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 2

B cell subsets in CSF and PB.

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B cell subsets in CSF and PB. Shown are representative FACS plots of per...
Shown are representative FACS plots of peripheral blood (PB) (A) and cerebrospinal fluid (CSF) (B) CD19+ B cell subsets (patient 56414), as defined based on the expression of IgD and CD27. The graphs in C–H summarize data from all patients, i.e., both Gd+ and Gd– patients combined, to provide an overall picture of B cell subset distribution in both compartments. CD19+ B cells are approximately 3-fold lower in CSF (C, 6.7% ± 2.6% in PB versus 2.25% ± 1.4% in CSF). The CSF contains B cell subpopulations predominantly that have undergone somatic rearrangement of their B cell receptors (F–H). Among CD19+ B cells, in CSF compared with PB, naive are approximately 5-fold lower (D, 56.8% ± 14.2% in PB versus 11.5% ± 7.6% in CSF); USM are slightly increased (E, 19.1% ± 11.7% in PB versus 22.8% ± 10.4% in CSF); DN are increased (F, 4.0% ± 2.5% in PB versus 7.7% ± 7.3% in CSF); and SM are increased 2.5-fold (G, 18% ± 7.5% in PB versus 45.9% ± 11.8% in CSF). Most significantly, the percentage of CD27hi B cells was increased 34-fold in CSF (H, 0.2% ± 0.2% in PB versus 7.6% ± 7.9% in CSF). Refer to Supplemental Table 1 for more information on the patients analyzed. Data are shown as scatter plots with mean ± 95% CI. Comparisons were made using paired t tests; ***P < 0.01, ****P < 0.0001.