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Kv1.3 channel Blockade Modulates the effector Function of B cells in granulomatosis with Polyangiitis

Land, J; Lintermans, LL; Stegeman, CA; Munoz-Elias, EJ; Tarcha, EJ; Iadonato, SP; Heeringa, P; ... Abdulahad, WH; + view all (2017) Kv1.3 channel Blockade Modulates the effector Function of B cells in granulomatosis with Polyangiitis. Frontiers in Immunology , 8 , Article 1205. 10.3389/fimmu.2017.01205. Green open access

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Abstract

B cells are central to the pathogenesis of granulomatosis with polyangiitis (GPA), exhibiting both (auto)antibody-dependent and -independent properties. Class-switched memory B cells in particular are a major source of pathogenic autoantibodies. These cells are characterized by high expression levels of Kv1.3 potassium channels, which may offer therapeutic potential for Kv1.3 blockade. In this study, we investigated the effect of the highly potent Kv1.3 blocker ShK-186 on B cell properties in GPA in vitro. Circulating B cell subsets were determined from 33 GPA patients and 17 healthy controls (HCs). Peripheral blood mononuclear cells (PBMCs) from GPA patients, and HCs were stimulated in vitro in the presence and absence of ShK-186. The production of total and antineutrophil cytoplasmic antibodies targeting proteinase 3 (PR3-ANCA) IgG was analyzed by enzyme-linked immunosorbent assay and Phadia EliA, respectively. In addition, effects of ShK-186 on B cell proliferation and cytokine production were determined by flow cytometry. The frequency of circulating switched and unswitched memory B cells was decreased in GPA patients as compared to HC. ShK-186 suppressed the production of both total and PR3-ANCA IgG in stimulated PBMCs. A strong decrease in production of tumor necrosis factor alpha (TNFα), interleukin (IL)-2, and interferon gamma was observed upon ShK-186 treatment, while effects on IL-10 production were less pronounced. As such, ShK-186 modulated the TNFα/IL-10 ratio among B cells, resulting in a relative increase in the regulatory B cell pool. ShK-186 modulates the effector functions of B cells in vitro by decreasing autoantibody and pro-inflammatory cytokine production. Kv1.3 channel blockade may hold promise as a novel therapeutic strategy in GPA and other B cell-mediated autoimmune disorders.

Type: Article
Title: Kv1.3 channel Blockade Modulates the effector Function of B cells in granulomatosis with Polyangiitis
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2017.01205
Language: English
Additional information: © 2017 Land, Lintermans, Stegeman, Muñoz-Elías, Tarcha, Iadonato, Heeringa, Rutgers and Abdulahad. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Science & Technology, Life Sciences & Biomedicine, Immunology, granulomatosis and polyangiitis, B cells, Kv1.3 potassium channels, antineutrophil cytoplasmic antibody, cytokines, ANCA-ASSOCIATED VASCULITIS, PRIMARY SJOGRENS-SYNDROME, RHEUMATOID-ARTHRITIS, DEPRESSED PERCENTAGE, INADEQUATE RESPONSE, ION CHANNELS, PHASE-II, MEMORY B, PATHOGENESIS, RITUXIMAB
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10057289
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