scholarly journals Emerging small-molecule treatments for multiple sclerosis: focus on B cells

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 245 ◽  
Author(s):  
Aaron Gregson ◽  
Kaitlyn Thompson ◽  
Stella E Tsirka ◽  
David L Selwood
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Small Molecule ◽  
Cell Biology ◽  
New Drugs ◽  
Risk Genes ◽  
Small Molecule Drugs ◽  
Patent Term ◽  
B Cell Subsets

Multiple sclerosis (MS) is a major cause of disability in young adults. Following an unknown trigger (or triggers), the immune system attacks the myelin sheath surrounding axons, leading to progressive nerve cell death. Antibodies and small-molecule drugs directed against B cells have demonstrated good efficacy in slowing progression of the disease. This review focusses on small-molecule drugs that can affect B-cell biology and may have utility in disease management. The risk genes for MS are examined from the drug target perspective. Existing small-molecule therapies for MS with B-cell actions together with new drugs in development are described. The potential for experimental molecules with B-cell effects is also considered. Small molecules can have diverse actions on B cells and be cytotoxic, anti-inflammatory and anti-viral. The current B cell–directed therapies often kill B-cell subsets, which can be effective but lead to side effects and toxicity. A deeper understanding of B-cell biology and the effect on MS disease should lead to new drugs with better selectivity, efficacy, and an improved safety profile. Small-molecule drugs, once the patent term has expired, provide a uniquely sustainable form of healthcare.

scholarly journals Selective Targeting of T and B Cell Populations by Alemtuzumab in the Treatment of Multiple Sclerosis

2017 ◽  
Vol 12 (02) ◽  
pp. 78
Author(s):  
Nikolaos C Grigoriadis ◽  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Types ◽  
Tolerability Profile ◽  
T And B Cells ◽  
Brain Volume Loss ◽  
Inflammatory Phenotype ◽  
B Cell Subsets

Upstream targeting of both T and B cells is a rational therapeutic approach in multiple sclerosis (MS) in view of how both cell types and the interaction between them contribute to MS pathophysiology. This article will discuss this new way of thinking in MS: the targeting of both T and B cells, with a focus on the recently developed therapy, alemtuzumab (Lemtrada®, Genzyme, UK). Alemtuzumab depletes T and B lymphocytes, mainly via complement-dependent cytolysis and antibody-dependent cytolysis; depletion of B cells is not an enduring effect compared with the depletion of T cells. After dosing, CD4+ and CD8+ T cells and CD19 B cells decrease initially but increase over the following 11 months. During repopulation after alemtuzumab treatment, there is a shift in the relative proportions of T cell and B cell subsets whereby proportions of regulatory T cells and memory-phenotype T cells are increased and the proportion of naive T cells is decreased. A switch from a pro- to an anti-inflammatory phenotype and cytokine profile caused by alemtuzumab may underpin the long-lasting suppression of MS activity that has been observed in clinical trials. Alemtuzumab treatment is also associated with a consistently good safety and tolerability profile. Further, alemtuzumab appears to promote neurorehabilitation by improving measures of physical functioning, disability, measures of quality of life, and brain volume loss. Alemtuzumab therefore has the potential to reduce disease burden and improve substantially the prognosis for patients with MS.

scholarly journals 3285 Toxicity of Released B Cell Products in Multiple Sclerosis: Effects on Neurons and Oligodendrocytes

2019 ◽  
Vol 3 (s1) ◽  
pp. 116-116
Author(s):  
Leah Zuroff ◽  
Hanane Touil ◽  
Micah Romer ◽  
Liljana Nedelkoska ◽  
Joyce A. Benjamins ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Chronic Inflammatory Disease ◽  
Conditioned Media ◽  
Pathogenic Potential ◽  
Cytotoxic Factor ◽  
B Cell Subsets ◽  
Normal Controls ◽  
Age And Sex

