasts.