B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue

Lehmann‐Horn, Klaus; Wang, Shengzhi; Sagan, Sharon A.; Zamvil, Scott S.; Büdingen, Hans‐Christian von

doi:10.1172/jci.insight.87234

Cited by 54 publications

(36 citation statements)

References 50 publications

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“…Here, we observed that clonally related SM and USM B-cells, which remain detectable in PB over time, may also have clonal relatives in CSF at the later time point. This finding is consistent with the concept that, upon peripheral activation, CXCR5+ USM and/or SM B-cells home to the brain parenchyma or leptomeninges along a CXCL13 gradient, where they participate in the formation of ectopic, tertiary germinal centers (8,31,39,40) capable of supporting B-cell receptor affinity-maturation and class-switch recombination (41). Whether USM B-cell receptors undergo Ig class-switching and contribute to high-affinity surface receptor or secreted antibody-mediated immune responses has been debated (42,43).…”

Section: Interestingly Usm B-cells Follow the Same Depletion And Recsupporting

confidence: 91%

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

Greenfield

Dandekar

Ramesh

et al. 2018

Preprint

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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 central nervous system (CNS) parenchyma of MS patients. Longitudinally stable CSF oligoclonal band (OCB) antibody patterns suggest some local CNS B-cell persistence; however, the longitudinal B-cell dynamics within and between the CSF and blood remain unknown. We sought to address this by performing immunoglobulin 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 five patients; these B-cells were frequently immunoglobulin (Ig) classswitched and CD27+. We identified specific blood B-cell subsets that 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 high-efficacy immune modulating therapy. Our findings support the concept that peripheral B-cell activation and CNS-compartmentalized immune mechanisms are in part therapy-resistant.

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Section: Interestingly Usm B-cells Follow the Same Depletion And Recsupporting

confidence: 91%

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

Greenfield

Dandekar

Ramesh

et al. 2018

Preprint

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“…Thus, GC functionality may only be partially represented intrathecally, providing support for class-switch recombination, SHM (19), and plasma cell maturation but not for further differentiation or survival of naive B cells. The latter point is also supported by the fact that, contrary to PB, naive B cells are among the least abundant B cells in CSF.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-CD20 therapy with rituximab reduces B cell numbers in CSF without eliminating OCBs (15); thus, intrathecal production of clonal IgG is largely a function of CD20 -, long-lived plasma cells in CNS survival niches. Inflammatory infiltrates with lymphoid follicle-like structures are present in the meninges of patients with secondary progressive MS and are quite likely also present during the earlier relapsing phase of MS (16)(17)(18); such ectopic lymphoid tissues could support germinal center (GC) activity (19), plasma cell maturation, and survival. Interestingly, however, natalizumab, an anti-VLA4 antibody that limits lymphocyte transmigration across the blood-brain barrier and effectively decreases MS disease activity reduces intrathecal IgG production at least in some patients (20)(21)(22), which may suggest that OCB production also partially relies on peripheral stimuli.…”

Section: Introductionmentioning

confidence: 99%

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

Eggers¹,

Michel²,

Wu³

et al. 2017

JCI Insight

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“…Immunoglobulin messenger RNA amplification and immunoglobulin repertoire sequencing Sequencing work flow was performed as previously described, 9 with modifications to sequence human samples. In brief, total RNA was isolated from CSF cells and PB B-cell subsets, followed by reverse transcription into complementary DNA (cDNA).…”

Section: Cell Staining and Sortingmentioning

confidence: 99%

Intrathecal B-cell activation in LGI1 antibody encephalitis

Lehmann‐Horn

Irani

Wang

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis. MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB. ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls. ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.

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B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue

Cited by 54 publications

References 50 publications

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

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

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

Intrathecal B-cell activation in LGI1 antibody encephalitis

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