OBJECTIVES/SPECIFIC AIMS: We previously demonstrated that products released by cultured B cells from patients with Multiple Sclerosis (MS) are cytotoxic to neurons and oligodendrocytes, while minimal toxicity was observed in response to B cell secretory products from age- and sex-matched normal controls. The goal of this proposal is to identify the range of brain cells susceptible to MS B cell-mediated cytotoxicity, to define the cytotoxic factor(s) released by MS B cells, and to determine whether particular subset(s) of MS B cells harbor the greatest pathogenic potential. METHODS/STUDY POPULATION: The toxicity of B cell products will be demonstrated by incubating primary rat cultures of neurons, oligodendrocytes, and oligodendrocyte progenitor cells (OPCs) with B cell supernatants. B cells will be isolated from the peripheral circulation of untreated relapse-remitting MS (RRMS) patients and age- and sex-matched normal controls. The identification of specific toxic factor(s) in MS B cell supernatants will be achieved through a combination of exosome-depletion/enrichment of conditioned media, proteomics, next generation sequencing, and lipidomics. Determining pathogenic B cell subsets will be achieved by cell sorting into memory and naïve B cell subsets prior to collection of supernatants. RESULTS/ANTICIPATED RESULTS: We hypothesize that the toxicity of MS B cell products is mediated, at least in part, by extracellular vesicles, such as exosomes. We expect depletion of these exosomes from the B cell conditioned media or inhibition of their biogenesis will mitigate the observed toxicity. Furthermore, differences in B cell-derived exosomal content, such as proteins, (mi)RNAs, or lipids, likely explain the differences in observed toxicity. Lastly, we hypothesize that memory B cells, which are enriched in the CNS of MS patients and demonstrate a more pro-inflammatory profile than naïve B cells, are responsible for the toxicity observed in supernatants of total B cells. DISCUSSION/SIGNIFICANCE OF IMPACT: MS is the most prevalent chronic inflammatory disease of the CNS, affecting more than 2 million people worldwide. Although over a dozen disease-modifying therapies are approved for the treatment of RRMS, none are meaningfully effective at limiting disease progression. This proposal will provide new insight into immune-CNS interactions in progressive MS and provide much-needed novel targets for therapeutic intervention, either via blocking identified toxic molecule(s) or by selectively depleting pathogenic B cell subsets.

Thymosin-α1 expands deficient IL-10-producing regulatory B cell subsets in relapsing–remitting multiple sclerosis patients

2017 ◽  
Vol 24 (2) ◽  
pp. 127-139 ◽  
Author(s):  
Elena Giacomini ◽  
Fabiana Rizzo ◽  
Marilena P Etna ◽  
Melania Cruciani ◽  
Rosella Mechelli ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Thymosin Α1 ◽  
Regulatory B Cell ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
B Cell Subsets ◽  
Relapsing Remitting Multiple Sclerosis

Background: B cells are key pathogenic effectors in multiple sclerosis (MS) and several therapies have been designed to restrain B cell abnormalities by directly targeting this lymphocyte population. Objectives: Moving from our data showing a Toll-like receptor (TLR)7-driven dysregulation of B cell response in relapsing–remitting multiple sclerosis (RRMS) and having found a low serum level of Thymosin-α1 (Tα1) in patients, we investigated whether the addition of this molecule to peripheral blood mononuclear cells (PBMCs) would influence the expansion of regulatory B cell subsets, known to dampen autoimmune inflammation. Methods: Serum Tα1 level was measured by enzyme immunoassay. Cytokine expression was evaluated by Cytometric Bead Array (CBA), enzyme-linked immunosorbent assay (ELISA), and real-time reverse transcription polymerase chain reaction (RT-PCR). B cell subsets were analyzed by flow cytometry. Results: Tα1 pre-treatment induces an anti-inflammatory status in TLR7-stimulated RRMS PBMC cultures, reducing the secretion of pro-inflammatory interleukin (IL)-6, IL-8, and IL-1β while significantly increasing the regulatory IL-10 and IL-35. Indeed, Tα1 treatment enhanced expansion of CD19+CD24+CD38hi transitional-immature and CD24low/negCD38hi plasmablast-like regulatory B cell subsets, which likely inhibit both interferon (IFN)-γ and IL-17 production. Conclusion:: Our study reveals a deficient ability of B cells from MS patients to differentiate into regulatory subsets and unveils a novel anti-inflammatory and repurposing potential for Tα1 in MS targeting B cell response.

