B cell exchange across the blood-brain barrier in multiple sclerosis
H.-Christian von Büdingen, Tracy C. Kuo, Marina Sirota, Christopher J. van Belle, Leonard Apeltsin, Jacob Glanville, Bruce A. Cree, Pierre-Antoine Gourraud, Amy Schwartzburg, Gabriella Huerta, Dilduz Telman, Purnima D. Sundar, Tyler Casey, David R. Cox, Stephen L. Hauser
H.-Christian von Büdingen, Tracy C. Kuo, Marina Sirota, Christopher J. van Belle, Leonard Apeltsin, Jacob Glanville, Bruce A. Cree, Pierre-Antoine Gourraud, Amy Schwartzburg, Gabriella Huerta, Dilduz Telman, Purnima D. Sundar, Tyler Casey, David R. Cox, Stephen L. Hauser
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Research Article Neuroscience

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

Abstract

In multiple sclerosis (MS) pathogenic B cells likely act on both sides of the blood-brain barrier (BBB). However, it is unclear whether antigen-experienced B cells are shared between the CNS and the peripheral blood (PB) compartments. We applied deep repertoire sequencing of IgG heavy chain variable region genes (IgG-VH) in paired cerebrospinal fluid and PB samples from patients with MS and other neurological diseases to identify related B cells that are common to both compartments. For the first time to our knowledge, we found that a restricted pool of clonally related B cells participated in robust bidirectional exchange across the BBB. Some clusters of related IgG-VH appeared to have undergone active diversification primarily in the CNS, while others have undergone active diversification in the periphery or in both compartments in parallel. B cells are strong candidates for autoimmune effector cells in MS, and these findings suggest that CNS-directed autoimmunity may be triggered and supported on both sides of the BBB. These data also provide a powerful approach to identify and monitor B cells in the PB that correspond to clonally amplified populations in the CNS in MS and other inflammatory states.

Authors

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

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Figure 1

Clusters of B cells expressing identical and/or related IgG-VH are shared between CSF and BP.

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Clusters of B cells expressing identical and/or related IgG-VH are share...
Closely related IgG-VH sequences from (A) patients with MS and (B) patients with ONDs were clustered and colored according to their compartment (blue circles or arrowheads indicate CSF; red circles or arrowheads indicate PB) and depicted as networks. Only clusters containing at least one CSF node (i.e., IgG-VH clone) are shown. Directly connected nodes differ in their H-CDR3 by 1 amino acid; node sizes are proportional to the total number of identical H-CDR3 sequences identified. Clusters shaded in gray are presented as lineage trees in Figures 2–5, as indicated by labels with figure number and panel designation. Overall, IGHV4 germline segments are preferentially used in MS CSF; round nodes (circles) indicate clusters of related IgG-VH using IGHV4; v-shaped nodes (arrowheads) indicate clusters using all other IGHV subfamilies. The smallest nodes represent 2 IgG-VH sequences; the largest node (patient MS-6) represents 4,278 IgG-VH sequences.