Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Mar 21;4(6):e126599.
doi: 10.1172/jci.insight.126599.

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

Ariele L Greenfield  1 , Ravi Dandekar  1 , Akshaya Ramesh  1 , Erica L Eggers  1 , Hao Wu  1 , Sarah Laurent  1 , William Harkin  1 , Natalie S Pierson  1 , Martin S Weber  2 , Roland G Henry  1 , Antje Bischof  1 , Bruce Ac Cree  1 , Stephen L Hauser  1 , Michael R Wilson  1 , H-Christian von Büdingen  1
Affiliations

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

Ariele L Greenfield et al. JCI Insight. .

Abstract

B cells are key contributors to chronic autoimmune pathology in multiple sclerosis (MS). Clonally related B cells exist in the cerebrospinal fluid (CSF), meninges, and CNS parenchyma of MS patients. We sought to investigate the presence of clonally related B cells over time by performing Ig heavy chain variable region repertoire sequencing on B cells from longitudinally collected blood and CSF samples of MS patients (n = 10). All patients were untreated at the time of the initial sampling; the majority (n = 7) were treated with immune-modulating therapies 1.2 (±0.3 SD) years later during the second sampling. We found clonal persistence of B cells in the CSF of 5 patients; these B cells were frequently Ig class-switched and CD27+. Specific blood B cell subsets appear to provide input into CNS repertoires over time. We demonstrate complex patterns of clonal B cell persistence in CSF and blood, even in patients on immune-modulating therapy. Our findings support the concept that peripheral B cell activation and CNS-compartmentalized immune mechanisms can in part be therapy resistant.

Keywords: B cell receptor; B cells; Immunology; Multiple sclerosis; Neuroscience.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: ALG has a patent pending for Method for High Percentage Recovery of Rare Cells (European application 18185007.4). MSW receives research support from the DFG (WE 3547/5-1), Novartis, Teva Pharmaceutical Industries, Biogen Idec, Roche, Merck, and the ProFutura Program of the Universitätsmedizin Göttingen. MSW is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen Idec, Merck Serono, Novartis, Roche/Genentech, Teva Pharmaceutical Industries, Bayer, and Sanofi Genzyme. RGH has received research funding from Roche/Genentech and Sanofi Genzyme. BAC has received personal compensation for consulting from EMD Serono and Novartis. SLH currently serves on the scientific advisory board of Symbiotix, Annexon, Bionure, Molecular Stethoscope, and Alector and on the board of trustees of Neurona. SLH also has received travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd. for CD20-related meetings and presentations. MRW has received research support from Roche/Genentech and has a patent pending for Method for High Percentage Recovery of Rare Cells (European application 18185007.4). HCVB is an employee of F. Hoffmann-La Roche Ltd., Basel, Switzerland (Roche) and reports equity in Roche and income as full-time employee.

Figures

Figure 1
Figure 1. Persistent CSF Ig-VH clusters are present in MS patients.
Shown are the numbers of Ig-VH clusters within CSF (blue circles) and PB (red circles) at T1 and T2. Circle overlap values, Ig-VH clusters found in both CSF and PB at T1 or T2; nonoverlap circle values, Ig-VH clusters exclusively found in CSF or PB, not both. Arrows, of total Ig-VH clusters in CSF or PB (nonoverlap portion of circle + circle overlap), the number of Ig-VH clusters that are present at both T1 and T2. Patients (Pts) 1–5 have persistent CSF Ig-VH clusters; Pts 6–10 did not have identifiable persistent CSF Ig-VH clusters.
Figure 2
Figure 2. Persistent CSF Ig-VH clusters have multiple patterns of persistence in relation to PB.
Persistent CSF Ig-VH clusters can be exclusive to CSF (far left, Pts 1, 2, 5), link to T1-PB (second from left, Pts 1, 2), link to T2-PB (second from right, Pt 4), or link to both PB time points (far right, Pts 1–4). Blue circles, CSF; red circles, PB; circles on left, T1; circles on right, T2; arrows, shared Ig-VH clusters between time points or between CSF and PB.
Figure 3
Figure 3. B cells that persist in the CSF are often SM and plasma cells.
(A) Clonally related B cell subsets are connected by lines between CSF (top half of circle) and PB (bottom half) at T1 (left half) and T2 (right half). Each segment along the circle represents a B cell subset from CSF or PB. Lines connecting B cell subsets indicate B cell subsets that share 1 or more Ig-VH clusters in common. Gray lines, PB-only Ig-VH clusters; blue lines, persistent CSF Ig-VH clusters; red lines, CSF Ig-VH clusters with PB contribution; yellow lines, T1-PB Ig-VH clusters that share clonal relatives with T2-CSF yet not with T1-CSF. Gray font indicates subsets or Ig isotypes from which no Ig-VH libraries could be obtained. Persistent CSF Ig-VH clusters were linked to PB Ig-VH sequences derived from Ig class-switched memory (SM) B cells (n = 4 patients), double-negative (DN) B cells (n = 3 patients at T1, n = 2 patients at T2), and plasmablasts/plasma cells (PCs) (n = 2 patients at T1 and 1 patient at T2). (B) T1-PB B cell subsets that are clonally related to T2-CSF without involving T1-CSF (i.e., quantitation of yellow lines depicted in A). USM, unswitched memory.
See this image and copyright information in PMC

References

    1. Molnarfi N, et al. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J Exp Med. 2013;210(13):2921–2937. doi: 10.1084/jem.20130699. - DOI - PMC - PubMed
    1. Montalban X, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017;376(3):209–220. doi: 10.1056/NEJMoa1606468. - DOI - PubMed
    1. Hauser SL, et al. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017;376(3):221–234. doi: 10.1056/NEJMoa1601277. - DOI - PubMed
    1. Hauser SL. The Charcot Lecture | beating MS: a story of B cells, with twists and turns. Mult Scler. 2015;21(1):8–21. doi: 10.1177/1352458514561911. - DOI - PMC - PubMed
    1. Dalakas MC. B cells as therapeutic targets in autoimmune neurological disorders. Nat Clin Pract Neurol. 2008;4(10):557–567. doi: 10.1038/ncpneuro0901. - DOI - PubMed

Publication types

Substances