scholarly journals Jo-1 autoantigen-specific B cells are skewed towards distinct functional B cell subsets in anti-synthetase syndrome patients

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Jennifer Young-Glazer ◽  
Alberto Cisneros ◽  
Erin M. Wilfong ◽  
Scott A. Smith ◽  
Leslie J. Crofford ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Biology ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Cell Subset ◽  
Trna Synthetase ◽  
B Cell Subsets ◽  
Antibody Secreting Cells

Abstract Background Anti-Jo-1 autoantibodies which recognize histidyl-tRNA synthetase identify patients with the rare rheumatologic disease, anti-histidyl-tRNA synthetase syndrome (Jo-1 ARS), a phenotypically distinct subset of idiopathic inflammatory myopathies (IIM). Jo-1-binding B cells (JBCs) are implicated in disease pathogenesis, yet they have not been studied directly. We therefore aimed to characterize JBCs to better understand how they expand and function in Jo-1 ARS. Methods We enrolled 10 IIM patients diagnosed with Jo-1 ARS, 4 patients with non-Jo-1 IIM, and 8 age- and sex-matched healthy controls. We phenotypically characterized peripheral blood mononuclear cells (PBMCs) ex vivo using flow cytometry to define the B cell subsets in which JBCs reside. We further tested their ability to differentiate into antibody-secreting cells following stimulation in vitro. Results The majority of JBCs were IgM+ (not class-switched). Compared to non-JBCs in the same donors, JBCs contained a higher percentage of autoimmune-prone CD21lo cells and were increased in the CD21lo IgM+ IgD− CD27+ memory subset relative to healthy donor B cells. Whereas non-JBCs were present in the anergic BND B cell subset, JBCs were nearly absent from this compartment. JBCs were detected among plasmablasts in some donors, but a reduced frequency of JBCs differentiated into CD38hi24− plasmablasts compared to non-JBCs present in the same wells following in vitro stimulation. Conclusions JBCs are enriched for autoimmune-prone CD21lo B cells, some of which exhibit a memory phenotype in the peripheral repertoire of Jo-1 ARS patients. JBCs undergo limited class switch and show reduced capacity to differentiate into antibody-secreting cells. This suggests complex B cell biology exists beyond class-switched cells that differentiate to secrete anti-Jo-1 autoantibody (i.e., what is captured through serum autoantibody studies). New Jo-1 ARS therapies should thus ideally target non-class-switched JBCs in addition to those that have undergone IgG class-switching to most effectively block cross-talk with autoreactive T cells.

scholarly journals Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ide Smets ◽  
Teresa Prezzemolo ◽  
Maya Imbrechts ◽  
Klara Mallants ◽  
Tania Mitera ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Cell Biology ◽  
Interferon Β ◽  
Cross Sectional ◽  
Transitional B Cells ◽  
Rna Levels

Although fingolimod and interferon-β are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-β and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10-6), decrease in switched B cells (P = 3.29 x 10-4), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.

scholarly journals Multimodal repertoire analysis unveils B cell biology in health and immune-mediated diseases

2022 ◽  
Author(s):  
Mineto Ota ◽  
Masahiro Nakano ◽  
Yasuo Nagafuchi ◽  
Satomi Kobayashi ◽  
Hiroaki Hatano ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Biology ◽  
Memory B Cells ◽  
Dependent Manner ◽  
Cell Repertoire ◽  
Repertoire Analysis ◽  
Immune Mediated ◽  
B Cell Subsets

