Dataset Information

Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients.

ABSTRACT:

Introduction

B cells are acknowledged as crucial players in the pathogenesis of multiple sclerosis (MS). Several disease modifying drugs including cladribine have been shown to exert differential effects on peripheral blood B cell subsets. However, little is known regarding functional changes within the peripheral B cell populations. In this study, we obtained a detailed picture of B cell repertoire changes under cladribine treatment on a combined immunoglobulin (Ig) transcriptome and proteome level.

Methods

We performed next-generation sequencing of Ig heavy chain (IGH) transcripts and Ig mass spectrometry in cladribine-treated patients with relapsing-remitting multiple sclerosis (n = 8) at baseline and after 6 and 12 months of treatment in order to generate Ig transcriptome and Ig peptide libraries. Ig peptides were overlapped with the corresponding IGH transcriptome in order to analyze B cell clones on a combined transcriptome and proteome level.

Results

The analysis of peripheral blood B cell percentages pointed towards a significant decrease of memory B cells and an increase of naive B cells following cladribine therapy. While basic IGH repertoire parameters (e.g. variable heavy chain family usage and Ig subclasses) were only slightly affected by cladribine treatment, a significantly decreased number of clones and significantly lower diversity in the memory subset was noticeable at 6 months following treatment which was sustained at 12 months. When looking at B-cell clones comprising sequences from the different time-points, clones spanning between all three time-points were significantly more frequent than clones including sequences from two time-points. Furthermore, Ig proteome analyses showed that Ig transcriptome specific peptides could mostly be equally aligned to all three time-points pointing towards a proportion of B-cell clones that are maintained during treatment.

Discussion

Our findings suggest that peripheral B cell related treatment effects of cladribine tablets might be exerted through a reduction of possibly disease relevant clones in the memory B cell subset without disrupting the overall clonal composition of B cells. Our results -at least partially- might explain the relatively mild side effects regarding infections and the sustained immune response after vaccinations during treatment. However, exact disease driving B cell subsets and their effects remain unknown and should be addressed in future studies.

SUBMITTER: Ruschil C

PROVIDER: S-EPMC10028280 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients.

Ruschil Christoph C Gabernet Gisela G Kemmerer Constanze Louisa CL Jarboui Mohamed Ali MA Klose Franziska F Poli Sven S Ziemann Ulf U Nahnsen Sven S Kowarik Markus Christian MC

Frontiers in immunology 20230307

<h4>Introduction</h4>B cells are acknowledged as crucial players in the pathogenesis of multiple sclerosis (MS). Several disease modifying drugs including cladribine have been shown to exert differential effects on peripheral blood B cell subsets. However, little is known regarding functional changes within the peripheral B cell populations. In this study, we obtained a detailed picture of B cell repertoire changes under cladribine treatment on a combined immunoglobulin (Ig) transcriptome and pr ...[more]

PMID: 36960053

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Project description:Background and objectivesMultiple sclerosis (MS) is a chronic, progressive neurological disease characterized by early-stage neuroinflammation, neurodegeneration, and demyelination that involves a spectrum of heterogeneous clinical manifestations in terms of disease course and response to therapy. Even though several disease-modifying therapies (DMTs) are available to prevent MS-related brain damage-acting on the peripheral immune system with an indirect effect on MS lesions-individualizing therapy according to disease characteristics and prognostic factors is still an unmet need. Given that deregulated miRNAs have been proposed as diagnostic tools in neurodegenerative/neuroinflammatory diseases such as MS, we aimed to explore miRNA profiles as potential classifiers of the relapsing-remitting MS (RRMS) patients' prospects to gain a more effective DMT choice and achieve a preferential drug response.MethodsA total of 25 adult patients with RRMS were enrolled in a cohort study, according to the latest McDonald criteria before (pre-cladribine, pre-CLA; pre-ocrelizumab, pre-OCRE, time T0) and after high-efficacy DMTs, time T1, 6 months post-CLA (n = 10, 7 F and 3 M, age 39.0 ± 7.5) or post-OCRE (n = 15, 10 F and 5 M, age 40.5 ± 10.4) treatment. A total of 15 age- and sex-matched healthy control subjects (9 F and 6 M, age 36.3 ± 3.0) were also selected. By using Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells (PBMC). miRNA-target networks were obtained by miRTargetLink, and Pearson's correlation served to estimate the association between miRNAs and outcome clinical features.ResultsFirst, the miRNA profiles of pre-CLA or pre-OCRE RRMS patients compared to healthy controls identified modulated miRNA patterns (40 and seven miRNAs, respectively). A direct comparison of the two pre-treatment groups at T0 and T1 revealed more pro-inflammatory patterns in the pre-CLA miRNA profiles. Moreover, both DMTs emerged as being capable of reverting some dysregulated miRNAs toward a protective phenotype. Both drug-dependent miRNA profiles and specific miRNAs, such as miR-199a-3p, miR-29b-3p, and miR-151a-3p, emerged as potentially involved in these drug-induced mechanisms. This enabled the selection of miRNAs correlated to clinical features and the related miRNA-mRNA network.DiscussionThese data support the hypothesis of specific deregulated miRNAs as putative biomarkers in RRMS patients' stratification and DMT drug response.

Project description:This study aimed to explore the influence of chronic stress, measured through hair cortisol, on executive functions in individuals with chronic pain. We expected that there would be significant differences in chronic stress and executive functioning between pain patients and healthy controls, as well as between primary and secondary pain classifications. We also hypothesized that hair cortisol concentration was predictive of worse performance on tests of executive functions, controlling for objective and subjective covariates. For this study, 122 participants provided a hair sample (n = 40 with fibromyalgia; n = 24 with peripheral neuropathic pain; n = 58 matched healthy controls). Eighty-four of these participants also completed highly detailed testing of executive functions (n = 40 with fibromyalgia; n = 24 with peripheral neuropathic pain; n = 20 healthy controls). To assess differences in stress levels and executive functions, t-tests were used to compare patients with controls as well as fibromyalgia with peripheral neuropathic pain. Then, univariate regressions were used to explore associations between stress and executive functioning in both chronic pain classifications. Any significant univariate associations were carried over to hierarchical multivariate regression models. We found that patients with chronic pain had significantly higher cortisol levels than healthy controls, but all groups showed similar executive functioning. Hierarchical multiple regression analyses disclosed that in a model controlling for age, sex and pain medication usage, hair cortisol levels explained 8% of the variance in spatial working memory strategy in individuals with chronic pain. The overall model explained 24% of the variance in spatial working memory. In a second model using imputed data, including both objective and subjectively reported covariates, hair cortisol levels explained 9% of the variance, and the full model 31% of the variance in spatial working memory performance. Higher levels of cortisol indicated worse performance. In this study, an applied measure of chronic stress, namely hair cortisol, explained a substantial part of the variance on a spatial working memory task. The current results have important implications for understanding and treating cognitive impairments in chronic pain.

Dataset Information

Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients.

Introduction

Methods

Results

Discussion

Publications

Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients.

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