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

Eggers, Erica L.; Michel, Brady; Wu, Hao; Wang, Shengzhi; Bevan, Carolyn; Abounasr, Aya; Pierson, Natalie S.; Bischof, Antje; Kazer, Max; Leitner, Elizabeth; Greenfield, Ariele L.; Demuth, Stanislas; Wilson, Michael R.; Henry, Roland G.; Cree, Bruce A.C.; Hauser, Stephen L.; Büdingen, Hans‐Christian von

doi:10.1172/jci.insight.92724

Cited by 84 publications

(110 citation statements)

References 54 publications

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“…The presence of oligoclonal immunoglobulin bands in the majority of patients with MS suggests that B‐cell clonal expansion is a feature of the disease,69, 79, 80 specifically as IgG and IgM 81. However, there is no definitive evidence that these B‐cells target myelin or other CNS components.…”

Section: Msmentioning

confidence: 99%

“…B‐cell receptor sequencing has shown that CSF‐infiltrating B‐cells exhibit evidence of somatic mutation69, 79, 80, 84, 85, 88 and CSR 79, 80, 83, 84. Indeed, ectopic lymphoid tissues have been found in the meninges of patients with MS and these exhibit germinal centre activity, and both IgM and class‐switched B‐cells have been found in the CSF.…”

Section: Msmentioning

confidence: 99%

“…This allows direct inference of clonal tracking between peripheral blood and CSF. Indeed, clonally related B‐cells have been identified spanning both the peripheral blood and CSF in several studies derived from post‐germinal centre B‐cells, as evidenced by extensive levels of SHM 80, 83. These studies are suggestive of bi‐directional exchange of B‐cells across the blood–brain barrier.…”

Section: Msmentioning

confidence: 99%

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Antibody repertoire analysis in polygenic autoimmune diseases

2018

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SummaryHigh‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear.

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Section: Msmentioning

confidence: 99%

Section: Msmentioning

confidence: 99%

Section: Msmentioning

confidence: 99%

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Antibody repertoire analysis in polygenic autoimmune diseases

2018

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“…Fourth, we have demonstrated that, at 1-year postcycle, cladribine treatment is associated with a profound reduction in peripheral unswitched memory B cells (IgD+CD27+) and class-switched memory B cells (IgD-CD27+) compared with healthy controls and untreated pwMS 55. Given the recent observation that the abundance of some subsets of antigen-experienced B cells (IgD-CD27+ switched memory cells and plasma cells) within the CSF is correlated with disease activity,56 it is plausible to suggest that cladribine reduces disease activity in MS by depleting circulating memory B cells and thus reducing the influx of these cells into the CNS.…”

Section: Introductionmentioning

confidence: 83%

Cladribine: mechanisms and mysteries in multiple sclerosis

Jacobs

Ammoscato

Giovannoni³

et al. 2018

J Neurol Neurosurg Psychiatry

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Cladribine is a safe and effective form of induction therapy for relapsing MS. Its mechanism of benefit is not fully understood but the most striking action is selective, long-lasting, depletion of B lymphocytes with a particular predilection for memory B cells. The in vivo relevance of its other immunomodulatory actions is unknown. The hypothesis that cladribine's action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications.

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“…77 More recent work has begun to address the molecular mechanism of anergy in humans. [143][144][145] Similarly, in RA, increased levels of IGHV4 family, and in particular IGHV4-34 have been seen. 140 In keeping with this notion, published BCR repertoire sequencing using NGS has demonstrated significant alterations in autoimmune patients relative to HC.…”

Section: Toler An Ce Check P Oints and Immunodeficien Cie Smentioning

confidence: 89%

Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease

Cashman

Jenks

Woodruff

et al. 2019

Immunological Reviews

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It is well established that normal immune systems are endowed with a significant degree of autoreactivity. Accordingly, effective tolerogenic mechanisms are required to censor autoreactive cells and to ultimately prevent their differentiation into pathogenic effector cells. In this review, we will discuss how immunological tolerance is enforced in the human B-cell compartment. We shall also discuss the breakdown of B-cell tolerance in human autoimmune diseases.Finally, we will review different experimental approaches to measure B-cell tolerance in human disease. | B-CELL TOLER AN CE . CHECK P OINTS AND MECHANIS MS . LE SSONS LE ARNED THROUG H MOUS E S TUD IE SMouse models have been instrumental in defining multiple checkpoints and distinct mechanisms underpinning the enforcement of B-cell tolerance. Tolerance checkpoints are classified into central and peripheral mechanisms based on anatomical location and stage AbstractThe maintenance of immunological tolerance of B lymphocytes is a complex and critical process that must be implemented as to avoid the detrimental development of autoreactivity and possible autoimmunity. Murine models have been invaluable to elucidate many of the key components in B-cell tolerance; however, translation to human homeostatic and pathogenic immune states can be difficult to assess.Functional autoreactive, flow cytometric, and single-cell cloning assays have proven to be critical in deciphering breaks in B-cell tolerance within autoimmunity; however, newer approaches to assess human B-cell tolerance may prove to be vital in the further exploration of underlying tolerance defects. In this review, we supply a comprehensive overview of human immune tolerance checkpoints with associated mechanisms of enforcement, and highlight current and future methodologies which are likely to benefit future studies into the mechanisms that become defective in human autoimmune conditions.

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

Cited by 84 publications

References 54 publications

Antibody repertoire analysis in polygenic autoimmune diseases

Antibody repertoire analysis in polygenic autoimmune diseases

Cladribine: mechanisms and mysteries in multiple sclerosis

Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease

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