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https://hdl.handle.net/2440/139888
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Type: | Journal article |
Title: | Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity |
Author: | Polmear, J. Hailes, L. Olshansky, M. Rischmueller, M. L'Estrange-Stranieri, E. Fletcher, A.L. Hibbs, M.L. Bryant, V.L. Good-Jacobson, K.L. |
Citation: | Clinical & Translational Immunology, 2023; 12(10):e1470-1-e1470-12 |
Publisher: | Wiley |
Issue Date: | 2023 |
ISSN: | 2050-0068 2050-0068 |
Statement of Responsibility: | Jack Polmear, Lauren Hailes, Moshe Olshansky, Maureen Rischmueller, Elan L'Estrange-Stranieri, Anne L Fletcher, Margaret L Hibbs, Vanessa L Bryant, Kim L Good-Jacobson |
Abstract: | Objectives. B cells drive the production of autoreactive antibodysecreting cells, ASCs, in autoimmune diseases such as Systemic Lupus Erythematosus, SLE, and Sjogren, s syndrome, causing long-, term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-, could deplete ASCs in autoimmune conditions in vivo and in vitro. Methods. Use of a BMI-, inhibitor in both mouse and human autoimmune settings was investigated. Lyn, mice, a model of SLE, were treated with the BMI-, small molecule inhibitor PTC-, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-, on ASCs derived from Sjogren, s syndrome, patients was evaluated. Results. BMI-, inhibition significantly decreased splenic and bone marrow ASCs in Lyn, mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG, immune complexes and anti-DNA IgG. PTC-, was also efficacious in reducing ex vivo plasma cell survival from both Sjogren, s syndrome, patients and age-matched healthy donors. Conclusion. These data provide evidence that inhibiting BMI-, can deplete ASC in a variety of contexts and thus BMI-, is a viable therapeutic target for antibody-mediated autoimmune diseases. |
Keywords: | antibody autoimmunity B cells BMI‐1 Sjögren's syndrome Systemic Lupus Erythematosus |
Rights: | © 2023 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
DOI: | 10.1002/cti2.1470 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1108066 http://purl.org/au-research/grants/nhmrc/2004253 |
Published version: | http://dx.doi.org/10.1002/cti2.1470 |
Appears in Collections: | Medicine publications |
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hdl_139888.pdf | Published version | 1.13 MB | Adobe PDF | View/Open |
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