Despite involvement of B cells in the pathogenesis of immune-mediated diseases, biological mechanisms underlying their function are scarcely understood. To overcome this gap, comprehensive analysis of the B cell repertoire is essential. Here, we cataloged and investigated the repertoire of five B cell subsets from 595 cases under immune-mediated diseases and health. CDR-H3 length among naive B cells was shortened among autoimmune diseases in an interferon signature-dependent manner. VDJ gene usage was skewed especially in plasmablasts and unswitched-memory B cells of systemic lupus erythematosus patients with frequent usage of VDJ genes used mainly in naive B cells and not unswitched-memory B cells of healthy controls. We developed a scoring system for this skewing, and it correlated with peripheral helper T cell transcriptomic signatures and disease activity and decreased after belimumab treatment. Moreover, genetic association analysis identified three molecules possibly involved in somatic hyper-mutation processes in humans. Our multimodal repertoire analysis brings new insights to B cell biology.

scholarly journals FcγRIIb Expression Is Decreased on Naive and Marginal Zone-Like B Cells From Females With Multiple Sclerosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Stephanie Trend ◽  
Jonatan Leffler ◽  
Ingrid Teige ◽  
Björn Frendéus ◽  
Allan G. Kermode ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
Immune Complexes ◽  
Marginal Zone ◽  
Serum Levels ◽  
Blocking Antibody ◽  
Barr Virus ◽  
Epstein Barr ◽  
B Cell Subsets

B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which they contribute to the disease are poorly defined. We hypothesised that the expression of CD32b (FcγRIIb), a receptor for the Fc region of IgG with inhibitory activities in B cells, is lower on B cell subsets from people with clinically isolated syndrome (CIS) or MS. CD32b expression was highest on post-naive IgM+ B cell subsets in healthy controls. For females with MS or CIS, significantly lower CD32b expression was identified on IgM+ B cell subsets, including naive and IgMhi MZ-like B cells, when compared with control females. Lower CD32b expression on these B cell subsets was associated with detectable anti-Epstein Barr Virus viral capsid antigen IgM antibodies, and higher serum levels of B cell activating factor. To investigate the effects of lower CD32b expression, B cells were polyclonally activated in the presence of IgG immune complexes, with or without a CD32b blocking antibody, and the expression of TNF and IL-10 in B cell subsets was assessed. The reduction of TNF but not IL-10 expression in controls mediated by IgG immune complexes was reversed by CD32b blockade in naive and IgMhi MZ-like B cells only. However, no consequence of lower CD32b expression on these cells from females with CIS or MS was detected. Our findings highlight a potential role for naive and marginal zone-like B cells in the immunopathogenesis of MS in females, which requires further investigation.

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

2018 ◽  
Author(s):  
Ariele L. Greenfield ◽  
Ravi Dandekar ◽  
Akshaya Ramesh ◽  
Erica L. Eggers ◽  
Hao Wu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Variable Region ◽  
B Cell Activation ◽  
Cell Dynamics ◽  
Autoimmune Pathology ◽  
B Cell Subsets

AbstractB-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) class-switched 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.

scholarly journals Two subsets of human marginal zone B cells resolved by global analysis of lymphoid tissues and blood

2021 ◽  
Author(s):  
Jacqueline HY Siu ◽  
Michael J Pitcher ◽  
Thomas J Tull ◽  
William Guesdon ◽  
Lucia Montorsi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Biology ◽  
Marginal Zone ◽  
Global Analysis ◽  
Lymphoid Tissues ◽  
Cellular Interactions ◽  
B Cell Differentiation ◽  
Marginal Zone B Cells ◽  
B Cell Subsets

B cells generate antibodies that are essential for immune protection. Major events driving B cell responses occur in lymphoid tissues, which guide antigen acquisition and support cellular interactions, yet complexities of B cell subsets in human lymphoid tissues are poorly understood. Here we perform undirected, global profiling of B cells in matched human lymphoid tissues from deceased transplant organ donors and tracked dissemination of B cell clones. In addition to identifying unanticipated features of tissue-based B cell differentiation, we resolve two clonally independent subsets of marginal zone B cells that differ in cell surface and transcriptomic profiles, tendency to disseminate, distribution bias within splenic marginal zone microenvironment and immunoglobulin repertoire diversity and hypermutation frequency. Each subset is represented in spleen, gut-associated lymphoid tissue, mesenteric lymph node, and also blood. Thus, we provide clarity and diffuse controversy surrounding human MZB - the 'elephant in the room' of human B cell biology.

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